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Pharmacology Cancer Chemotherapy and Immunosuppressive Drugs

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					Pharmacology Review Sheets: Cancer chemotherapy drugs, p.1

Drug Selection
      Drugs partially effective when used alone, at optimal dose and schedule
      Drug selected from a class should not have any common toxicities w/other drugs in
combination therapy
      Give combinations at regular intervals, preferably as narrow as possible (to allow for
recovery of most sensitive tissues – bone marrow, GI tract, etc.)
      Advantages of selecting drugs in this way:
           - Provide maximal cell kill within the range of toxicity tolerated by the host for each drug
                     - Provide a broader range of coverage at the outset for possible resistant cell
lines in the heterogenous tumor population
           - Prevent or slow the development of new resistant cell lines.

Chromatin function inhibitors (Mitotic spindle poisons): Vinca alkaloids

Common properties
      Mechanism of action: Combines with tubulin, resulting in disassembly of microtubules;
specific for phases G2/M in the cell cycle
      Resistance:
           - Membrane P-glycoprotein pumps drug out (Note: P-glycoprotein is present in most
cells; resistant cells simply have an upregulation of P-glycoprotein)
           - Mutation to tubulin so it doesn’t bind the drug
      Pharmacokinetics:
           - Administration: IV
        - Distribution: Distributes well to heart, kidney, lung, liver. Does NOT distribute to
CSF. Passes the placental barrier.
        - Excretion: Feces (biliary route)
    Common Adverse Reactions/Drug Interactions:
        - Nausea, vomiting, diarrhea (NVD)
        - Alopecia
        - Severe constipation
        - Interaction: Itracanazole admin   time to neuromuscular problems.

Drug          Uses                          Adverse Effects

Vincristine (VX)  Acute lymphocytic leukemia (ALL)                   Peripheral neuropathy
           Hodgkin's & non-Hodgkin's lymphoma                   Inappropriate ADH secretion
    (avoid vigorous hydration in patients receiving high doses of vincristine)
           Wilms tumor
           Ewing's soft tissue sarcoma
Vinblastine (VBL)  Disseminated non-seminomatous testicular cancer            
Myelosuppression  granulocytopenia
           Choriocarcinoma
           Hodgkin's lymphoma.
Vinorelbine (VRB) (Not listed)                         Myelosuppression  granulocytopenia

Chromatin function inhibitors (Mitotic spindle poisons): Taxanes
Drug            Mechs of Action/Resistance                  Pharmacokinetics                   Uses
     Adverse Effects
Paclitaxel      Mechanism of action: Promotes and stabilizes the            Admin: IV infusion, but
w./special solvent b/c drug  Solid tumors             Severe neutropenia (Rx w/filgrastim – C-GSF)
             microtubule assembly; chromosome desegregation             is insoluble in water
       - Epithelial ovarian cancer - Don't give to pts w/neutrophil count < 1500/mm3
             won't take place – apoptosis results.            - Give immunosuppressants
(dexamethasone,         - Non-small cell lung cancer         Peripheral neuropathy ( risk in diabetics)
              Specific for the G2/M phases of the cell cycle. diphenylamine) +
cimetidine/ranitidine beforehand          (w/cisplatin or carboplatin)       Alopecia
           Resistance:                      Distribution: Extensively bound to serum proteins
            Cardiovascular toxicities
             - Membrane P-glycoprotein pumps drug out              but does NOT enter the brain
                       Onycholysis
             - Mutation to tubulin so it doesn’t bind the drug Metabolism: CYP2C8, then CYP3A4
                                      Excretion: Feces
Docetaxel             Mechanism of action: Same as w/paclitaxel but with Admin: Same as with
paclitaxel, but…           (Same as paclitaxel)              Severe neutropenia (Rx w/filgrastim – C-
GSF)
              affinity (thus  activity)               - Only dexamethasone needs to be given first!
                  - Don't give to pts w/neutrophil count < 1500/mm3
           Resistance: Same as w/paclitaxel                 Distribution: Same as paclitaxel but may
penetrate                   Peripheral neuropathy ( risk in diabetics)
                                        cells better                                   Alopecia
            Metabolism: CYP3A4    Fluid
retention
            Excretion: Feces      Erythema
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.2

Chromatin function inhibitors: Antibiotics

Drug/Class Mechs of Action/Resistance                      Pharmacokinetics                  Uses
      Adverse Effects
Dactinomycin Mechanism of action:                          Administration: IV                
Gestational choriocarcinoma  Hypersensitivity: anaphylactic reactions
  (aka Actinomycin D)         - Inhibit DNA-dependent RNA polymerase          Distribution: Well-
distributed, but does NOT          Wilms’ tumor (children)  Stomatitis and ulceration of oral
cavity and GI tract
               by intercalating between DNA strands and           penetrate CSF                   
      Rhabdomyosarcoma                  Pancytopenia (dose-limiting)
               blocking RNA chain elongation (Low conc) Duration of action: Long t½
           Ewing’s sarcoma              - Requires daily monitoring
             - Inhibition of DNA synthesis (High conc)          Metabolism: Minimal
                       Colors urine red (warn patients about this)
             - Cytotoxic to cells in any phase of the cell      Elimination: Urine and feces
               cycle, including those in stationary phase.
          Resistance:
             - Membrane P-glycoprotein pumps drug out
             - Some evidence of changes in topoisomerase II.
Doxorubicin Mechanism of action:                           Administration:                   
Doxorubicin:           Cardiotoxicity due to hydroxy radical formation
Daunorubicin - Intercalates between base pairs              - IV for doxorubicin, daunorubicin
- ALL                  - Dose-related, cumulative, non-reversible
  (Anthracyclines) - Inhibition of polymerase activity                 - Idarubicin can be given orally
            - Hodgkin’s lymphoma           - Rx by dexrasone, which is metabolized to EDTA,
            - Inhibits topoisomerase II activity; can cause single Distribution:                      -
Non-Hodgkin’s lymphoma             a metal chelator. It risks anemia though!
              or double-strand breaks in DNA                - Highest levels in heart, lung, kidney,
     liver - Breast cancer           Bone marrow depression – can be severe
            - Generation of hydroxyl free radicals          - Doesn’t penetrate CSF                   -
Liver cancer          Hyperpigmentation
            - Alterations in cell membrane fxn – alters transport - Penetrates placenta
- Neuroblastoma            Alopecia
           Resistance:                   Metabolism: Aldo-reductases, to cytotoxic products 
Daunorubicin:         Stomatitis
             Increased glutathione & glutathione              Excretion: Predominantly biliary
       - AML               Mutagenicity/carcinogenicity
               peroxidase activity                                          - Kaposi’s sarcoma
            - Membrane P-glycoprotein pumps drug out
            - Decreased topoisomerase II activity.
            - DNA repair
Bleomycin            Mechanism of action: Forms a ternary complex with Administration: IV, IM,
subcutaneous or intrapleural  Hodgkin’s & non-Hodgkin’s              Pulmonary toxicity – dose-
related, age-related
            Fe2+, O2, and DNA – forming superoxide and Distribution: High levels in skin, lung,
kidneys,     lymphomas          Mucocutaneous reactions – unusual erythema,
            hydroxy radicals which fragment DNA                 peritoneum, lymphatics. Low levels
in BM            Squamous cell carcinomas       peeling and hyperpigmentation.
            - Cells accumulate in the G2 phase           Metabolism: Hydrolase (high levels in BM,
low  Testicular carcinoma  Anaphylactoid-like reactions
          Resistance:                      levels in lung and skin) cleaves drug to less potent
(w/cisplatin and etoposide)  Alopecia
            - Hydrolase (present in sarcomas) inactivates drug       metabolite
                 Note: No myelosuppression
            - Increased levels of glutathione       Excretion: Urine
            - DNA repair.
            - Membrane P-glycoprotein pumps drug out
Etoposide       Mech. of action: Inhibits topoisomerase II, causing Administration: Oral, IV
           Testicular carcinoma, w/  Myelosuppression - dose-limiting
  (podophyllotoxin)         double-strand breaks; may also form free radicals Distribution:
             cisplatin and bleomycin  AML risk
            - Affects G2 phase of the cell cycle           - Well-distributed but doesn’t penetrate
     CSF  Small cell lung carcinoma  Hypotension when injected rapidly
          Resistance:                      - 97% bound to plasma proteins                 w/
     cyclophosphamide and  Anaphylactic reactions
            - Membrane P-glycoprotein pumps drug out          Metabolism: Glucuronidation,
sulfation         doxorubicin        Drug Interactions: Aspirin, phenylbutazone can
            - Mutation of topoisomerase II.              Excretion: Urine
             displace etoposide from plasma protein binding site
            - Mutation of p53 tumor suppressor gene
Topotecan           Mechanism of action: Inhibits topoisomerase I, Administration: IV
      Refractory metastatic ovarian  Bone marrow suppression  neutropenia
  (podophyllotoxin)        causing single-strand breaks                Metabolism: Reversible pH-
dependent hydrolysis;       cancer             - Dose-limiting
          Resistance: Poss. amplification of P-glycoprotein lactone ring is opened at physiologic
     pH (7.4)  Refractory small cell lung     - Treat with filgrastim (C-GSF)
            or mutation of topoisomerase I                and closed at pH 4
carcinoma              Don’t use in pts with neutrophils < 1500/mm3
                                   Elimination: Urine                                Nausea,
vomiting, diarrhea
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.3

Antimetabolites

Drug/Class Mechs of Action/Resistance                      Pharmacokinetics                    Uses
          Adverse Effects
Methotrexate Mechanism of action: Inhibitor of dihydrofolate Administration: Oral, IV, IM,
intrathecal           ALL                      Stomatitis
            reductase (DHFR), depriving cell of folate         Distribution:                   
Gestational choriocarcinoma           Alopecia
            coenzymes needed to synthesize purines,               - Well-distributed in all body fluids
except CSF  Epidermoid cancers of head and neck  Thrombocytopenia (BM suppression)
            thymidylic acid, and methionine            - 50% bound to plasma proteins                
Non-Hodgkin’s lymphoma                Megaloblastic anemia
            - Requires cycling cells; S phase.             Metabolism: Hydroxylation to less water-
soluble  Non-metastatic osteosarcoma (high dose            - Rx: leucovorin (N5-CHO-THFA)
            - Enters cell by diffusion; undergoes polyglutamation           metabolite; hydration
needed to prevent crystaluria w/leucovorin rescue)              Crystaluria w/high doses
              and is retained in the cell              - Recall intracellular conversion to
polyglutamates        Psoriasis and psoriatic arthritis (low dose)  Contraindicated in pregnancy;
          Resistance:                     Excretion: Urine (parent drug and metabolites)
             abortifacient
             Amplification of the DHFR gene
       Chronic low-dose therapy can lead to
             -  affinity of DHFR for MTX.
hepatic fibrosis (Rx for psoriatic arthritis)
                            -  permeability into neoplastic cells
                   Seizures, paraplegias, learning disabilities
             -  formation of MTX polyglutamic polymers
        w/intrathecal administration
             -  levels of thymidylate synthetase
6-mercaptopurine Mechanism of action: Hypoxanthine analog;                  Administration: Oral; well
absorbed           Remission maintenance in ALL               Bone marrow suppression – leukopenia,
  (Purimethol®)          once converted to the appropriate nucleotide, it uses Distribution: Widely
distributed, poor distr. to CSF                            thrombocytopenia
  Anti-purine HGPRT to form thioinosinic acid (TIMP), this Metabolism: Extensive in liver;
metabolized to                           Hepatotoxicity
             interferes with the de novo synthesis of purines thiouric acid (via xanthine oxidae,
XO) and                            If allopurinol is also being administered,
             - Effective S phase (cycling cells, obviously)         methylated products
                          reduce the dose b/c allopurinol is an
           Resistance:                       Excretion: Urine
XO inhibitor & will potentiate its effects
             - Inability to be transformed to T (IMP) due to:
       Don’t give to kids w/Lesch-Nyhan this
                -  levels of HGPRT (Lesch-Nyhan syndrome)
              drug b/c they have a deficiency of
                -  affinity for 6-MP
HGPRT
             -  entry into cells
             -  metabolism to thiouric acid by xanthine oxidase
             - Change in affinity of ribosylamine-5P synthase.
6-Thioguanine Mechanisms of action:                  Metabolism: via methylation              
Treatment of AML, w/daunorubicin            Allopurinol does NOT potentiate effects
  Anti-purine - Inhibition of purine ring synthesis
      Otherwise, similar to 6-MP
               (it’s a purine analog)
             - Blocks phosphorylation of GMP to GDP
Fludaribine Mechs of action: Incorporation into DNA, resulting in Administration: IV
      CLL (B-cell)                Severe myelosuppression (dose-limiting)
  (Unnatural        - Termination of chain elongation         Distribution: Not established
                        Autoimmune hemolytic anemia – fatal!!
   nucleotide of         -  RNA synthesis                    Metabolism: Usually to nucleotide;
intestinal bacteria                         Edema
   F-adenine)  Works on cycling cells in S phase               can split off the sugar, yielding a
toxic metabolite                            Pulmonary toxicity
             Undergoes dephosphorylation, then                 (F-adenine)
            Paresthesias, peripheral neuropathy
                 rephosphorylation intraceullarly, forming Excretion: Urine
                   Fever, infection
                F-ara ATP                                                                      High
doses: progressive encephalopathy,
           Resistance: Not established (DNA repair suggested)
              blindness, death
5-Fluorouracil Mechanism of action: Inhibition of DNA synthesis Administration: IV, topical
            Solid tumors: colon, breast, ovary,  Severe oral/GI tract ulceration (this is
  Anti-pyrimidine - After conversion to its corresponding nucleotide Distribution: Well-
distributed; penetrates ascites pancreas and stomach               why 5-FU can’t be given orally)
               (5-FdUMP), the drug competes w/dUMP for            fluid; also penetrates CSF
       Superficial basal cell carcinomas  Diarrhea (severe)
               thymidylate synthetase                Metabolism: Like uracil (look this up).
(topical admin)                   BM suppression – leukopenia
             - Note: The folate coenzyme N5,10 methylene THFA Excretion: Bile
                       Cardiotoxicity (arrhythmias, angina,
               is needed for 5-FU to be effective (the coenzyme        - Note: 5FdUMP and FUTP
have  t½                               heart failure)
               forms a ternary complex w/thymidylate synthetase
            Erythematous desquamation of the palms
               and the substrate). In the case of the drug, this
        and soles (following extended infusion)
               ternary complex is stable (not transitional) and the
            Acute cerebellar syndrome (nystagmus
               process is halted.
slurred speech, ataxia)
           Resistance:                                                                     - Rare, but
reversible!
             - Inability to make fraudulent deoxynucleotide.
 -  amount of dUMP via gene amplification
-  affinity of thymidylate synthetase for 5-FdUMP
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.4

Antimetabolites, continued

Drug/Class Mechs of Action/Resistance                     Pharmacokinetics                  Uses
           Adverse Effects
Capecitabine Mechanism of action: Prodrug is converted to Administration/Absorption: Oral;
well absorbed  Refractory metastatic breast cancer  Severe diarrhea
  Anti-pyrimidine cytotoxic 5-FU; w/same mech. of action;                Metabolism: Prodrug is
converted in the liver                           Erythematous desquam. of palms/soles
             however, the action is much more tumor-specific!         to dFCR, which is in turn
deaminated to dFUR.                               (palmar-plantar erythrodysesthesia)
             (Tumor’s thymidine phosphorylase does this)         The tumor specifically hydrolyzes
this to 5-FU.                         Use cautiously in patients with hepatic or
                                     Excretion: Products of 5-FU metabolism, in bile
         renal impairment
Cytarabine            Mechanism of action: Inhibits DNA polymerase Administration: IV,
subcutaneous, intrathecal        Acute non-lymphocytic leukemia (AML)  Potent
myelosuppression
  Anti-pyrimidine - Drug is converted into corresponding nucleotide -- Distribution: Well
distributed throughout body;       w/daunorubicin and 6-TG           Hepatic dysfunction
               an antagonist of dCTP                   penetrates poorly into CSF            ALL
                  Seizures with intrathecal therapy
             - Also inhibits reduction of CDP to dCDP          Metabolism: Extensively deaminated
to ara-U  CML (blast phase)
           - Affects cycling cells in S phase           Excretion: Urine
         Resistance:
           -  formation of unnatural nucleotide
           -  affinity of ara-CTP for DNA polymerase.
           -  levels of dCTP due to  CTP synthetase activity
           -  metabolism to uracil arabinoside (ara-U)
Gemcitabine Mechanism of action:                        Administration: IV               
Pancreatic adenocarcinoma            Myelosuppression
  Anti-pyrimidine - Converted intracellularly to dFCDP/dFCTP Metabolism: Deaminated to
dFU (inactive)       Locally advanced and metastatic          Flu-like symptoms
             by nucleoside kinase              Excretion: Urine (parent drug and dFU)
non-small cell lung cancer           Transient elevation of liver enzymes
             - dFCDP inhibits ribonucleotide reductase                                (in
combination w/cisplatin)        Proteinuria (rare)
               (which will  dCTP)
             - dFCTP is incorporated into DNA, which will
               inhibit DNA synthesis
         Resistance:
           - Possible alteration to nucleoside kinase

Alkylating agents
Drug/Class Mechs of Action/Resistance                    Pharmacokinetics                    Uses
          Adverse Effects
Mechlorethamine Mechanisms of action: Cytotoxicity (rapid)               Administration: IV only
           Hodgkin’s disease in MOPP regimen  Severe vomiting (centrally mediated)
            - Alkylation of N7 of guanine results in:           - Note: severe damage occurs if drug
     extravasates     (Mechlorethamine, Oncovin , Prednisone,  Severe BM depression
                                                    ®

              - Depurination makes “nicks” in the DNA chain,
Procarbazine)               GI toxicity
                making it easier to break                                      Some solid tumors
           Latent viral infections (herpes zoster) may
              - Cross-linkages in DNA
appear
          Resistance:
            - DNA repair
            -  permeability
Cyclophosphamide Mechanism of action: Cytotoxicity by cross-linking Administration: Oral
                 Malignant lymphomas          Hemorrhagic cystitis (leukopenia)
           ®
  (Cytoxan , CTX) DNA and depurination (by "nicking")               Distribution: Variable binding to
plasma proteins      Hodgkin's disease               - Treat w/MESNA (2-mercapto ethane
            - Must be biotransformed to active form           Metabolism: Liver cyt P-450 initially
hydrolyzes       Burkitt's lymphoma                    sulfonate) to remove toxic metabolites
              - Hydroxylation by liver cyt P-450         Excretion: Urine (parent drug and
metabolites)  Multiple myeloma                       secretion of ADH (risks water retention)
              - Non-enzymatic breakdown to phosphoramide                                      AML
                  so monitor hydration levels
                mustard and acrolein (both cytotoxic)                                 ALL
                 Females: Amenorrhea, sterility
              - Mustard cyclizes to form active compound                             
Neuroblastoma                  Males: Testicular atrophy, infertility
            Affects both cycling and resting cells                                   Ovarian
adenocarcinoma            Bone marrow depression (leukopenia)
          Resistance:                                             Retinoblastoma               2
malignancies years after therapy
           - Increased glutathione                                      Psoriasis
           - DNA repair.                                                Nephrotic syndrome (in
children)
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.5

Alkylating agents

Drug/Class Mechs of Action/Resistance                        Pharmacokinetics                   Uses
           Adverse Effects
Chlorambucil Mechanism of action: Cross-links DNA                      Administration: Oral
      Drug of choice for CLL                 BM suppression
                                       Distribution: Highly bound to plasma albumin and
            Sterility
                                         tissue proteins                                        
Leukemia
                                       Metabolism: Oxidized in liver to phenylacetic acid
                                         mustard (active agent); chlorambucil is a prodrug
                                       Excretion: Urine
Cisplatin        Mechanism of action: Cross-links DNA (G-G, G-A); Administration: IV in saline
solution, preferably  Solid tumors                Renal tubular damage
             Also inhibits RNA synthesis                       those containing chloride so conversion
doesn’t      - Metastatic testicular carcinoma - Dose-related and cumulative; make sure
             - Affects cells in all stages of the cell cycle but happen in the IV drip 
- Metastatic ovarian carcinoma                  renal fxn is normal before next dose
               especially those in S              Distribution: Concentrates in liver, kidney, intestine,
     - Bladder cancer                    - Damage potentiated by aminoglycosides
             - Note: Only the CIS- form is active!             and ovary, but does NOT penetrate CSF
                            Ototoxicity: tinnitus and hearing loss,
          Resistance:                     Excretion: Urine
especially in children
            - High intracellular glutathione
     Marked nausea and vomiting
            - DNA repair                                                               
Myelosuppression (leukopenia,

thrombocytopenia
                                                                              Sterility
                                                                              Peripheral
neuropathy
                                                                              Serum electrolyte
disturbances
                                                                               (hypocalcemia,
hypomagnesemia,
                                                                                hypokalemia,
hypophosphatemia)
Carmustine (BCNU)       Mechanism of action: Alkylating mechanism         Administration:
Carmustine-IV; Lomustine-Oral  Malignant gliomas (including               Delayed hematopoietic
depression
Lomustine (CCNU) inhibits DNA; requires bioactivation           Distribution: Readily penetrates
CSF!!           glioblastoma multiforme)           (may be due to metabolites)
  Nitrosoureas      - Note: cytotoxicity only affects non-resting cells Excretion: Urine
                             Renal toxicity related to therapy duration
          Resistance: Unknown, but DNA repair suggested
           CNS toxicity
Streptozotocin Mechanism of action: Nitrosurea w/cytotoxicity                           Insulin-
secreting islet cell carcinoma of  BM toxicity (minimal)
             specific for -cells of pancreas                                   pancreas

Antibodies

Antibody       Mechs of Action/Resistance            Pharmacokinetics                   Uses
          Adverse Effects
Rituximab            Mechanism of action: Binds to CD20 on all cells,    Admin: Slow infusion
at weekly intervals for 4 doses     Refractory CD20 B-cell non-Hodgkin’s  Fever, chills
                                                    +

            then promotes lysis                                            lymphoma
           Severe neutropenia, thrombocytopenia
                                                           - Note: This can only be used for a
reported
                                                             short time because of development
          of  Cardiac arrhythmias
                                                             antibodies against the drug by the
host  Hypotension, bronchospasm and
                                                                                 angioedema:
treat w/diphenhydramine
                                                                                 and
bronchodilator
Trastuzumab Mechanism of action: Selectively binds human Administration: IV infusion
       Metastatic breast cancer whose tumors        Fever, chills
            epidermal growth factor receptor 2 protein (HER2); Distribution: Blood levels
increased if given with      overexpress HER2; when given with  Cardiotoxicity – CHF, especially
if given
            the gene coding for it is amplified in 25-30% of paclitaxel (mechanism unknown)
        other agents, time to progression of     w/anthracyclines (doxorubicin,
            women with breast cancer (recombinant Ab) Metabolism/Excretion: Not described
        disease was lengthened by 25% daunorubicin) or paclitaxel
                                                                - Note: This can only be used for a
       Leukopenia, anemia
                                                                  short time because of development
of
                                                                  antibodies against the drug by the
host
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.6

Hormones/Hormone Antagonists

Drug            Mechs of Action/Resistance                Pharmacokinetics                 Uses
          Adverse Effects
Prednisone            Mechanism of action: Lympholytic effects           Administration: Oral
           Leukemias and lymphomas             Ophthalmic: Cataracts, glaucoma
            - Prednisolone (a metabolite) reacts w/the cytosolic Distribution: Binds to plasma
albumin and transcortin                         GI: ulcers, pancreatitis
              glucocorticoid receptor                Metabolism: Undergoes 11--hydroxylation in
liver                       Hyperglycemia, Cushing-like Sx
            - This receptor-glucocorticoid complex is transported         to prednisolone;
glucuronidation later on.                             Osteoporosis
               to the nucleus and interacts w/DNA  effects Excretion: Urine (parent drug and
metabolites)                          Alterations in mood and behavior
          Resistance: Not established                                                           
Susceptibility to infections
Tamoxifen             Mechanisms of action:               Administration: Oral                  
Breast cancer               Hot flashes
  anti-estrogen        - Competes with estrogen for the estrogen receptor Metabolism: Undergoes
extensive metabolism;  Prophylaxis in women at risk for breast  Vaginal bleeding, discharge
            - Drug-receptor complex interferes w/DNA binding, metabolites are glucuronidated
             cancer                   Endometrial hyperplasia; poss. cancer
              thus  TGF-(a promoter of tumor cell growth) Excretion: Feces
                       Hypercalcemia
            - Estrogenic-like activity in endometrium and bone
           Thromboembolism
          Resistance:
            - Downregulation of estrogen receptors
            - Possible change in affinity
Leuprolide            Mechanism of action:  testicular and ovarian Administration:
      Palliative treatment of advanced  Initial stimulation of FSH and LH release
Goserelin         steroidogenesis                      - Leuprolide: SC daily or IM depot form
prostate cancer                    lead to  testosterone levels, resulting in
            - LHRH agonists, but w/chronic administration, - Goserelin: Slow release implant
                             - Tumor flare
              pituitary cells are desensitized (they downregulate Metabolism/Excretion: Not
determined                                   - Hematuria
              GnRH receptors) and  lead to a  in FSH and LH
            - Urinary tract obstruction
          Resistance: Unknown                                                                     
Rx w/antiandrogen (i.e. flutamide)
                                                                                   Impotence, 
libido
                                                                                   Peripheral edema
Flutamide             Mechanisms of action:
      Hot flashes
           - Inhibits uptake of androgen
          Gynecomastia
           - Inhibits nuclear binding of androgen in target tissue
                     Hepatotoxicity
         Resistance: Unknown

Miscellaneous

Drug            Mechs of Action/Resistance              Pharmacokinetics                   Uses
          Adverse Effects
Procarbazine Mechanism of action: Inhibits DNA/RNA synthesis; Admin: Oral, parental
      Hodgkin’s disease (part of MOPP)  Nausea, vomiting, diarrhea
            also cuts DNA                    Distribution: Quickly distributes betw. plasma & CSF
                      Myelosuppression
            - May possibly involve free radical oxidation Metabolism: Oxidation to azo
derivative and H2O2;                          Psychic disturbances (it inhibits MAO)
            - Inhibits monoamine oxidase (MAO)          Excretion: Urine (metabolites and parent
drug)                           - Warn pt. against eating foods containing
          Resistance: Unknown
tyramine (aged cheeses, etc)
                                                                                  Disulfuram-like
reaction w/alcohol
                                                                                 Mutagenic (non-
lymphocytic)
                                                                                  Teratogenic
L-asparaginase       Mechanism of action: Hydrolyzes blood asparagine, Admin: IV or IM (b/c it
is destroyed by gastric  ALL (w/vincristine and prednisone)  Hypersensitivity (b/c it’s a
foreign protein)
            thus depriving cells of a required AA        enzymes)
       clotting factors
           Resistance: Inactivation of enzyme by protease Metabolism/Excretion: Undefined
                      Pancreatitis
                                                                                 Neurotoxicity
Hydroxyurea Mechanism of action: Inhibits ribonucleotide         Admin/Absorption: Oral; well
absorbed         Busulfan-resistant chronic granulocytic  BM suppression (leukopenia):
            reductase (thus preventing conversion of        Distribution: Very well, even to CSF
        leukemia                 - Dose-limiting
            ribonucleoside diphosphates to the corresponding Excretion: Urine
      Head and neck cancer (w/radiotherapy)  Megaloblastosis
            deoxyribonucleotide diphosphate)                                     Polycythemia
vera             Dermatologic problems (scaling and
                                                             Sickle cell anemia (b/c it causes the
atrophy of skin, hyperpigmentation,
                                                              body to produce fetal Hb)
nail damage, erythema) w/chronic therapy
                                                                                 Teratogenic
Pharmacology Review Sheets: Cancer chemotherapy drugs, p.7 – By excretion and major
side-effects

Renal Excretion                                     Biliary/Fecal Excretion
(Dactinomycin – minor route)            Gemcitabine                Vinca alkaloids (vincristine,
vinblastine, vinorelbine)
Bleomycin                     Cyclophosphamide                Taxanes (paclitaxel, docetaxel)
Etoposide                 Chlorambucil              Dactinomycin (major route of excretion)
Topotecan                     Cisplatin                  Anthracyclines (doxorubicin,
daunorubicin)
Methotrexate              Prednisone                     5-fluorouraci (5-FU)
6-mercaptopurine (6-MP)            Procarbazine               Capecitabine
Fludarabine               Hydroxyurea               Tamoxifen
Cytarabine

Bone marrow suppression                            Bone marrow suppression, continued
               NO bone marrow suppression
Vinblastine         myelosuppression granulocytopenia     Fludaribine
     myelosuppression                Vincristine
Vinorelbine         myelosuppression granulocytopenia     5-fluorouracil (5-FU)
     leukopenia                      Bleomycin
Paclitaxel          neutropenia                Cytarabine            myelosuppression
           Capecitabine
Docetaxel                neutropenia               Gemcitabine       myelosuppression
           Prednisone
Dactinomycin        pancytopenia                Mechlorethamine       severe BM suppression
          Tamoxifen
Doxorubicin         myelosuppression                 Cyclophosphamide      leukopenia
               Leuprolide
Daunorubicin        myelosuppression                 Chlorambucil     BM suppression
          Goserelin
Etoposide           myelosuppression                 Cisplatin        leukopenia,
thrombocytopenia              Flutamide
Topotecan                neutropenia                 Rituximab             neutropenia,
thrombocytopenia              L-asparaginase
Methotrexate        thrombocytopenia                 Trastuzumab      leukopenia, anemia
6-mercaptopurine (6-MP)       leukopenia, thrombocytopenia            Procarbazine
     myelosuppression
6-thioguanine (6-TG)          leukopenia, thrombocytopenia            Hydroxyurea
     leukopenia

Cardiovascular toxicities          Pulmonary toxicities         Hepatotoxicity
     Peripheral neuropathy         Contraindicated in pregnancy
Paclitaxel              Bleomycin                     6-mercaptopurine (6-MP)
     Vincristine                   Methotrexate (abortifacient)
Doxorubicin             Fludaribine              Cytarabine (hepatic dysfunction)       Paclitaxel
               Procarbazine (teratogenic)
Daunorubicin                                                    Docetaxel
     Hydroxyurea (teratogenic)
5-Fluorouracil (5-FU)                                                     Fludaribine
Trastuzumab                                                     Cisplatin
Rituximab (cardiac arrhythmias)

Alterations of sexual function
     Mutagenic/Secondary malignancies
Cyclophosphamide             Females: Amenorrhea, sterility
     Doxorubicin
                   Males: Testicular atrophy, sterility
     Daunorubicin
Chlorambucil            Sterility                                                Etoposide
     AML
Cisplatin               Sterility
     Cyclophosphamide
Tamoxifen                    Signs of menopause (hot flashes)
     Tamoxifen          Poss. endometrial cancer
Leuprolide, Goserelin             Impotence,  libido
     Procarbazine Non-lymphocytic leukemia
Flutamide                    Hot flashes, gynecomastia

Other adverse side-effects                                      Other adverse side effects,
continued
 Vincristine, cyclophosphamide          Inappropriate ADH secretion               Cisplatin
          Renal tubular damage (nephrotoxicity)
 Docetaxel              Fluid retention                    Cisplatin            Ototoxicity
 Dactinomycin                Colors urine red                        Cisplatin
     Electrolyte disturbances (hypocalcemia, hypomagnesemia,
 Methotrexate                Megaloblastic anemia (b/c of folate deficiency)
       hypokalemia, hypophosphatemia)
 Methotrexate                Crystaluria (at high doses)                   Prednisone
     Cataracts, glaucoma
 6-mercaptopurine (6-MP)         Potentiated by allopurinol (cp. 6-TG, which is not)         
Prednisone               Hyperglycemia
 Fludarabine            Autoimmune hemolytic anemia (fatal!!)                  Tamoxifen
     Hypercalcemia
 5-Fluorouracil (5-FU)       Acute cerebellar syndrome (reversible)            Procarbazine
     Psychic disturbances (MAO inhibitor)
 5-Fluorouracil, capecitabine          Palmar-plantar erythrodysesthesia            Procarbazine
          Disulfuram-like effect
                    (erythematous desquamation of palms/soles)
 Methotrexate, cytarabine        Seizures w/intrathecal administration
 Mechlorethamine             Latent viral infections (zoster) reappear
 Cyclophosphamide                Hemorrhagic cystitis
Pharmacology Review Sheets: Immunosuppressive Drugs, p.1

Glucocorticoids

Drug            Mechs of Action/Resistance              Pharmacokinetics                    Uses
         Adverse Effects
Prednisone            Mech of action: Non-specific immune suppression Administration: Oral
                 Leukemias and lymphomas            Ophthalmic: Cataracts, glaucoma
Prednisolone      - Peripheral lymphocytopenia; T-cells > B-cells Distribution: Binds to plasma
albumin and transcortin                         GI: ulcers, pancreatitis
           - Suppresses production of IL-1, IL-2        Metabolism: Undergoes 11--hydroxylation
in liver                         Hyperglycemia
           - Inhibits T-lymphocyte proliferation           to prednisolone; glucuronidation later on.
                            Osteoporosis
            Intracellular mechanism:               Excretion: Urine (parent drug and metabolites)
                       Alterations in mood and behavior
              - Prednisolone reacts w/cyt. glucocort. receptor
          Susceptibility to infections
              - Receptor-glucocorticoid complex is transported
                 to the nucleus, interacting w/DNA  effects
         Resistance: Not established

Antimetabolites
Drug             Mechs of Action/Resistance               Pharmacokinetics                    Uses
           Adverse Effects
Azathioprine Mechanism of action: Interferes in de novo synthesis Administration: Oral, IV
            Adjunct to prevention of rejection in  Bone marrow suppression – leukopenia,
  Pro-drug of 6-MP           of purine (non-specific); prodrug is reduced to 6-MP Metabolism:
Rapidly metabolized to either thiouric       renal transplantation          thrombocytopenia
             and then to TIMP                     acid or methylated derivatives in liver and RBCs
            Management of severe rheumatoid  Hepatotoxicity
             - Lymphocytes most affected b/c of dependence on Excretion: Urine
arthritis which doesn’t respond to other  Reduce dose if allopurinol is also being
               de novo purine synthesis; T- & B-cells both affected
medication                    administered, b/c it can potentiate effects
           Resistance: Similar to that of 6-MP
      Nausea, vomiting
                                                                                     Risk of infection
Mycophenolate         Mechanism of action: Interferes w/de novo synthesis
     Administration/Absorption: Oral (complete) or IV            Prophylaxis against rejection in
kidney,  GI: Vomiting, diarrhea, rare GI
  mofetil          of purines (non-specific)              Distribution: MPA is 97% bound to serum
albumin, heart transplants in combination with hemorrhage (3%)
             - Prodrug is metabolized to mycophenolic acid but no displacement reactions have
been reported       cyclosporine or glucocorticoids  Sepsis, CMV
               (MPA), which inhibits inosine monophosphateMetabolism: Liver, glucuronidation
        - Can be used to treat acute rejection  Abdominal pain
              dehydrogenase, which catalyzes formation of Excretion: Urine (glucuronide)
         refractory episodes         Leukopenia, thrombocytopenia
              guanosine from IMP                                                        
Mutagenic, but less than azathioprine
            - Inhibits glycosylation of adhesion molecules
      Drug Interactions:
            - Inhibits production of Abs, possibly cytokines
       - Acyclovir/gancyclovir: may compete for
                                                                                 tubular secretion
                                                                               - Mg2+ and Al3+
antacids  oral absorption
                                                                               - Cholestyramine
Rx   blood levels

Antibodies

Antibody       Mechs of Action/Resistance               Pharmacokinetics                  Uses
           Adverse Effects
Antilymphocyte & Mechanism of action: Binds to surface of circulating Admin: IM, IV (over
several hours)       Treatment of allograft rejection during     Foreign proteins – can lead to
fever, chills,
  antithymocyte       T-cells; leads to opsonization/phagocytosis in Duration of action: t½ = 3-9
days             acute phase & steroid-resistant rejections   leukopenia, thrombocytopenia,
rashes
  globulins      liver and spleen
Muromonab-CD3 Mechanisms of action:                         Admin: IV, usually following
methylprednisone,  Prevention of acute rejection (depletes             Anaphylaxis
             - Blocks CD3 receptor so CD3 can’t bind                diphenhydramine, and acetaminophen
to alleviate      T-cells from donor BM before BM  Cytokine release syndrome (first dose):
             - Binds T-cells to inhibit T-cell participation in cytokine release syndrome
transplant)                  - Mild flu-like illness to life-threatening
               immune response (this will deplete the T-cells)
               shock-like reaction; high fever
                                                                                       CNS: seizures,
encephalopathy, cerebral
                                                                                        edema, aseptic
meningitis, headache
                                                                                       CMV infection
                                                                                       Contraindicated
in patients w/seizure
                                                                                        history,
uncompensated heart failure,
                                                                                        pregnant or
breast feeding
Daclizumab Mechanism of action: Blocks IL-2 receptor                   Duration of action: Basiliximab >
Daclizumab                            No adverse reactions…yet
Basiliximab                                                                                 Do not seem
to cause Ab formation
Pharmacology Review Sheets: Immunosuppressive Drugs, p.2

Signal Induction Inhibitors

Drug            Mechs of Action/Resistance                  Pharmacokinetics                  Uses
          Adverse Effects
Cyclosporine Mechanism of action: Specific inhibition of              Admin: Oral (by capsules and
microemulsion)          Prevention of rejection after kidney,  Nephrotoxicity (reversible w/dose )
             T lymphocytes                        Absorp: Microemulsion absorbed more completely
     heart, liver transplantation (also  Hepatotoxicity (reversible w/dose  )
             - Cyclosporine enters cell, binds to cyclophilin; Distribution: Varies among
individuals; check       used for pancreas)                  Lymphoma (reversible w/dose )
                                                           2+
             - This complex interacts w/calcineurin, Ca and            blood levels                 -
Always given with:            Infection (esp. CMV)
               calmodulin, inhibiting the dephosphorylation of         - 50% taken up by RBC; 4-9%
by lymphocytes             - Glucocorticoids + azathioprine, or - Do NOT reduce dose; makes it
worse!
               NFATc; this interrupts the formation of IL-2 - 90% of plasma fraction bound to
proteins             - Mycophenolate mofetil           Others: Seizures, Hirsutism, Gingival
               (b/c genes aren’t induced)                (primarily lipoproteins)              Severe
rheumatoid arthritis or               hyperplasia, HTN, tremor
             -  IL-2   promotion of T-cell clonal expansion Metabolism: CYP3A isozyme
                         psoriasis that doesn’t respond to  Drug Interactions:
                                         - 30 metabolites identified              usual therapies
                                           in cyclosporine concentrations:
                                    Excretion: Bile (mostly metabolites)
    2+
- Ca channel blockers: diltiazem,
                                                                                nicardipine,
verapamil
                                                                            - Antifungals:
fluconazole, itraconazole,
                                                                              ketoconazole.
                                                                            - Antibiotics:
erythromycin,

clarithromycin
                                                                            -
Glucocorticoids: methylprednisolone
                                                                            - Others:
allopurinol, bromocriptine,
                                                                                danazol,
metocopramide
                                                                             Foods:
Grapefruit juice.
                                                                             in
cyclosporine concentrations:
                                                                            - Antibiotics:
nafcillin, rifampin
                                                                            -
Anticonvulsants: carbamazepine,
                                                                                     phenobarbital
and phenytoin.
                                                                                 - Other drugs:
octreotide, ticlopidine
                                                                                Potentiation of
renal dysfunction:
                                                                                 - Antibiotics:
gentamicin, tobramycin,
                                                                                     vancomycin,
tri/sulfa
                                                                                 -
Antineoplastics: melphalan
                                                                                 - Antifungals:
amphotericin B,
                                                                                     ketoconazole.
                                                                                 -
Antiinflammatories: diclofenac,
                                                                                     naproxen,
sulindac
                                                                                 - GI agents:
cimetidine, ranitidine
                                                                                 -
Immunosuppresants: tacrolimus
Tacrolimus (FK506)         Mechanism of action: Similar to cyclosporine but    Admin/Absorption:
Oral, IV; best abs. in fasted state  Approved for liver & kidney transplants,  Hypersensitivity
            100 times more potent                - Fat  absorption                   but have been
used for other organs       Neurotoxicity (tremor, headache, seizures,
            - Binds to a distinct cyclophilin, FKBP-12         Distribution: Levels variable; highly
bound to RBCs,         - Used to switch from cyclosporine in coma, delirium) at high doses
              ( FK binding protein) which binds to calcineurin,        plasma albumin, a1-acid
     glycoprotein             cases where a renal transplant is failing,  Nephrotoxicity (high doses)
              Ca2+ and calmodulin to result in  IL-2          Metabolism: CYP3A. Mostly
metabolized.             and cyclosporine may be involved  Hyperkalemia
                                     Excretion: Urine                                        
Hyperglycemia  insulin-dependent DM
                                                                                    Hypertension
                                                                                    Infections
                                                                                    Lymphoma
                                                                                    Drug
Interactions: Same as cyclosporine
Sirolimus            Metabolism of action: Interference w/G1 phase Administration: Oral (fasting
state)           Prevention of rejection in patients w/  High blood chol., hypertriglyceridemia
  (rapamycin) progression in lymphoid and other cells                Absorption: Food interferes
w/absorption.           renal transplants (w/cyclosporine and  HTN
            - Binds to FKBP-12, but inhibits mTOR (a kinase) Metabolism: CYP3A isozyme
             corticosteroids)               Rash, acne
                                     Excretion: Urine                                        
Anemia, thrombocytopenia
                                                                                    Hypokalemia
                                                                           Joint pain
                                                                           Drug interactions:
Same as cyclosporine
                                                                            and tacrolimus.
Pharmacology Review Sheets: Immunosuppressive Drugs, p.3

Renal Excretion             Biliary/Fecal Excretion
Prednisone                  Cyclosporine
Prednisolone
Azathioprine
Mycophenolate mofetil
Tacrolimus
Sirolimus

Bone marrow suppression                             Mutagenic
     Contraindicated in pregnancy
Azathioprine       leukopenia, thrombocytopenia              Azathioprine
     Muromonab-CD3
Mycophenolate mofetil leukopenia, thrombocytopenia                Mycophenolate mofetil (<
than azathioprine)
Antilymphocyte and           leukopenia, thrombocytopenia             Cyclosporine
(lymphomas, reversible)
  antithymocyte globulins                           Tacrolimus (lymphomas)
Sirolimus          anemia, thrombocytopenia
Nephrotoxicity              Hepatotoxicity              Neurotoxicity        Infections
(Exception: Sirolimus)
Cyclosporine (reversible)       Cyclosporine (reversible)       Tacrolimus
    Prednisone
Tacrolimus                                                  Prednisolone
                                                        Azathioprine
                                                        Mycophenolate mofetil CMV, HSV
                                                        Muromonab-CD3         CMV
                                                                     Cyclosporine
    CMV
                                                        Tacrolimus

				
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Description: Pharmacology Cancer Chemotherapy and Immunosuppressive Drugs