Docstoc

ANTICANCER DRUGS

Document Sample
ANTICANCER DRUGS Powered By Docstoc
					ANTICANCER DRUGS
I. Classical chemotherapy
    1. Cytostatics
    2. Enzymes
    3. Hormons and related agents (GKs, progestins, estrogens, androgens, antiandrogens,
        antiestrogens- SERMS, SERDs, aromatase inhibitors)
II. Guided therapy
    1. Protein tyrosine kinase inhibitors
    2. Angiogenesis inhibitors
    3. Proteasome inhibitors
    4. Histone deacetylase inhibitors
    5. Farnesyl transferase inhibitors
    6. Differentiating agents A. Retinoids B. Arsenic trioxide (ATO)
III. Immunotherapy- biological response modifiers
    1. Monoclonal antibodies
    2. Immunological response modifiers
    A. Cytokines, immunotoxin
    B. Interferones

A typical malignant cell spends 40% of time in G1 phase, 39% in S phase, 19% in G2 phase,
2% in M phase of the cell cycle.
I. Classical chemotherapy
1. Cytostatics:
Anticancer drugs exert their action on cells traversing the cell cycle: CCS (cell cycle-specific
drugs).
Anticancer drugs can sterilize tumor cells whether they are cycling or resting in the G0
compartment; kill both G0 and cycling cells (cycling cells are more sensitive): CCNS (cell
cycle- nonspecific drugs)
CCS drugs:
    I.     Antimetabolites (S phase)
           1. capecitabine 2. cladribine 3. clofarabine 4. cytarabine (ara- C) 5. fludarabine
           6.5- fluorouracil (5-FU) 7. gemcitabine 8. 6- mercaptopurine (6- MP)
           9. methotrexate (MTX) 10. 6- tioguanine (6- TG)

   II.   Epipodophyllotoxins (topoisomerase II inhibitor) (G1- S phase)
         1. etoposide
  III.   Taxanes (M phase)
         1. albumin- bound paclitaxel 2. docetaxel 3. paclitaxel
  IV.    Vinca alkaloids (M phase)
         1. vinblastine 2. vincristine 3. vinorelbine
  V.     Antimicrotubule inhibitor (M phase)
         1. ixabepilone
  VI.    Antitumor antibiotics (G2- M phase)
         1. bleomycin
CCNS drugs:
  VII.    Alkylating agents
         1. altretamine 2. bendamustine 3. busulfan 4. carmustine 5. chlorambucil
         6. cyclophosphamide 7. dacarbazine 8. lomustine 9.mechlorethamine
        10.melphalan11. temozolomide 12.thiotepa
   VIII.   Anthracyclines- antitumor antibiotics 1. daunorubicin 2. doxorubicin 3. epirubicin
           4. idarubicin 5. mitoxantrone
   IX.     Antitumour antibiotics- other
           1. dactinomycin 2. mitomycin
   X.      Camptothecins (topoisomerase I inhibitors)
           1. irinotecan 2. topotecan
   XI.     Platinum analogs
           1. carboplatin 2. cisplatin 3. oxaliplatin
Combination chemotherapy:
   1. maximal cell kill within the range of toxicity tolerated by the host for each drug as
       long as dosing is not compromised
   2. broader range of interaction between drugs and tumor cells with different genetic
       abnormalities in a heterogeneous tumor population
   3. prevents or slow the subsequent development of cellular drug resistance
The following factors are taken into account when drugs for a combination therapy are
choosen: 1. efficacy 2. toxicity 3. optimum scheduling 4. mechanism of interaction
         5.avoidance of arbitrary dose changes 6. cellular drug resistance (primary- absence
           of response on the first exposure, acquired- in response to an exposure to a given
           anticancer drug)


I ANTIMETABOLITES (CCS, S phase):
Quantitative differences in metabolism between cancer cells and normal cells→ cancer cells
more sensitive to the antimetabolites
   1. Antifolates
   A. methotrexate (MTX, i.v., intrathecal, p.o.)
    Mechanism of action: a. a folic acid analog- binds with dihydrofolate reductase
   (DHFR)→ interferention with the synthesis of tetrahydrofolate (THF)= a key one- carbon
   carrier in synthesis of thymidylate, purine nucleotides, serine and methionine→
   interferention with DNA, RNA and cellular proteins synthesis; b. MTX→ intracellular
   formation of polyglutamates (addition of up to 5-7 glutamate residues)- katalyzed by
   folypoliglutamate synthase (FPGS) → polyglutamates exert the inhibitory effects on
   enzymes involved in purine nucleotide and thymidylate biosynthesis within cancer cells→
   ↑MTX cytotoxic action;
   aspirin, NSAID, penicillins, cephalosporins inhibit the renal excrection of MTX!!! The
   MTX effect- reversed by 5- formyltetrahydrofolate (reduced folate leucovorin) or by L-
   leucovorin→ leucovorin rescue→ in conjunction with high-dose MTX (to rescue normal
   cells from MTX toxicity)or in MTX overdose;
   The adverse effects: mucositis, diarrhea, myelosuppression (neutropenia,
   thrombocytopenia)
   Clinical application: breast cancer, head and neck cancer, osteogenic sarcoma, nervous
   system lymphoma, non-Hodgkin’s lymphoma, bladder cancer, choriocarcinoma
   B. pemetrexed- the inhibition of thymidylate synthase;
   The adverse effects: myelosuppression, skin rash, mucositis, diarrhea, the hand- foot
   syndrome (recurrent painful swelling on the hands and feet)- dexamethasone treatment
   needed
   folic acid and vit. B12 supplementation reduce its toxicity
   Clinical application: mesothelioma, non- small cell lung cancer
   2. Fluoropyrimidines
   A. 5-fluorouracil (5-FU), i.v., t½= 10- 15 min., prodrug
Mechanism of action: inhibits thymidine synthase; incorporation of its metabolite=FUTP
into RNA→ alteration in RNA processing; incorporation of its metabolite= FdUTP into
DNA → inhibition of DNA synthesis and function
The adverse effects: nausea, diarrhea, mucositis, bone marrow depression, neurotoxicity,
the hand-foot syndrom
Clinical applications: colorectal cancer, anal cancer, brest cancer, gastroesophageal
cancer, head and neck cancer, hepatocellular cancer
B. capecitabine- prodrug
Mechanism of action: as 5-FU
The adverse effects: as 5-FU but the incidence is less
Clinical application: as 5-FU + pancreatic cancer
3. Deoxycytidine analogs
A. cytarabine (ara-C), continuous infusion over a 5-7 day period→ ara-CTP= the main
    cytotoxic metabolite)
Mechanism of action: inhibits DNA polymerase ᾳ→ blockade of DNA synthesis;
inhibits DNA polymerase ϐ→ blockade of DNA repair; ara-CTP→ incorporated in DNA
strand→ inhibition with DNA chain elongation; inhibits ribonucleotide reductase → ↓
formation of dNTPs
The adverse effects: nausea, vomiting, myelosuppression, cerebellar ataxia
Clinical applications: acute muelogenous leukemia, acute lymphoblastic leukemia,
chronic lymphocytic leukemia in blast crisis
B. gemcitabine
Mechanism of action: inhibits DNA synthesis and repair; inhibits ribonucleotide
reductase→↓ formation of dNTPs; gemcitabine incorporation into DNA→ inhibition of
DNA synthesis and function
The adverse effects: nausea, vomiting, diarrhea, myelosuppression
Clinical applications: pancreatic cancer, bladder cancer, breast cancer, non-small cell lung
cancer, ovarian cancer, non-Hodgkin’s lymphoma, soft tissue sarcoma
4. Purine antagonists
A. 6-thiopurines: 6-mercaptopurine, 6-thioguanine- inhibit purine nucleotide synthesis;
    incorporation of trifosphate into RNA and into DNA
The adverse effects: myelosuppression, hepatotoxicity
Clinical applications: acute myelogenous leukemia, acute lymphoblastic leukemia (6-
thioguanine)
B.fludarabine (prodrug)
Mechanism of action: active metabolite (triphosphate form)→ 1. inhibits DNA
polymerase ᾳ→ blockade of DNA synthesis; inhibits DNA polymerase ϐ→ blockade of
DNA repair; 2. incorporated into DNA→ inhibition of DNA synthesis and function;
3.diphosphate form→ inhibits ribonucleotide reductase→ inhibition of essential
deoxyribonucleotide triphosphates; 4. induction of apoptosis of susceptible cells
Clinical applications: low-grade non-Hodgkin’s lymphoma, chronic lymphocytic
leukemia (CLL)
The adverse effects: myelosuppression, inhibition of CD4 and CD8 T cells, ↑risk of
oportunic infections (fungi, herpes, Pneumocystis jiroveci pneumonia (PCP)→ PCP
prophylaxis needed- with trimethoprrim-sulfamethoxazole (double strength) at least three
times a week, this should be continue for up to one year after stopping fludarabine
therapy; fever, myalgias, arthralgias
C. cladribine- high specificity for lymphoid cells, prodrug
     Mechanism of action: triphosphate form)→ 1. inhibits DNA polymerase ᾳ→ blockade of
     DNA synthesis; inhibits DNA polymerase ϐ→ blockade of DNA repair 2. incorporated
     into DNA
     The adverse effect: myelosuppresia, immunosuppressive effect (decrease in CD4 and
     CD8 T cells lasting for over 1 year); nausea, vomiting
     Clinical application: hairy cell leukemia, chronic lymphatic leukemia, non-hodgkin’s
     lymphoma
     D. clofarabine is a purine nucleoside
     The adverse effects: tumor lysis syndrome (TLS): clofarabine quickly kills leukaemia
     cells in the blood. The body may react to this. Symptoms include fast breathing, fast heart
     beat, low blood pressure, and fluid in the lungs. TLS is very serious and can lead to death
     if it is not treated right away; myelosuppression; nausea,vomiting, diarrhea→
     dehydratation; fever, livre and kidney damage
     Clinical applications: acute lymphoblastic leukaemia (ALL) in children, acute myeloid
     leukaemia (AML)
     II. EPIPODOPHYLLOTOXINS (G1-S phase)
     Mechanism of action: topoisomerase II inhibition→ DNA damage through strand breake
     induced by the formation of a ternary complex of drug, DNA and enzyme
     A. etoposide (i.v., p.o., oral bioavailability = 50%)
     The adverse effects: 1. acute: nausea, vomiting, hypotension, 2. delayed: alopecia,
      myelosuppression
Clinical applications: germ cell cancer, small-cell and non- small cell lung cancer,
Hodgkin’s and non-Hodgkin’s lymphomas, gastric cancer, high doses: transplant setting for
breast cancer and lymphomas
     B. teniposide (as etoposide; related drug outside USA)
III. TAXANES (M phase)- alkaloids derived from the Pacific yew (paclitaxel) and European
yew (docetaxel- semisynthetic)
A. paclitaxel
Mechanism of action: high-affinity binding to microtubules with enhancement of tubulin;
polymerization→ mitotic spindle poison→ inhibition of mitosis and cell division;
Metabolized by P450
The adverse effects: 1. acute: nausea, vomiting, hypotension, arrhythmias, hypersensitivity in
5% of patients (premedication with dexamethasone, diphenhydramine and H2-blocker
needed), 2. delayed: myelosuppression, peripheral sensory neuropathy
Clinical applications: breast cancer, non-small cell and small cell lung cancer, ovarian
cancer, gastroesophageal cancer, prostate cancer, bladder cancer, head and neck cancer
B. albumin-bound paclitaxel formulation (Abraxane): no hypersensitivity reactions→ no
premedication with dexamethasone, reduced myelosuppressive effect, reduced neurotoxicity
(easier to reverse) compared to paclitaxel
Clinical applications; metastatic breast cancer
C. docetaxel (the adverse effectsas paclitaxel)
Clinical applications: advanced breast cancer, head and neck cancer, non-small and small
cell lung cancer, gastric cancer, platinum-refractory ovarian cancer, bladder cancer
Clinical applications: metastatic breast cancer
IV VINCA ALKALOIDS (M phase)
Mechanism of action: inhibition of tubulin polymerization→ disruption of assembly of
microtubules (part of cytoskeleton and of mitotic spindle)→ mitotic arrest in metaphase→ no
cell division→ cell death
A.vinblastine- derived from Vinca rosea
Metabolized by P450
The adverse effects: 1. acute: nausea, vomiting, 2. delayed: myelosuppression, mucositis,
alopecia, vascular events, SIADH (syndrome of inappropriate antidiuretic hormone secretion)
Clinical applications: Hodgkin’s and non-Hodgkin’s lymphoma, germ cell cancer, breast
cancer, Kaposi’s sarcoma
B.vincristine- derived from Vinca rosea
The adverse effects: 1. acute; none, 2. delayed: neurotoxicity (peripheral sensory neuropathy,
autonomic nervius system dysfunction→ orthostatic hypotension, urinary retention, paralytic
ileus, constipation), cranial nerve palsies, ataxia, seizures, coma; myelosuppression (milder,
less significant than with vinblastine
Clinical applications: remission induction in acute lymphoblastic leukemia, Hodgkin’s and
non-hodgkin’s lymphomas, multiple myeloma, rhabdomyosarcoma, neuroblastoma, Ewing’s
sarcoma, Wilm’s tumor
C. vinorelbine- semisynthetic
The adverse effects: 1. acute; nausea, vomiting, 2. delayed: myelosuppression (neutropenia),
neurotoxicity, constipation, transient elevation in liver function tests, SIADH
Clinical applications: non-small cell lung cancer, breast cancer, ovarian cancer

V MICROTUBULE INHIBITOR (not taxane, novel), (M phase):
 ixabepilone- semisynthetic analog of epothilone B
Mechanism of action: binds directly to ϐ-tubulin subunits on microtubules→ inhibition of
normal microtubule dynamics; activity in drug- resistant tumors
Adverse effects: myelosuppression, hypersensitivity reactions, neurotoxicity (peripheral
sensory neuropathy)

VI ANTITUMOR ANTIBIOTICS (G2-M phase)
bleomycin (s.c., i.m., i.v.)- small peptide with DNA-binding region and iron-binding
domain→ DNA-bleomycin-Fe complex→ oxidation→ chromosomal abberations
Mechanism of action: binds to DNA→ single-strand and double-strand breaks→ inhibition of
the DNA synthesis
The adverse effects: 1. acute: allergic reactions, fever, hypotension, 2. delayed: skin toxicity,
pneumonitis (cough, dyspnea, dry inspiratory crackles) pulmonary fibrosis (X-ray→
infiltrates), mucositis, alopecia
Clinical applications: Hodgkin’s and non-Hodgkin’s lymphomas, germ cell tumor, head and
neck cancer, squamous cell skin/cervix cancer
VII ALKYLATING AGENTS (CCNS):
Cells are most succeptible to alkylation in late G1 and S phase , blockage in G2 phase.
Mechanism of action: transfer their alkyl groups to various cellular constituents→ chemical
reaction with sulfhydryl, amino, hydroxyl, carboxyl, phosphate groups of cellular constituents
(DNA alkylation within the nucleus, N-7 position of guanine, especially→ cell death).
Resistance: DNA lesions repair, ↓ transport of the drug into the cell, ↑production of
glutathione (needed to the conjugation of the alkylating agent, ↑glutathione S-transferase
activity (needed to catalyse of conjugation)
The adverse effects: 1. acute: GI (nausea, vomiting), 2. delayed: bone marrow depression
(leucopenia, thrombocytopenia, bleeding), infertility, alopecia, busulfan→ skin pigmentation,
pulmonary fibrosis, adrenal insufficiency; carmustine, lomustine → interstitial lung disease,
interstitial nephritis; temozolomide→ photosensitivity, elevation in liver function tests;
dacarbazine→ CNS toxicity→ neuropathy, ataxia, lethargy, confusion;
carcinogeneticy→ secondary malignancies (acute myelogenous leukemia).
Preparations: cyclophosphamide (high oral bioavailability→ p.o., i.v., inactive in parent
form→ activation via microsomal P450 enzymes→ active metabolites delivered to tissues→
nonenzymatic cleavage→ phosphoramide mustard + acrolein→ hemorrhagic cystitis
Clinical applications: Hodgkin’s and non- Hodgkin’s lymphoma (mechlorethamine,
chlorambucil, carmustine), non Hodgkin’s lymphoma (cyclophosphamide), breast cancer,
ovarian cancer, soft tissue sarcoma, neuroblastoma, Wilm’s tumor, rhabdomyosarcoma
(cyclophosphamide), chronic myelogenous leukemia (busulfan), chronic lymphocytic
leukemia (chlorambucil), brain cancer (carmustine, temozolomide), melanoma
(temozolomide, dacarbazine)
VIII Anthracyclines (i.v. administered on an every-3- week schedule, low-dose weekly,
72- 96 hour continuous infusion)
Mechanism of action:1. inhibition of topoisomerase II 2. high-affinity binding to DNA
through intercalation→ inhibition of DNA and RNA synthesis 3. generation of semiquinone
free radicals and oxygen free radicals through an iron dependent enzymatic reaction→
cardiotoxicity also!!! 4. binding to cellular membranes→ altering fluidity and iron transport
The adverse effects: 1. acute: nausea, vomiting, fever, diarrhea, cardiotoxicity (arrhythmias,
conduction abnormalities, pericarditis, myocarditis within 2-3 days of the therapy- transient,
asymptomatic) 2. delayed: daunorubicin, doxorubicin, idarubicin→ cardiotoxicity- dilated
cardiomyopathy→ heart failure (dose- dependent increased free radicals production in the
myocardium) , alopecia, myelosuppression (neutropenia!); mitoxantrone→ mucositis (dose-
limiting), alopecia; a “radiation recall reaction” (erythema, desquamation of the skin observed
at sites of prior radiation therapy)
Clinical applications: brest (doxorubicin, epirubicin, mitoxantrone), endometrium, testicle,
thyroid, stomach, blader, liver, lung cancer, soft tissue sarcomas, childhood cancers
(neuroblastoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma), hematological
malignancies (acute lymphoblastic leukemia, multiple myeloma, Hodgkin’s, non-Hodgkin’s
lymphomas (doxorubicin); acute myeloid leukemia (daunorubicin, idarubicin); advanced,
hormone-refractory prostate cancer, low-grade non-Hodgkin’s lymphoma (mitoxantrone)
mitomycin (CCNS):
The adverse effects: 1. acute: nausea, vomiting 2. acute: myelosuppression, mucositis,
anorexia, fatigue, hemolytic- uremic syndrome
Clinical applications: superficial bladder cancer, gastric cancer, breast cancer, non- small
cell lung cancer, head and neck cancer
IX Antitumor antibiotics (CCNS)- other
A. dactinomycin
The adverse effects: alopecia, nausea and vomiting (occurs within hours to days), mouth
sores, diarrhea, follicular acne, redness of the skin, darkening of the skin where previous
radiation treatment has been given (radiation recall), hepatotoxicity
Clinical applications: Wilms' tumor, rhabdomyosarcoma, germ cell tumors, gestational
trophoblastic disease, Ewing's sarcoma, testicular cancer, melanoma, choriocarcinoma,
neuroblastoma, retinoblastoma, uterine sarcomas, Kaposi's sarcoma, soft tissue sarcoma
B. mitomycin- prodrug
Mechanism of action: 1. cross-link DNA (alkylating agent), 2. formation of oxygen free
radicals→ DNA
The adverse effects: 1.acute: nausea, vomiting, 2. delayed: myelosuppression, mucositis,
anorexia, fatigue, hemolytic- uremic syndrome (microangiopathic hemolytic anemia,
thrombocytopenia, renal failure, interstitial pneumonitis)
Clinical applications: superficial bladder cancer, gastric cancer, breast cancer, non-small cell
lung cancer, head and neck cancer
X CAMPTOTHECINS (CCNS)
A. irinotecan
B. topotecan
Mechanism of action: inhibition of the activity of topoisomerase I (responsible for cutting
and religating single DNA strands→ DNA damage
The adverse effects: 1. acute: diarrhea, nausea, vomiting 2. delayed: myelosuppression
Clinical applications: small cell lung cancer (topotecan, irinotecan), ovarian cancer
(topotecan), colorectal cancer, gastroesophageal cancer, non- small cell lung cancer
( irinotecan)
 XI PLATINUM ANALOGS (CCNS):
Mechanism of action: 1.cytotoxic effect in the same manner as alkylating agents (DNA-
intrastrand and interstrand links) 2. binding of both cytoplasmic and nuclear proteins
 cisplatin, carboplatin (less renal and GI toxicity, intravenous hydration is not required during
therapy; myelosuppression! → used in refractory hematologic malignancies), oxaliplatin (no
cross resistance with cisplatin and carboplatin)
Clinical applications: solid tumors- non- small cell and small cell lung cancer, esophageal
and gastric cancer, head and neck cancer, genitourinary cancers- testicular, ovarian, bladder
ones (cisplatin), GI cancers, i.e.,colorectal cancer (oxaliplatin)
The adverse effects: 1. acute: nausea, vomiting, acute neurotoxicity (triggered and worsened
by exposure to cold- oxaliplatin) 2. delayed: myelosuppression, nephrotoxicity (cisplatin-
non- reversible), chronic neurotoxicity (dose dependent; reversible- oxaliplatin); ototoxicity
(cisplatin)



I.2. Enzymes
asparaginase- an enzyme- hydrolizes L-asparagine to aspartic acid + ammonia; tumor cell
lack asparagines synthase- need exogenous source of L-asparagine; asparaginase→ L-
asparagine depletion→ inhibition of protein synthesis→ for children with acute lymphoblastic
leukemia (normal cell can synthesize L-asparagine)
The adverse effects: hypersensitivity reaction (fever, chills, nausea, vomiting, skin rash,
urticaria, bronchospasm, respiratory failure, hypotension); ↑ risk of clotting/bleeding,
pancreatitis, neurologic toxicity (lethargy, confusion, hallucinations, coma); renal toxicity

I.3. Hormons and related agents (GKs, progestins, estrogens, androgens, antiandrogens,
antiestrogens- SERMS, SERDs, aromatase inhibitors)
    • hormones- essential for normal tissue growth and development
    • hormone- dependent neoplasms: breast , uterine, prostate glands, thyroid gland cancer
    • hormones→ cell division promotion
GKs: prednison, prednisolon, methylprednisolone
Somatostatin analogs: octreotide, lanreotide, vapreotide
Adrenal gland hormones synthesis inhibitors: mitotane, aminoglutetymide
Estrogens
Antiestrogens: SERMs (tamoxifen, toremifene), anastrozol, formestan, exmestane, SERDs
(fulvestrant)
Antiandrogens: cyproterone acetate, flutamide, bicalutamide
Progestagens: megestrole
GnRH long-acting analogs: gosereline, busereline, triptoreline, leuprolide
SERMs: bind to estrogen receptors→ either estrogenic or antiestrogenic effects on the
specific organ- tissue selective actions: beneficial estrogenic actions in bone, brain, liver
  + antagonist activity in breast, endometrium: tamoxifene, tamoxifene analogs: toremifene,
droloxifene, idoxifene, „fixed ring” compounds: raloxifene, lasofoxifene, arzoxifene,
miproxifene, levormeloxifene


 II. Guided therapy
7.Protein tyrosine kinase inhibitors
     genetic defect in the hematopoetic stem cells of bone marrow → hybrid bcr-abl fusion
     gene on chromosome 22 (Philadelphia chromosome)- encodes a tyrosine kinase mutant
     with unregulated, enhanced activity → promotion of cells proliferation→ chronic
     myelogenous leukemia (CML) Ph+→ Imatinib (Glivec) = tyrosine kinase inhibitor

8. Angiogenesis inhibitors and growth factor receptor inhibitors

A.cetuximab (chimeric monoclonal antibody against EGFR (the epidermal growth factor
receptor)→ inhibits downstream EGRF signaling; enhances response to chemotherapy and
radiotherapy
The adverse effects: 1. acute: infusion reaction, 2. delayed: hypomagnesemia, interstitial lung
disease, acneiform rash;for metastatic colon cancer, head and neck cancer, non-small cell lung
cancer
B.panitumumab- human monoclonal antibody against EGFR
The adverse effects as A. for colorectal cancer
C.gefitinib- inhibitor of the tyrosine kinase domain associated with EGFR; for refractory to
chemotherapy non-small cell lung cancer; metabolized by CYP 3A4
The adverse effects: 1. acute: hypertension, diarrhea, 2. acneiform skin rash, diarrhea,
anorexia, interstitial lung disease
D.erlotinib- as D + pancreatic cancer
E.bevacizumab- humanized monoclonal antibody against VGEF-A→ prevents VEGF-A from
interacting with VEGF-A receptors→ inhibits tumor vascular permeability, enhances tumor
blood flow and drug delivery (VEGF inhibitors- antiangiogenic agents- new class of
anticancer medication→ solid tumors treatment)
The adverse effects: 1. acute: hypertension, infusion reaction, 2. delayed: arterial
thromboembolic events, gastrointestinal perforations, impaired wound healing, proteinuria;
for colorectal cancer, breast cancer, non-small cell lung cancer, renal cell cancer
F.sorafenib- inhibitor of multiple receptor tyrosine kinases (RTKs: VEGF-R2, VEGF-R3),
platelet-derived growth factorϐ and raf kinase→ inhibition of angiogenesis, invasion,
metastasis; metabolized by P450
The adverse effects: 1. acute; nausea, hypertension, 2. delayed: skin rash, asthenia, bleeding,
hand- foot syndrome, hypophosphatemia; for renal cell cancer, hepatocellular cancer
G.sunitinib- as F + cardiac dysfunction + for gastrointestinal stromal tumors
V.A. imatinib- inhibitor of tyrosine kinase domain of the Bcr-Abl oncoprotein→ prevents
phosphorylation of the kinase substrate by ATP
The adverse effects: 1.acute: nausea, vomiting, 2. delayed: fluid retention (edema), diarrhea,
myalgias, congestive heart failure; for chronic myelogenous leukemia, gastrointestinal stromal
tumor, acute lymphoblastic leukemia Philadelphia chromosome positive
 B. dasatinib- inhibitor of several kinases, binds to active and inactive conformations of
kinases→ overcomes imatinib resistance
C. nilotinib- inhibits tyrosine kinases with higher binding affinity to Abl kinase compared
with imatinib→ overcomes imatinib resistance; for chronic phase and accelerated phase of
chronic myelogenous leukemia; A, B, C- metabolized by P450
   7. Proteasome inhibitors→ bortezomib- used in multiple myeloma
   proteasomes’ substrates- mediators of metabolic pathways in the cell which are disturbed
   in neoplastic plasmocytes
   multiple myeloma →↑ NFκβ activity (in B cell neoplasms)
   proteasome inhibition→ inhibition of NFκβ→ apoptosis by disrupting the regulated
   degradation of pro-growth cell cycle proteins

   8. Histone deacetylase inhibitors→ vorinostat, romidepsin used in multiple myeloma,
      skin T-cell lymphoma (many malignant cells- ↑ histones’ deacetylation)

   9. Farnesyl transferase inhibitors→ tipifarnid , lonafarnib used in multiple myeloma
   (farnesylated proteins are involved in cellular signaling→uncontrolled cell proliferation)

    10. Differentiating agents A. Retinoids B. Arsenic trioxide (ATO)
 A.Retinoid acid derivatives
tretinoin (all-trans-retinoid acid- induction of terminal differentiation of leukemic
promyelocytes in acute promyelocytic leukemia patients
The adverse effects: vitamin A toxicity (headache, fever, dry skin and mucous membranes,
skin rash, pruritus, conjunctivitis); retinoic acid syndrome ( fever, dyspnea, weight gain,
leukocytosis, diffuse pulmonary infiltrates, pleural, pericardial effusions); ↑chol, ↑TG, CNS
toxicity (dizziness, anxiety, depression, confusion, agitation), abdominal pain, diarrhea, ↑ in
liver function tests

B.arsenic trioxide(As2O3)- induces cell differentiation and apoptosis-for induction of
remission in acute promyelocytic leukemiarefractory to or relapsed following therapy with
all-trans-retinoic acid and anthracyclines
The adverse effects: QT prolongation in ecg, arrhythmias, fever, dyspnea, skin rash, fluid
retention, weight gain

III. Immunotherapy- biological response modifiers
1.Monoclonal antibodies:
     naked m.a., m.a.- cytotoxoc conjugates, m.a.- radioimmuno-conjugates
             Monoclonal antibodies approved for hematopoietic and
                                 solid tumors
    Antigen/tumor        Antigen function      Naked             Radioisotope-       Toxin-based
    cell targets                               antibodies        based               antibodies
                                                                 antibodies

    Antigen CD20         Proliferation/        Rituximab         I131-               none
    Tumor type: B-cell   differentiation       (chimeric)        tositumomab
    lymphoma and CLL
                                                                 Y90-iritumomab
                                                                 tiuxetan
    Antigen CD52         unknown               Alemtuzumab       none                none
    Tumor type: B-cell                         (humanized)
    CLL and T-cell
    lymphoma




    Antigen CD25α        Activation            Daclizumab        none                Denileukin
    subunit              antigen               (humanized)                           diftitox
    Tumor type: T-cell                                                               (diphteria toxin)
    mucosis fungoides

    Antigen CD33         unknown               Gemtuzumab        none                Gemtuzumab
    Tumor type: acute                          (humanized)                           ozogamcin
    myeloid leukemia                                                                 (kalicheamcin)




        Monoclonal antibodies approved for hematopoietic and
                            solid tumors
Antigen/tumor      Antigen function        Naked             Radioisotope-       Toxin-based
cell targets                               antibodies        based               antibodies
                                                             antibodies
Antigen         Tyrosine kinase            Trastuzumab       none                none
HER2/neu (ErbB-                            (humanized)
2)
Tumor type:
breast cancer
Antigen EGFR       Tyrosine kinase         Cetuximab         none                none
(ErbB-1)                                   (chimeric)
Tumor type:
colorectal, non-
small-cell-lung
cancer,
pancreatic,
breast cancer
Antigen VEGF       angiogenesis            Bevacizumab       none                none
Tumor type:                                (humanized)
colorectal
cancer
      2.Immunological response modifiers
      A.Cytokines, immunotoxin: IL2=Aldesleukin (→ ↑ differentiation of lymphocyte) used in
      renal cell cancer, metastatic melanoma; IL11 (→↑ platelet formation) used in
      trombocytopenia, filgrastim (G-CSF)(→↑ granulocytes) used when marrow recovery needed,
      sargramostim (GM-CSF) (→↑ granulocytes and macrophages) used when marrow recovery
      needed, erythropoietin used in anemia in course of renal failure, thrombopoietin used in
      trombocytopenia
      B.Interferones: antiviral, immunomodulating, antiproliferative
      IFNα, β (no penetration into CNS; exception- very large doses)→ antineoplastic (hairy-cell
      leukemia).: Alfaferone (IFNα-2b; i.m., s.c., i.v.), Intron A (i.m., s.c.), Roferon-A (IFNα-2a;
      s.c.)
      IFN γ→ renal cancer, melanoma: Imukin (s.c.), Actimmune (s.c.)

      HEAD AND NECK CANCERS (5% of all cancers): oral, throat, larynx, pharynx, nose,
      sinuses, thyroid, parathyroid
      ORAL CANCERS→ found incidentally during a routine dental examination!!!!!
      I. squamous cell carcinomas (90%; of epithelium origin) 1. lip ca 2. gums ca 3. cheek-
      buccal mucosa 4. hard palate ca 5. tongue ca (responds strongly to irradiation, frequently
      metastasizes to the lymph nodes, has poorly differentiated histology, usually treated by
      radiotherapy)→ in situ, invasive squamous cell carcinoma
      II. adenocarcinoma (glandular cells)→ salivary gland carcinoma
      III. tonsil cancer (lymphoid tissue)→ treatment: surgery, radiation therapy, chemotherapy (a
      part of initial treatment= neoadjuvant treatment, curable with radiation therapy, palliative)

      in general: chemotherapy is not curative and is used only as an adjunct (neoadjuvant
      treatment-applied as induction): 1.improvement of survival 2.reduction of the incidence of
      distant metastases, 3. an adjunct to radiotherapy for organ preservation, 4.selection of patients
      for subsequent therapy based on their response to chemotherapy→ before radiation or surgery
      (neoadjuvant treatment), chemoradiation (at the same time as radiotherapy), adjuvant
      chemotherapy (after radiation or surgery);
      in most cases- chemotherapy is palliative= shrink tumor+ relieve symptoms

The most common chemotherapeutics used:

            cisplatin
            5-fluorouracil (5-FU)
            methotrexate
            carboplatin
            docetaxel
            paclitaxel
            bleomycin

and

            immunologic response modifiers (alpha interferon, interleukin)
            monoclonal antibodies to an individual tumor (cetuximab)
            cancer growth inhibitors (gefitinib)
DENTISTRY IMPLICATIONS OF ANTICANCER THERAPY
- most anticancer drugs do not distinguish between normal and malignant cells→ damage of
both
- oral mucosa: rapid cellular turnover, bacterial flora (indigenous oral flora, i.e. opportunistic
pathogens, acquired pathogens), reactivations of latent herpesviruses, micro-damages every
day→ high risk of drug-induced toxicity→ stomatitis, haemorrhage, acute/chronic infections,
rapid progression of caries, periodontal bone loss, pain+ salivary gland dysfunction→
disturbed nutrition
- direct toxic effects→ oral complications of anticancer therapy: oral mucositis (mucosal
inflammation, cytotoxicity, bacterial infection), salivary gland dysfunction→ xerostomia,
neurotoxicity (trigeminal nerve neuropathies, dentinal hypersensitivity, taste dysfunction),
temporomandibular dysfunction (myofascial pain, temporomandibular joint dysfunction),
dental and skeletal growth and development
- indirect toxic effects→ oral complications of anticancer therapy: myelosuppression,
infections (bacterial, fungal, viral), gastrointestinal mucositis (↓ nutrition), nausea, vomiting
(acidic damage to oral tissues, ↑ gag reflexes)
- oral complications of cancer radiotherapy:
  1. acute: oral mucositis, infections (bacterial, fungal), salivary gland dysfunction
  (sialoadenitis, xerostomia), taste dysfunction
  2. chronic: xerostomia, dental caries, infections (bacterial, fungal), mucosal fibrosis and
  atrophy, muscular/cutaneous fibrosis, soft tissue necrosis, osteoradionecrosis, taste
  dysfunction (dysgeusia, ageusia)

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:12
posted:1/25/2013
language:English
pages:12