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Cancer Therapeutics

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Cancer Therapeutics Powered By Docstoc
					    Cancer Therapeutics
                  Philip J Moos
           Pharmacology & Toxicology
                    585-5952
          philip.moos@pharm.utah.edu

Optional Suggested Reading:
Katzung, 9th Edition, Chapter 55
Goodman & Gilman, 11th Edition, Chapter 51
Harrison, 16th Edition, Chapter 70
                   Objectives
   Understand cancer basics.
   Understand the models of tumor growth.
   Be able to describe and define cell cycle, doubling
    time and growth fraction.
   Know the drugs discussed in lecture, their drug
    classes and mechanisms of action, their major
    uses, dose-limiting toxicities, and notable ADME
    characteristics.
   Understand the rationale of treatment scheduling
    and combination therapy.
   Understand limitations of therapy due to
    heterogeneity, resistance of tumors, patient
    status, etc.
                           Outline
   Clinical scope & Cancer concepts
   Cancer chemotherapeutics
    •   Alkylating agents
    •   Antimetabolites
    •   Antibiotics
    •   Antimitotic agents
    •   Misc
            Molecular targeted treatments
            Hormones
   A few more clinical considerations
         Tumor Characteristics
   Benign                    Malignant
    • Noncancerous             • Uncontrolled growth
    • Encapsulated             • Invasive
    • Localized                • Metastasizes
    • Typical of cell of       • Atypical of cell of
      origin                     origin
    • Indolent                 • Anaplastic
    • Not Recurrent            • Recurrent
                 Cancer Causes
   Spontaneous mutation
    • Overall error rate during replication: 1 base per 1 billion
      base pairs copied per cell cycle
   Genetic predisposition
   Environmental/chemical
    • Geophysical: radon, UV exposure, etc.
    • Toxins: arsenic, asbestos, benzene, nickel dust, vinyl
      chloride, polycyclic hydrocarbons, aromatic amines
      (dyes), etc.
   Infection
    • Viral (HPV, HIV, Hepatitis B or C, etc.), Bacterial (H.
      pylori)
   Life style choices
    •   Tobacco use/smoking
    •   Diet
    •   Alcohol
    •   Sexual behavior
Scope of the “Cancer Problem”
 Trends in Age-Standardized Death Rates for the 6
Leading Causes of Death in the United States, 1970-
                      2002



                                                                   -52.1%




                                                                    -2.7%



                                                                   -63.1%




                       Jemal, A. et al. JAMA 2005;294:1255-1259.




 Copy right restrictions may apply .
      Age-Specific US Death Rates for the 4 Leading
        Causes of Death by 5-Year Intervals, 2002




                      Jemal, A. et al. JAMA 2005;294:1255-1259.




Copy right restrictions may apply .
Disease of Aging but NOT just for
             Adults
Incidence
    and
 Mortality
     of
Common
 Cancers
in the US
Incidence Trends by Gender
Cancer Death Trends by Gender
    Male             Female
Cancer is
a world-
  wide
 issue
   Many
    cancers are
    common in
    both
    developed
    and
    developing
    countries
           So what about Utah?




   Relative low rate of cancer likely due to
    low smoking rate since the lung cancer
    incidence is much lower than the national
    average
    Biological Perspective of “Cancer
                Problem”

   Cancer has six
    characteristics
   Cancer arises from
    genetic lesions that
    cause an excess of
    cell growth or
    division, with
    inadequate cell
    death.
    •   Genetic disease
    •   Developmental disease
    •   Metabolic disease
    •   Stem cell disease
          Pathways to Cancer
   Loss of
    function or
    gain of
    function can
    occur in
    different
    sequence
    eventually
    leading to
    unregulated
    growth
Cancer Related Pathways
      Purpose of Chemotherapy
   Curative
          Elimination of all known tumor mass (Complete
           Response)
   Palliation
          Treatment aimed at improving symptoms and
           controlling tumor growth
   Adjuvant
          Chemotherapy which attempt to eliminate
           micrometastatic disease following primary treatment
   Nonadjuvent
          Chemotherapy offered prior to other primary
           potentially curable therapy
Sites of Antineoplastic Action




     PALA = N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.
Model of Chemotherapeutic Action
                            Theoretical relationship between drug-
                            induced cell kill and lifespan. Assumptions
                            in this model include no lag phase in drug
                            action, near constant generation time in
Most anticancer drugs are   surviving cells (Gompertzian growth
thought to work by First    model) , no resistance, no compartments,
Order Kinetics (based on    and no drug induced lethality.
model organism studies).


                                                               Remission &
                                                               recurrence

               106 to                                   1 cm3 mass
                 103
                cells
      99.9%




                                 30-40 cell doublings
    Why does chemotherapy fail?
   Patient status may limit therapy
    • Overall health status v. toxicity of therapeutic
   Cancer growth fractions can be very low
   Cancer cells may not be in a sensitive
    stage of the cell cycle
   Cancer cells are not homogeneous
   Tumor perfusion is not uniform
   Cancer spreads to different body
    compartments
   Cancers can display intrinsic resistance, or
    develop resistance
        Narrow Therapeutic Index of
              Cancer Drugs
   The therapeutic
    index is the degree
    of separation
    between toxic and
    therapeutic doses.
   Relationship
    Between Dose,
    Therapeutic Effect
    and Toxic Effect.
    The Therapeutic
    Index is Narrow
    for Most Cancer
    Drugs                 100×    10×
          Bone Marrow Suppression
             Following Therapy
   Rapid Recovery                            10000



    • Drugs:                                                     Recovery
                                                                                                                          Recovery




                             Polymorphonuclear and
                                                 3
                                                                                                                          day 42-50
                                                                 day 17-21




                              band leukocytes/mm
      cyclophosphamide,                                                                          plateau
      methotrexate,                                                                   st
                                                                                  1 valley
      vinblastin, cytosine                                                        day 8-10

      arabinoside
   Delayed Recovery                                        Rapid                 Delayed
                                                                                                                nd
                                                                                                               2 valley
                                                 1000                                                          day 27-32
    • Drugs/treatments:                                     Recovery              Recovery

      BCNU, Melphalan,
      irradiation                                       0    6   12   18   24 0   6        12   18   24   30   36    42   48   54

                                                                 TIme (days following therapy)
                                Cell Cycle




Doubling time – time to double
cell population
Growth fraction – fraction of cells
in the cell cycle


    Cell Cycle Specific Drugs (e.g., antimetabolites, tubulin poisons, topoisomerase
    inhibitors, some antitumor antibiotics) Act In Specific Phases of the Cell Cycle.
    Cell Cycle Nonspecific Drugs (e.g., alkylating agents, platinum analogs,
    anthracyclins) Act Effectively Following Bolus Injection.
  Drug Sensitivity of Cancers that
     Grow at Different Rates
   Doubling Times of Human Tumors
                     Doubling Time    Treatment
    Tumor
                        (Days)         Regimen
Burkitt’s lymphoma                   Single Drug/Drug
                         1-1.5
 Choriocarcioma                        Combinations
      ALL
                          3-4        Drug Combinations
Hodgkin’s Disease
                                       Surgery/Drug
      Colon              80-90
                                       Combinations
                                       Surgery/Drug
      Lung               90-150
                                       Combinations
                                       Surgery/Drug
     Breast             100-150
                                       Combinations
Growth and Development of
 Heterogeneity in Cancer
                       Even though
                       clonal in origin,
                       many additional
                       changes during
                       tumor
                       progression and
                       escape immune
                       surveillance
                       Differences in
                       accumulated
                       mutation rate
                       May take 30
                       years to develop
                       into clinical
                       tumor
   Acquisition of Mutations in Colon
                Cancer
Chromosome:          5q             12q            18q               17p

 Alteration:        Loss         Activation        Loss              Loss

   Gene:            APC            K-Ras           DCC               p53

Overall DNA Methylation Changes: general hypomethylation, specific
hypermethylation
Other mutations/alterations
   Metastasis: Lethal Mechanism of
           Cancer Spread

Primary Neoplasm
Vascularization
Invasion of Lymphatics or
Blood Vessels
Transport
Arrest in Capillary Beds
Adherence
Escape and Growth
Establishment of New
Vascularization and Tumor
                    Tumor Perfusion
The Further
From the Vessel,
The Lower The
Concentration Of
Oxygen,
Nutrients and
Drugs. Cells
Deprived Of
Nutrients May
Not Be Cycling
And Would Be
More Resistant
To Drugs. They
May Survive
Initial Treatment
And Begin
Dividing.                             Nature: 407: 249-257
     Resistance to Chemotherapy
   Decrease in cellular uptake or increase in efflux
    of drugs (multidrug resistance MDR; P-
    glycoprotein active transport of organic
    molecules)
    • actinomycin D, daunorubicin, doxorubicin, melphalan, 6-
      mercaptopurine, methotrexate, nitrogen mustard,
      vincristine, vinblastine
   Increased proficiency of repair of DNA
    • cisplatin, cyclophosphamide, melphalan, mitomycin C,
      nitrogen mustard, nitrosoureas
   Increase in levels of “target” enzyme
    • methotrexate, imatinib
   Alterations in “target” enzyme
    • 5-fluorouracil, 6-mercaptopurine, methotrexate, 6-
      thioguanine, imatinib
   Decrease in drug activation
    • Cytosine arabinoside, doxorubicin, 5-fluorouracil
Resistance: MDR/cancer stem cells

   Not all cancer cells are
    equal – intrinsic
    differences to
    proliferate and form
    tumors in vivo
    • A subset of cancer cells
      have the ability to self-
      renew
   MDR expression
    observed in stem cells
    and after drug
    selection
    Cancer Concepts - Summary
   Severity of the cancer health problem
   Cancer cell characteristics
   Purposes for cancer chemotherapy
   General targets for cancer chemotherapy
   General concepts indicating how cancer
    chemotherapy works
   Issues relating to limitations in cancer
    chemotherapy
                   Alkylating Agents
Largest class of antineoplastics
General Properties/Mechanism:
   All are electrophilic molecules that covalently modify
    nucleophilic molecules in cells
     • DNA most important adduct (N7 and O6 of
        Guanine) for anticancer properties             6
                                                                   O          R+
General Types of Alkylating Agents:                                               7
                                                              HN              N
 Monofunctional
    • Cause single strand DNA breaks                     H2 N         N   N
   Bifunctional
    • Inhibit DNA replication and transcription by crosslinking DNA
Subtypes:
 Nitrogen mustards
 Nitrosoureas
 Platinum Compounds
            Alkylating Agents (cont)
   The beginning of modern chemotherapy              CH2-CH2-Cl
    • ~WWII
                                                  S
   Mustard gas/derivatives: highly cytotoxic
                                                      CH2-CH2-Cl
    Exposure damaged:
    • white blood cells                               Mustard Gas
    • lymphoid tissues
    • bone marrow
    • GI tract mucous membranes
   Nitrogen Mustards                                               G
                                      G-N7
    • Mechanism:                                          O
                           O
                        HO P
                                  +
                                  N
                                             x2        HO P N
                            NH2                           NH2
                                       Cl                           G
                                                        DNA Adduct
                                          CH2-CH2-Cl
   Nitrogen Mustards                R N
                                          CH2-CH2-Cl

   R          Compound
              Mechlorethamine (Mustargen)
  CH3-        Hodgekin’s/other lymphomas
              and chronic leukemias.
              • MOPP regimen

              MOPP (Mechlorethamine, Vincristine
              (Oncovin), Procarbazine, Prednisone)

              Chlorambucil (Leukeran)
HOOC (CH2)3   Chronic lymphocytic leukemia,
              malignant lymphomas
              • Reactivity: >Alkeran, <Mustargen
              • Less alopecia and nausea
              • Cumulative bone marrow toxicity
  Mechlorethamine (Mustargan)
• Mustargan serves as a prototype for the mustards (and other
alkylating agents) because of its spectrum of activity, its
toxicities and its mechanism of action. It is highly unstable and
reactive – still in use in combination therapy, MOPP, 80%
response, >50% cure
• Toxicity: Nausea and vomiting (N&V). Dose limiting toxicity
(DLT) is bone marrow suppression, white blood cells, esp.
granulocytes. Max suppression at 10-12 days, recovery
around 42 days.
• ADME: t1/2 less than 30 min., admin in free flowing catheter
• Analogs: Chlorambucil (Leukeran), Chronic Lymphocytic
Leukemia; Melphalan (Alkeran), Multiple Myeloma (longer half-
lives, p.o.); Busulfan (Busulfex), CML
  Most Common                                         CH2-CH2-Cl
                                                R N
 Nitrogen Mustards
                                                      CH2-CH2-Cl

       R                Compound
                        Cyclophosphamide (Cytoxan)
  H        O            Malingnant lymphomas, various carcinomas.
      N P               • Activated by P450 enzymes
           O            • Most versatile nitrogen mustard
                        • Better bone marrow recovery than Mustargen




  O        CH2-CH2-Cl
       N
                             Ifosphamide (Isophosphamide, Ifex)
O P
           H                 Lung, breast, ovarian, lymphomas
  N
      CH2-CH2-Cl
  Cyclophosphamide (Cytoxan)
• Use: Most widely used alkylating agent. Non-
Hodgkin's lymphomas (CHOP), Breast (CMF increases
7 yr survival form 31% to 49 %)
• Toxicity: N&V, anaphalactoid rxns. DLT, bone marrow
suppression, max 10-12 days, recovery by 21 days
(relatively platelet sparing); alopecia, hemorrhagic
cystitis (minimized by diuresis), etc.
• ADME: May be administered parenterally, in a large
range of doses. Resistant cells may have aldehyde
oxidase (like the liver)
• Analog: Isofosfamide (Ifex)
     Bioactivation of Cyclophosphamide
               Cl                                     Cl
     O O            Cytochrome P450        O O
       P N                                   P N
     N                                     N
       H       Cl                     HO     H        Cl
Cyclophosphamide

                                            O                   Acrolein
B:                      Cl
                                           HC CH CH2
      H        O O
                 P N                                       Cl
 O           H2N                                O
       H                Cl                 HO P N
                                                NH2
                                                           Cl
                                           Phosphoramide mustard
                                               N R
  Nitrosoureas                             O
                                               N R'
                                               N O

   R               R'
                                   Compound
                                       Bischloronitrosourea
-CH2CH2Cl       -CH2CH2Cl
                                       (Carmustine, BCNU)
                                       Chloroethylcyclohexyl
                 -CH2CH2Cl             nitrosourea
                                       (Lomustine, CCNU)
BCNU and CCNUs: Brain tumors, Hodgkin’s disease, melanoma.
•Lipid soluble: (CNS active)
•O6 of Guanine preferred alkylation site
•Prolonged cummulative myelosuppression
•Teratogenic
Alkylation mechanism: Nitrosoureas
                                         O
                       Cl                        R
                                     N       N
                                             H
                                     N               H2O
                                     O
                                                       Isocyanate
        Cl             N                               R N C O
                  N         OH

Carbonium Ion
                                 _
  Cl    CH
           +      N2        OH                        Carbamoylation
             2
                                                      of protein amino
                                                      groups

 DNA Alkylation
                BCNU (Carmustin)
• Use: Primary glioblastoma (with surgery and radiation can
increase live span from 20 weeks to 50 weeks)
• Toxicity: N&V. DLT bone marrow suppression, max 28 days;
recovery by 42 days.
• ADME: Administered by injection. Unique among
antineoplastics for its high oil-to-water partition coefficient
(very lipophillic) and low ionization at physiological pH – risk of
hematological toxicity persist due to storage in the liver &
adipose tissue
• Analog: CCNU (lomustine), may be administered orally.
Temozolomide (Temodar) is a new non-nitrosourea used
frequently in glioblastoma
             Platinum compounds
    Cl                 Cisplatin (Platinol)
                       • testicular, ovarian, head and neck, lung,
H3N Pt    Cl           bladder cancer
                       • Curative in combination for metastatic
    NH3                testicular cancer
                       Carboplatin (Paraplatin)
   O
                  Cl   • ovarian, non-small cell and small cell lung
         O             cancers
             Pt
         O        Cl   • less toxic (~45×) than cisplatin but is
   O                   generally less active

                       Oxaliplatin (Eloxatin)
                       • broad anticancer activity: colorectal,
                       ovarian, pancreatic, non-Hodgkins lym,
                       breast, lung, prostate, etc
                       • Lacks cross-resistance with other
                       platinum compounds
                       • Generally less toxic than other platinum
                       compounds
                Alkylation mechanism: Cisplatin
                                                                                               O
    Cl
                                                           Cl
H3N Pt    Cl
                      H2O                                           +              N
                                                                                       7
                                                                                                   NH
                                                  H3N Pt            OH   2
                                                                                       N       N           NH2
    NH3                                                    NH3
                                                                                       Sugar
                                                                                                                NH3
                     NH3                                                                   H3N                            O
         H3N                   O                                                                           Pt
                Pt                                         H 2O                                                   N           NH
                      N              NH                                                        H2O +
                                                                                                                      N   N    NH2
           Cl
                           N   N           NH2
                                                                                                       N              Sugar
                           Sugar                                                                                  O
                                                                                                   N
                                                                                       Sugar
                                                                                                       N        NH
                                                 NH3
                               H3N                              O                                           NH2
                                           Pt
                                                  N                 NH                         DNA Adduct
                                       N
                                                       N        N            NH2
                                   N               O
                                                       Sugar
                       Sugar
                                       N         NH
                                                                                       DNA Crosslink
                                            NH2
          Cisplatin (Platinol)
Use: Most used in combination therapy - testicular
tumors (PEB ~ 85% curative)
Toxicity: DLT – nephrotoxicity, can be treated with
Amifostine (a thiophosphate) Major N&V, hearing
loss at high end.
ADME : Administered i.v. after 1-2 liters saline and
mannitol (chloride diuresis)
 Analog: Carboplatin (Paraplatin), Oxaliplatin
(Eloxatin) is now a first line drug for combination
therapy of colon cancer
                  Other Alkylators
   Streptozocin (Zanosar), a nitrosourea
    • Use: Malignant pancreatic insulinoma, pancreatic carcinoid,
      doubles 1 yr survival rates (Nausea and vomiting notable,
      renal toxicity in 2/3 cases – bone marrow suppression in ~
      20%)
   Procarbazine (Mutalane)
    • Use: Hodgkin’s Disease (MOPP protocol)
    • Few reports of cross resistance, minor toxicities (bone
      marrow suppression), psychic disturbances, nausea,
      vomiting, Weak MAO inhibitor - available orally
   Dacarbazine (DTIC)
    • Temozolomide & DTIC are metabolized to same active
      compound: 5-amino-imidizole-4 carboxamide - thought to
      be the active alkylating species
    • DTIC Use: Melanoma, Hodgkin’s disease (ABVD), dose i.v.
    • Temozolomide Use: malignant gliomas
    Alkylating Agents - Summary
   Largest class of antineoplastic drugs
    • Nitrogen Mustards
    • Nitrosoureas
    • Platinum Compounds
   All are electrophilic compounds that react with
    DNA
    • Bifunctional: Nitrogen mustards & platinum compounds
    • Monofuctional: Nitrosoureas
   Toxicities vary depending on the particular
    compound
    • Many have severe bone marrow suppression
    • Platinum compounds tend to show more renal toxicities
              Metabolites and their
                Antimetabolites
General Properties/Mechanism:
   Antimetabolites resemble cellular metabolites and act to
    interfere with DNA synthesis or the synthesis of DNA
    precursors.
   These are classical cell cycle specific anti-cancer agents
     • Most are prodrugs that must be activated through
       incorporation into the normal biosynthetic pathways
   Toxicities: only partially selective to tumor cell –
    toxic to all rapidly dividing normal cells
    • Bone marrow and intestinal epithelium are particularly
      sensitive
   General Drug classes:
    • Antifolates
    • Antinucleotide analogs
                  Folate Antimetabolites
              O           H
     H    H                         OH
HOOC C    N   C       N
                                N
                                        N

   COOH                         N   N       NH2
                                H
              Dihydrofolate
                                                  1st remissions in Leukemia, 1948
     H    H
              O           CH3
                                    NH2
                                                  1st cure of solid tumor, 1963
HOOC C    N   C       N
                                N
                                        N
                                    4
   COOH                         N   N       NH2
              Methotrexate          1

Methotrexate, Amethopterin
Trophoblastic choriocarcinoma, lymphoblastic leukemia, Burkitt’s
lymphoma
•Class: Folate antagonist
•Mechanism: Dihydrofolate Reductase inhibitor: inhibits dTMP
synthesis. Kills in S-phase (G1 and S RNA and protein synthesis)
•Toxicity: bone marrow, GI, renal, alopecia, teratogen
•Resistance: increased/altered DHFR, decreased uptake
  Binding Affinity for Dihydrofolate
              Reductase
    Dihydrofolate Reductase Binding
              O
                                                                   Km
     H                H
          H                     OH
HOOC C    N   C   N
                            N
                                    N         Folic Acid          1.1 x 10-7
   COOH                     N   N       NH2
              O       H
     H    H                     OH
HOOC C    N   C   N
                            N
                      H
                                    N         Dihydrofolic Acid   1.0 x 10-5
   COOH               H     N   N       NH2
                            H
              O       H
     H    H                     NH2
HOOC C    N   C   N
                            N
                                    N
                                              Aminopterin         6 x 10-10
   COOH                     N   N       NH2
              O       CH3
     H    H                     NH2
HOOC C    N   C   N
                            N
                                    N         Methotrexate        6 x 10-10
   COOH                     N   N       NH2
  Methotrexate mechanism of action
                        O           H
           H    H                                       OH
      HOOC C    N       C       N
                                                N
                                    H
                                                            N
                                                                          Methotrexate
         COOH                       H           N       N        NH2
                                                H
                                                                                  Inhibits DHFR
               Dihydrofolic Acid                                                  and production of
                                                                                  Tetrahydrofolate
                            Dihydrofolate
                            Reductase
                            O           H
            H       H                                       OH
       HOOC C       N       C       N       H       H
                                                    N                     Methyl needed here for
                                                                N

          COOH
                                        H
                                        H
                                                                          transfer to dUMP????
                                                    N       N       NH2
                                                    H

           Tetrahydrofolic Acid
              Thymidylate
 dUMP         Synthase        dTMP
2'-Deoxyuridine-MP        Thymidylate                                                    DNA
                  Nucleotide Analogs
                             5-Fluorouracil; 5-FU (Efudex)
                             Colorectal, breast, gastric, pancreatic colon
                             cancers (35% decrease in recurrence).
       OH           OH       Used topically for premalignant skin
                         F   lesions.
  HN           HN
                             •Class: Pyrimidine analog
 O     N
       H
              O     N
                    H
                             •Mechanism: irreversible inhibition of
 Uracil     5-Fluorouracil   thymidylate synthase (TS). Incorporation into
                             DNA/RNA. Kills in G1 and S-phases. Penetrates
                             CNS.
                             •Toxicity: N&V, GI toxicity. DLT bone
                             marrow suppression
                             •Resistance: increased/altered TS
• F-UMP: incorporated into RNA affecting processing/function
• F-dUMP: Inhibits Thymidylate Synthase
• ADME: Administered i.v., half-life in the blood of ~10-20 min
• Analog: Floxuridine (FUDR), often infused into the hepatic
artery for liver cancer
    Normal thymidine synthesis:
          Mechanism of 5-FU action
                  O        THF                             O
                                                                CH3                                             O

           HN
                       H                              HN            H   :B                                 HN
                                                                                                                     CH3

                                       O          O        N
   O      O       N
                                        P O                         S                         O
                                                                                               P O
                                                                                                       O        N
    P O       O                     -O                O
                                                                                                           O
-O                                       O                                                 -O
     O                                                                                          O
                      SH
          HO H
                                               Thymidylate
                                                  HO H
                                                                                                      HO H

                      Thymidylate              Synthase
   dUMP                         Inhibition of TS by 5-FU:                                            dTMP
                      Synthase

                                                      HO         THF                           HO
                                                                                                     CH3
                                                                F                                               :B
                                                  N                                        N
                                                                                                      F
                                    O         O        N                        O      O        N
                                     P O                                         P O       O
                                                                                                      S
                                 -O               O                          -O
                                      O                        SH                 O
                                                                                                     Thymidylate
                                           HO H                                        HO H
                                                               Thymidylate                           Synthase
                                      5-FU                     Synthase


                                                                        Irreversible inhibition of TS
 Thymidylate Synthase



               5-FU




                      Active-Site
                      Cysteine

Methyl-DHF
Modulation of 5-FU & MTX with
     Leucovorin Rescue
    Leucovorin (reduced form of folic acid)
     is commonly used to rescue cells
     exposed to folate antagonists (i.e.,
     methotrexate) - does not function as a
     cytotoxic chemotherapy agent
     • High-dose methotrexate with leucovorin
       rescue (HDM-L) is a component of the
       standard regimen for adjuvant therapy of
       osteosarcoma, produces a high complete
       response rate in CNS lymphomas, and is a
       part of standard curative therapy for
       childhood ALL
    Leucovorin promotes 5-FU inhibition of
     Thymidylate Synthase – used in colon
     cancer
More nucleotide                            Cytosine arabinoside; araC;
  analogs…                                 Cytarabine (Cytosar)
                                           Acute myelogenous leukemia
              NH2                   NH2    •Class: Nucleoside sugar analog
          N                    N
                                           •Mechanism: activated to ara-CTP (DNA
                                           polymerase inhibitor) by dCMP kinase. Kills in
      O       N            O        N
HO        O           HO       O
                                           S-phase
                               HO          •Toxicity: severe bone marrow hypoplasia,
      HO OH                OH              GI
     Cytidine       Cytosine arabinoside   •Resistance: polymerase alteration,
                                           decreased activation, increased deactivation
                                           (dCMP deaminase)

 •Seen as a 2'-deoxynucleoside
 •Phosphorylated and competes with dCTP for incorporation
 into DNA
 •2'-OH in  position: Steric hindrance with base affects base
 stacking interactions in DNA helix
 •1 AraC per 2000 bases reduces growth rate by 50%
     More nucleotide analogs…
                                                 6-Mercaptopurine; 6-MP (Purinethol)
          O
         NH2                   SH
                                                 Acute leukemias (40% remission in
H                                                children)
               NN
    NN                   N              N
                                                 •Class: Purine analog
         N     NN                       N        Mechanism: HPRTase: Hypoxanthine-
          N                    N
                HH                       H       guanine phosphoribosyltransferase makes
    Adenine 6-Mercaptopurine
    Inosine                                      the nucleoside phosphate from the free
                                                 base - inhibition of purine synthesis;
                                                 incorporation into RNA/DNA unclear. Kills
                                                 in S-phase.
                                                 •Toxicity: bone marrow, nausea, vomiting
                                                 •Resistance: decreased HPRTase activity
                                                 (needed to incorporate 6-MP into
                                                 RNA/DNA)
               O                    SH
                                             N
         HN          N         N                  6-Thioguanine (Thioguanine)
    H2N        N     N   H2N        N        N    Same as 6-MP
                     H                       H
          Guanine        6-Thioguanine               Used against granulocytic Leukemia
                                                     with cytarabine
     Antimetabolites - Summary
   Classical cell-cycle dependent agents
   Require bioactivation
   Classes
    • Antifolates
    • Antinucleotide analogs
   Inhibit enzymes required for DNA
    synthesis
   Toxicities extend to tissues with
    higher rates of cellular turnover
                      Antibiotics
General classes of carcinolytic antibiotics:
   Cyclic pentapeptides
   Anthracyclines
   Complex glycopeptides

General Properties/Mechanism:
   All bind to DNA or DNA associated proteins.
   All inhibit RNA synthesis (transcription)
   Most are Isolated from Steptomyces broths
   Some induce DNA strand breaks by free radical production
    and/or inhibition of Topoisomerase II (Topo-II)

Pure Topoisomerase Inhibitors:
   Two Classes: Topo I and Topo II
   Inhibit topoisomerase enzymes resulting in DNA breaks
                                                               Actinomycin D (Cosmogen)
            H3C CH3             H3C CH3                        Wilm’s tumor (kidney, in children),
O C   64
              60   CH            31   CH                       Ewing’s and Kaposi’s sarcomas,
                   CH            HC
                                                     40   O
                                                      C        MTX-resistant choriocarcinoma.
                   N-CH3              N-CH3                    •Class: Cyclic pentapeptide
                   C=O                C=O                      •Mechanism: DNA intercalation;
  O                CH2                CH2             O        inhibits transcription. Kills in the G1
                   N-CH3              N-CH3
                                                               and S phases.
                   L-Pro              L-Pro
                                                               •Toxicity: Myelosuppression, GI, skin.
                   D-Val              D-Val
                        O                  O
H3C CH             CH            HC            CH-CH3
                                                              •RNA polymerase much more
                   NH                 NH
                        O                  O
                                                              sensitive than DNA polymerase.
                            N                  NH2

                                                              •Causes single-strand DNA
                            O                  O
                   CH3                CH3
                                                              breaks.
                                                                 –Free radical formation
                                                                 –Topo II inhibition
           One of the most potent anticancer drugs per mole
Pentapeptide




               Phenoxazone ring




                        Sequence
                        specificity:
                       GC         CC
                            NOT
                       CG         GG
Anthracyclines                                 Doxorubicin (Adriamycin,
                O        OH           O        ADM)
                                           1   Breast, head, neck, thyroid,
                                           R   bladder, testes, prostate, ovary,
                                      OH       Wilm’s and Ewing’s sarcomas,
                                               leukemias and lymphomas
                                  H            •Class: Anthracycline
      O         O        OH                    •Mechanism: DNA intercalator,
H3C                           O
                                               DNA breaks by free radical
          H3C                                  damage and Topo-II interference.
                         O
                                               Kills in S phase.
      O             NH                         •Toxicity: DLT - cardiotoxicity
      R2            R3                         (total dose, often irreversible),
                                               myelosuppression
 R1=R2=R3=H:                                   •Resistance: decreased/altered
 Daunarubicin (Cerubidine)                     Topo-II, P-glycoprotein activity
                                               (decreased accumulation)
 R1=OH, R2=R3=H:
 Doxorubicin (Adriamycin, ADM)

Doxorubicin-polymer conjugates have reduces toxicity, increases targeting
         Doxorubicin (Adriamycin)
Mech: Intercalation and blockage of topoisomerase II, oxygen radical
production because of quinone structure. One of the most useful cancer
drugs – new formulations extending uses.
Toxicity: Myelosuppression max in week 2; recovery in week 4.
Radiation recall. Toxicity limiting total dose is a cardiomyopathy, a
unique toxicity in 1/3 of patients if the total dose exceeds 550 mg/m2.
Dexrazoxane (Zinecard) an antioxidant metal chelator can reduce
anthracycline cardiotoxicity.
ADME: Administered i.v., cleared by the liver.

Analogs: Daunomycin (Daunorubicin), doxorubicin, about ½ as
potent, Mitoxantrone (Novantrone), a synthetic doxorubicin
with reduced cardiotoxicity; Idarubacin (Idamycin).
Daunosamine




              Tetracycline ring
     H2N
          Bleomycin A2 and B2
               O
                                                                                    Complex
                           NH2
                   H
                   N             O

                               NH2
                                                                                  Glycopeptides
           N       N             O        CH3   CH3           O
                           H                          H                           Bleomycin A2
                           N                          N
     H2N                              N                             NH
                                      H
               CH3     O                    OH    O                               _ NH           CH3
                                      N                                                      S
                           O                          HO      CH3            R=
                                      N                                                      CH3
                                      H                             N    S
                           O
                   O
                                     OH
HO                                                            N
               O                                                    S
                                                                                  Bleomycin B2
                                     OH               R
     O     O       OH          OH                         O                                          NH
                                                                             R=    _ NH
         NH2                                                                                     N     NH
                                                                                                 H

Bleomycin (Blenoxane, BLM; mixture of A2 and B2)
Head, neck, testes (Curative with vinblastine and cisplatin), uterine, cervix,
Hodgkin’s and non-Hodgkin’s lymphomas.
•Class: Complex glycopeptide
•Mechanism: DNA binding region. DNA breaks by free radical damage. Kills in G2
phase.
•Toxicity: Cardiotoxicity, edema, lung and skin fibrosis - Minimal myelo- or
immunosuppression
•Resistance: Increased DNA repair
         Bleomycin (Blenoxane)
   Mech.: Has DNA binding region & metal binding
    region (Cu2+ or Fe2+) Transfers e- from M2+ to O2
    to form activated oxygen species. Causes double
    strand breaks in DNA - Cytotoxicity correlates
    with DNA fragmentation
   Use: Testicular tumors - curative in combination
    with cisplatin and etoposide (PEB)
   Toxicity: N&V, skin toxicity. DLT - pulmonary
    fibrosis at total dose of 400 U.
   ADME: Bleomycin is excreted primarily by the
    kidneys Pulmonary toxicity is probably enhanced
    when dosage is not adjusted for renal
    dysfunction.
   Resistance: Bleomycin appears to undergo
    extensive metabolism by a specific cysteine
    proteinase, bleomycin hydrolase – low levels in
    the lungs and skin.
DNA binding
region




              Metal chelating
              region
    Pure Topo-II Inhibitor
                                           Etoposide (VePesid, VP-16)
                   O
                       R                   Testicular, small cell lung
                                           • Mechanism: Stabilizes Topo-II-DNA
    O
                                 O         complex. Causes double strand break.
                                           Kills in G2 and S phases.
O
                                     O     • Toxicity: DLT - bone marrow, nausea,
                                           diarrhea (GI), UNCERTAIN effect on
                                           secondary neoplasia
                                           • ADME: Administered p.o. and i.v,
        MeO                 OMe            largely cleared by kidney
                   OMe                     • Resistance: P-glycoprotein activity
                                           (decreased accumulation)
    R=H Podophyllotoxin
                                                Source: mandrake plant
                                 H
               O            O
                                                (podophyllum peltatum)
        R=                   O       CH3
                                            •Podophyllotoxin binds microtubules
             HO
                       OH                   and inhibits assembly.
              Etoposide                     •Etoposide does not inhibit assembly
                                            of microtubules
Topo II model/mechanism




   Etoposide mechanism


                 Results in Topo II
                 covalently modified to
                 DNA and double strand
                 DNA breaks
     Etoposide
               Pure Topo-I Inhibitor


   CPT 11, Irinotecan (Camptosar)
     • Mech: “Pure” Topoisomerase I poison - source:
       derivatives of camptothecin (CPT), a cytotoxic
       plant alkaloid isolated from the Chinese tree
       Camptotheca acuminata
     • Use: Colorectal cancer, and small cell and non-
       small cell lung cancer - has also shown positive
       responses in pancreatic cancer, refractory
       lymphoma, malignant gliomas, and gynecologic
       cancers
     • Toxicity: GI toxicity, severe diarrhea. DLT - bone
       marrow suppression
     • ADME: Administered i.v., cleared by kidney
     • Analogs: topotecan (Hycamtin)
        Topo-I cleavable complex
   Topoisomerase I relieves          Topo I
    the torsional strain in the
    DNA helix during
    replication and RNA
    transcription by inducing       Inhibited Topo I
    single-strand breaks.
   Binding with the
    topoisomerase I—DNA
    complex, irinotecan prevents
    the relegation of the single-
    strand breaks
   Irreversible DNA damage
    occurs when a DNA
    replication fork encounters     DNA strand break
    the irinotecan or SN-
    38/topoisomerase I
    complexes resulting in
    double-strand DNA breaks
    (Fork Collision Model).
        Antimitotic Agents
General Properties/Mechanism:
 Disrupt chromosomal dynamics.

 Disrupt cellular machinery necessary for DNA

  replication and mitosis.

General Types of antimitotics:
 Microtubule inhibitors

  • Stabilizers
       Taxanes

  • Destabilizers
       Vinca alkaloids
                                                   Paclitaxel (Taxol)
     Taxanes                                       Breast, ovary, lung, head and neck
                                                   •Mechanism: Stabilizes microtubule
                        Ac
H3C                O                               assembly “mitotic spindle poison” G2/M
                            O                      arrest.
                   CH3      CH3 OH                 •Toxicity: DLT - Myelosuppression,
R                  CH3                             peripheral neuropathy, allergic
      HO                               H           reactions to injection are a
                   H
      O                O                           problem
                                  O
               O       Ac                          •ADME: Administered i.v., cleared
                                                   by the liver, susceptible to MDR
                                                   •Resistance: Altered tubulin, P-
                                                   glycoprotein activity (decreased
                                                   accumulation)
                       OH
               H
               N            O__                    • Analog: docetaxel – semisynthetic,
           O            O         Paclitaxel       similar to paclitaxel
    R=
                                  (Taxol)
                                                       •Taxol source: Taxus brevifolia
     H3C      H
                       OH                                  •Limited supply
                                O__
    H3C
          O   N
                                                       •Now made semisynthetically
      H3C   O               O         Docetaxel            •From needles of the Himalayan
    R=                                (Taxotere)           Yew (Taxus bacatta)
                  Taxane mechanism




     DNA Replicated
                                 Taxanes
Don’t allow disassembly of
microtubules: cell becomes
“clogged-up” with microtubules and
enters death pathway(s).
                                 Vincristine (Oncovin)
  Vinca alkaloids                Hodgkin’s disease, childhood leukemia
                                 •Mechanism: Destabilizes microtubule
                                 assembly “mitotic spindle poison”
                                 G2/M arrest.
                                 •Toxicity: DLT - peripheral neuropathy
                                 •Resistance: Altered tubulin, P-
                                 glycoprotein activity (decreased
                                 accumulation)

                                 Vinblastin (Velban)
                                 Testicular (cisplatin, bleomycin)
Source: periwinkle plant         •Mechanism: Destabilizes
(Vinca rosea)                    microtubule assembly “mitotic spindle
                                 poison” G2/M arrest.
Despite similar structures,      •Toxicity: DLT – bone marrow
incomplete cross-resistance      suppression
Administered i.v., susceptible   •Resistance: Altered tubulin, P-
to MDR, cleared largely by the   glycoprotein activity (decreased
liver                            accumulation)
             Vinca alkaloid Mechanism




                         Vinca
                       Alkaloids
    DNA Replicated

Don’t allow assembly of
microtubules: cannot
separarate sister chromatids.
Cell senses too much DNA and
enters death pathway(s).
     Natural products - Summary
   Classes – broad variety of microbial and
    plant sources that target many distinct
    cellular processes
    • Antibiotics
          Target DNA
    • Topoisomerase inhibitors
          Target topo enzymes – result in DNA strand breaks
    • Antimitotics
          Target microtubule function
   Toxicity is not uniform – even within
    subgroups
                       Misc. agents
   Hydroxyurea
    • Use: AML or the blastic phase of CML
          Because of its radiosensitizing effects, it is used with
           radiation therapy to treat head and neck carcinoma
    • Mechanism: Hydroxyurea blocks ribonucleotide
      reductase, the rate-limiting enzyme of DNA synthesis.
          Hydroxyurea inhibits ribonucleotide reductase by binding to
           the M2 subunit and disrupting the iron complex.
          This enzyme is responsible for converting ribonucleotides
           to deoxyribonucleotide triphosphates (dNTPs), which are
           critical to DNA synthesis and repair.
    • Toxicity: Hematopoietic depression is the major toxic
      effect; UNCERTAIN risk of secondary leukemia;
      teratogen
    • Resistance: alterations in sensitivity of ribonucleotide
      reductase
Misc. Agents cont. – Hormonal
                        Tamoxifen (Nolvadex)
         O        CH3
              N         Estrogen Receptor (ER) positive breast cancer
              CH3       •Class: Antiestrogen SERMS (synthetic estrogen
                        receptor modulators)
                        •Mechanism: Block estrogen response by competitive
CH3                     inhibition of ER. Inhibits G1 to S transition.
                        •Toxicity: rarely severe adverse reactions to
                        tamoxifen include vasomotor symptoms (hot flushes),
      Tamoxifen
                        N&V & vaginal bleeding . Tamoxifen also increases the
                        incidence of endometrial cancer by two- to threefold


                        Anastrozole (Arimidex)
                        Fourth generation of aromatase inhibitor - effective
                        against ER positive breast cancer
                        •Class: Aromatase inhibitor
                        •Mechanism: Anastrozole significantly suppresses
                        serum estradiol levels Anastrozole inhibits
                        aromatase (CYP19), the enzyme that catalyzes the
                        final step in estrogen production.
      Anastrozole       •Toxicity: rarely severe adverse reactions – some
                        musculoskeletal toxicity
Other Hormone/hormone-related

                   OH O
                                Prednisone
       O
                           OH
                                Hodgkin's disease, acute lymphocytic
                                leukemia (ALL), lymphomas
                                •Class: Corticosteroid
 O                              •Mechanism: Antianabolic effects
                                •Toxicity: Cushingoid symptoms
     Prednisone

             CH3      OH          Diethylstibestrol, DES
                                  Prostate cancer
                                  •Class: Estrogenic (non-steroid)
HO     H3C                        •Mechanism: Block androgen
                                  dependence
     Diethylstibestrol            •Toxicity: developmental
     DES                          mutagen/teratogen
    Hormones-related therapy cont.
   Leuprolide (Lupron),
    GnRH peptide, used with
    Flutamide
   Mech.: Acts on pituitary to
    inhibit FSH and LH release
    • Constant GnRH Causes
      Testosterone or Estrogen
      Levels to Fall to Castration
      Levels
   Use: Prostate cancer, and
    breast cancer prevention
   Toxicity: Less than DES,
    N&V, hot flashes
   Analog: Goserelin
    (Zoladex)
               Antiandrogens
                 Flutamide (Eulixen)
                 Oral nonsteroidal antiandrogen - metastatic prostatic
                 carcinoma
                 •Mechanism: Inhibits the uptake and/or nuclear
                 binding of testosterone and dihydrotestosterone by
                 prostatic tissue - most effective when combined with
                 LHRH agonists
Flutamide        •Toxicity: rarely severe adverse


                Bicalutamide (Casodex)
                oral nonsteroidal antiandrogen structurally related to
                flutamide but has a long plasma half-life (once daily
                dosing)
                Mechanism: Inhibits the uptake and/or nuclear
                binding of testosterone and dihydrotestosterone by
                prostatic tissue - most effective when combined with
Bicalutamide    LHRH agonists - bicalutamide is more selective for the
                peripheral androgen receptor and has less activity at
                the central androgen receptor
                •Toxicity: rarely severe adverse
    Hormone-related - Summary
   Breast and Prostate cancers frequently
    demonstrate hormone-dependent growth
    (at least in early stage disease)
   Classes:
    • GnRH agonists
    • Antiestrogens (includine for prevention)
          Aromatase inhibitors
    • Antiandrogens
    • Corticosteroids
   Toxicities tend to be more mild
           Newer Molecularly Targeted
                  Agents (1)
   Tyrosine Kinase Inhibitors
    • imatinib (Gleevec) – Bcr-Abl/c-
      kit kinase inhibitor (CML, GIST)
          Toxicity: generally mild – N&V,
           edema & muscle cramps,
           Neutropenia and
           thrombocytopenia
    • gefitinib (Iressa) - EGFR
      tyrosine kinase inhibitor (non-
      small cell lung cancer)
Antibodies
    • Trastuzumab (Herceptin) – anti-HER2/neu monoclonal
      (breast cancer)
    • Bevacizumab (Avastin) - anti-VEGF monoclonal (colon
       cancer)
    • Cetuximab (Erbitux) - anti-EGFR monoclonal antibody
      (colon cancer)
    • Others – including antibody conjugates to drug/toxin
           Newer Molecularly Targeted
                  Agents (2)
   Differentiation Inducers
    • Retinoic Acid derivatives
          Tretinoin, ATRA (Avita)
             • Uses: acute promyelocytic leukemia
               (APL) and undergoing phase III
               investigation in the treatment of
               Kaposi's sarcoma. Frequently given in
               combination with an anthracycline
             • Toxicities: Generally mild - cause dry
               skin, cheilitis, reversible hepatic enzyme
               abnormalities, bone tenderness, and
               hyperlipidemia
   Others - proteasome inhibitor
    • Bortezomib (Velcade) –
          Uses: Multiple Myeloma, in trials for
           other leukemias
          dose-limiting toxicities in the following
           organ systems: gastrointestinal,
           hematopoietic, lymphatic, and renal
    Important Cytokines and Biological
           Response Modifiers
    Biologic Agents Used to bolster immune
    response:
      IL-2 (interleukin-2) T cell stimulation, highly
       toxic, used in metastatic melanoma
     • Interferons (Inf 2a,b) used in hairy cell
       leukemia
     • Filgrastim (Neupogen) G-CSF
     • Sargramostim (Leukine) GM-CSF
     • BCG (Bacillus Calmette-Guerin Live-
       Mycobacterium bovis ) used in bladder cancer
         Combination Chemotherapy
              Considerations
Most cancers are/become refractory to treatment by a single agent,
  combinations of anticancer drugs are often used. The following rules
  apply to combining drugs in cancer chemotherapy:
1. The drugs each must have some activity against the cancer.
2. The drugs should act via different mechanisms.
3. The drugs should have minimal overlapping toxicity.
4. Cellular resistance to each drug should occur by different
   mechanisms.


The first drug combination, made famous by Dr. V. DeVita and others at
  NIH, is called MOPP (Mechlorethamine, oncovonin, procarbazine, and
  prednisone). MOPP is a curative treatment for Hodgkin's disease and
  its development was a major step forward.
    Current Combinations of Therapy
     ABVD: Doxorubicin (adriamycin), bleomycin,
      vinblastine, dacarbazine – Used for: Hodgkin’s disease
     CHOP: Cyclophosphamide, doxorubicin
      (hydroxydaunorubicin), vincristine (oncovin),
      prednisone – Used for: Non-Hodgkin's lymphoma or CLL
     CMF: Cyclophosphamide, methotrexate, fluorouracil –
      Used for Breast carcinoma
     IFL: Irinotecan, fluorouracil, leucovorin – Used for:
      Colorectal carcinoma with or without oxaliplatin
     MOPP: Mechlorethamine, vincristine (oncovin),
      procarbazine, prednisone – Used for: Hodgkin’s disease
     PEB: Cisplatin (platinum), etoposide, bleomycin – Used
      for Testicular carcinoma

                     Alkylating agents
                     Antimetabolites
                       Antimitotics
                        Antibiotics
    Drug combo’s for Major Cancers
     Carcinoma of lung:
    •    Cisplatin + taxane, or cisplatin + etoposide, or cisplatin +
         irinotecan
     Carcinoma of breast:
    •    Hormonal therapy (Tamoxifen or Anastrozole)
    •    FAC: Fluorouracil, doxorubicin (adriamycin), cyclophosphamide
    •    FEC: Fluorouracil, epirubicin, cyclophosphamide
    •    CMF: Cyclophosphamide, methotrexate, fluorouracil
     Carcinoma of prostate:
    •    Hormonal therapy: GnRH agonist plus androgen antagonist
     Carcinoma of colon:
    •    IFL: Irinotecan, fluorouracil, leucovorin – with or without
         oxaliplatin
    •    In trials: cisplatin, irinotecan, and a taxane
     Pedicatric Leukemia – a success story for Oncology
    •    Acute lymphocytic leukemia. Induction: vincristine plus prednisone.
         Remission maintenance: mercaptopurine, methotrexate, and
         cyclophosphamide in various combinations.
    •    Acute myelocytic and myelomonocytic leukemia. Combination
         chemotherapy: cytarabine and mitoxantrone or daunorubicin or
         idarubicin
           Clinical Considerations
   Many cancer drugs can be extremely toxic agents. The condition
    of the patient has a profound impact on the ability to tolerate drug
    therapy (or bone marrow replacement, or surgery, etc.).
     • Organ function is frequently effected by illness (e.g., tumor
        infiltration, hepatitis), age, prior injury or therapy.
     • It is the metabolic capacity of the liver, kidney, and the ability
        to produce blood cells (bone marrow reserve) under stress, and
        sometimes the ability of the GI tract to recover, that determine
        which therapy is used and the therapeutic outcome.
     • Drugs like Doxorubicin and Cisplatin depend on liver and
        kidneys for metabolism and clearance, respectively. Patients
        with compromised function cannot receive as much drug.
     • Patients with poor bone marrow reserve may suffer
        overwhelming toxicities at standard doses of myelosuppressive
        drugs and develop excessive bleeding and infection.
   Patients who are asymptomatic, active, have good appetites and
    who have not lost weight do better than those with unremitting
    pain, no appetite, who are bedridden or who have lost 10% - 15%
    body weight. Satisfactory categorization of patient status is
    important for deciding the extent and course of therapy.
     Medical Complications of
      Neoplastic Diseases
1.    Anemias can occur in up to 50% of patients but
      RBC transfusions are available (dec. RBC prod.)
2.    Infection
3.    Bleeding and coagulopathy
4.    Mechanical obstruction
5.    CNS involvement
6.    Pain
7.    Bone invasion
8.    Constitutional symptoms
            Curability of Cancers with
                 Chemotherapy
       Advanced cancers with possible cure
          Testicular cancer, Hodgkin’s disease, pediatric ALL (and
           other pediatric cancers)
       Advanced cancers possibly cured by chemotherapy and
        radiation
          Squamous carcinoma, Breast carcinoma, lung cancers
       Cancers possibly cured with chemotherapy as adjuvant to
        surgery
          Breast carcinoma, colorectal carcinoma
       Cancers possibly cured with "high-dose" chemotherapy
        with stem cell support
          “Relapsed” leukemias, “relapsed” lymphomas
       Cancers responsive with useful palliation, but not cure, by
        chemotherapy
          Head & neck carcinomas, advanced breast carcinoma,
           advance colon carcinoma
       Tumor poorly responsive in advanced stages to
        chemotherapy
          Pancreatic cancer, melanoma, renal carcinoma
     Combination therapy & Clinical
      Considerations - Summary
   Most therapy today is combination
    chemotherapy
    • Better clinical outcomes by using combinations
      of drugs with non-overlapping toxicities and
      mutliple mechanisms of action
   Patient overall health status is crucial
    when selecting drug combinations
    • Altered metabolism means altered dose
    • Complications frequently arise resulting from
      the treatment regimen
   Still much work to be done – many
    cancers still cannot be treated adiquately.
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