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CANCER CHEMOTHERAPY
FRANCIS RAYMOND M. CASTOR, M.D.
F.P.C.S.DEPARTMENT OF PARMACOLOGY
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CANCER
Cellular disease Shift in the control mechanism that controls
proliferation Neoplastic transformation Express surface antigens of the normal fetal
type Immaturity, chromosomal abnormalities
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Excessive proliferation = Tumors Invade or compress other structures
Tumor stem cells Can express colony forming capabilities Invasion and metastases cause death
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CAUSES OF CANCER
Environmental exposure to chemicalcarcinogens
Herpes/ papilloma group DNA viruses/ type CRNA viruses
Cellular genes/ oncogene/ deleted ordamaged tumor suppressor genes
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THERAPEUTIC MODALITIES
Reduction of tumor burden by Radiation
Surgery Chemotherapy
Killing 99.99% of colonogenic tumor cells willresult in remission of neoplasm= symptomaticimprovement
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THE IDEAL ANTI CANCER DRUG
Eradication of tumor cells without damage tonormal cells
No drugs meets this criterion
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BASIC PHARMACOLOGY
Polyfunctional alkylating agents Antimetabolites
Plant alkaloids Antitumor antibiotics Hormonal agents Miscellaneous anticancer agents Anti VEGF agents
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POLYFUNCTIONAL ALKYLATINGAGENTS
Contains ethylene amines or a nitrosoureamoiety
Cytotoxic effects via transfer of alkyl groups tovarious cellular constituents.
Lysine carbamoylation via isocyanateformation in nitrosoureas
Major site is N7 position of guanine in DNA /N1, N3 of adenine, N3 of cytosine, O6 ofguanine
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Chlorambucil, Mechlorethamine Cyclophosphamide Melphalan Thiotepa Busulfan Carmustine/ lomustine Altretamine Procarbazine Cisplatin, carboplatin, oxaliplatin
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Resistance: increased capability of cells torepair DNA lesions, decrease permeability tothe drug and increased GSH formation
Increased GSH production inactivates thealkylating agent via conjugation (catalysed by S-transferase )
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Has direct vesicant effects and can damagetissues at the injection site/ systemic toxicity.
Toxicity is generally dose related Produces nausea and vomiting 30-60 mins. of
administration, relieved by pre- treatmentwith a SSRI Ondansetron or Granisetron
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Major toxicities
Moderate depression of peripheral bloodcount ( indication for adequate absorption)
Excessive doses: bone marrow depression Alopecia , hemorrhagic cystitis Nephrotoxicity, peripheral sensory neuropathy
Hepatic dysfunction
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Nitrosoureas
Non cross resistant with other alkylatingagents
Highly lipid soluble and crosses the bloodbrain barrier, useful for CNS tumors
More effective in the plateau phase than inexponentially growing cells
Streptozocin: Insulin secreting cell carcinomaof the pancreas
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Drugs probably acting as alkylatingagents
Procarbazine : Hodgkins disease / nonHodgkin s lymphoma
Produces chromosome breaks, prolongsinterphase
Increased risk of secondary cancers : leukemia Carcinogenic potential is higher
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Dacarbazine : melanoma, Hodgkins and softtissue sarcomas
Altretamine: ovarian CA who have progresseddespite treatment with an alkylating agentand a platinum based drug/ neurotoxicity,somnolence, mood changes, peripheralneuropathy
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Cisplatin / carboplatin / Oxaliplatin: Platinumanalogs, complexes and synergizes with otherdrugsBroad range of solid tumors, Non small cell LungCA, Esophageal CA, Gastric CA, GU and headand neck CA.Neurotoxicity limits dose: peripheral sensoryneuropathy worsened upon exposure to cold (Oxaliplatin) cumulative but reversible
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Antimetabolites (structural analogs)
Acts on the intermediary metabolism ofproliferating cells
IncludesMethotrexatePurine antagonists
Mercaptopurine, Fludarabine, CladribinePyrimidine antagonists5 FU, Capecitabine, Cytarabine, Gemcitabine
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Methotrexate
Folate antagonists via DHFR Interrupts synthesis of thymidilate, purine
nucleotides, serine and methionine Polyglutamate derivatives of MTX are retained
in CA cells Inc. inhibitory action on folate enzymes
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Resistance to MTX due to Decreased drug transport Decreased polyglutamate formation Increased DHFR synthesis via gene amplification Altered DHFR with reduced MTX affinity Decreased drug accumulation via multidrug
resistant P170 glycoprotein transporter
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Administered IV Intrathecal Oral: 90% of dose excreted in urine within 12
hoursThe drug is not subject to metabolismSerum levels are proportionate to dose as long asrenal function and hydration is adequateEffects of MTX are reversed by Leucovorin( rescue drug for overdosage)
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Purine anragonists
Mercaptopurine Used primarily for the treatment of acute
childhood leukemia Azathioprine, an analog is an
immunosuppressive agent Synergystic with cytarabine
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Resistance occurs most common by decreasein HGPRT activity or elevated levels of alkylphosphatase
Simultaneous therapy with allopurinol resultsin excessive toxicity unless the dose ofMercaptopurine is reduced to 25%
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Fludarabine
Low grade non Hodgkins lymphoma andChronic lymphocytic leukemia
Given parenterally Dose limiting toxicity is myelosuppression
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Cladribine
Hairy cell leukemia, CLL, NHL Single 7 day infusion
Immunosuppressive with decreased CD4 andCD8 lasting over 1 year
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Pyrimidine antagonists
5 FU: inhibition of DNA synthesis throughthymineless death
Normally given per IV due to erraticbioavailability via oral route ( high levels ofbreakdown enzyme in the gut)
Widely used in colorectal CA
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Plant Alkaloids
Vinblastine Depolymerization of microtubules
Mitotic arrest at metaphase Hodgkins lymphoma, non Hodgkins
lymphoma, Breast CA
Vinblastine: multiple myeloma,Rhabdomyosarcoma, Neuroblastoma, E wingssarcoma, W ilms tumor
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Epidophyllotoxins
Etoposide and Teniposide Block cell division at S-G 2 phase of cell cycle
Etoposide: germ cell CA, small cell CA, nonsmall cell lung CA, gastric CA, Hodgkins/ NHL Teniposide: ALL
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Camptothecins
Irinotecan Secondline monotherapy for metastatic
colorectal CA, who have failed 5 FU/Leucovorin
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Taxanes
Paclitaxel Microspindle poison
Cas: ovarian, breast, non small cell, bladder,Kaposis sarcoma Docetaxel: advanced breast CA, small cell Lung
CA, ovarian, Bladder CA, Head and neck CA
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Antitumor antibiotics
Doxorubicin/ daunorubicin : solid tumors/AML
Anthracyclines: cardiotoxicUsed in combination with cyclophosphamide,cisplatin and 5 FU
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Dactinomycin
Inhibits all forms of DNA dependent RNAsynthesis
Wilms tumor, Rhabdomyosarcoma , Ewingssarcoma
Radiation recall reaction
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Mitomycin C
Squamous cell CA of the anus with 5 FU Intravesical treatment for superficial bladder
CA Non absorbed systemically via this route No systemic toxicity for intravesical treatment Common toxicities are hemolytic uremic
syndrome, hemolytic anemia,thrombocytopoenia, renal failure, interstitialpneumonitis
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Hormonal agents Estrogen and Androgen inhibitors
Tamoxifen Flutamide Bicalutamide
Gonadotropin releasing hormone agonists Leuprolide Goserelin
Aromatase inhibitors Aminogluthetimide Letrozole Exemestane
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Tamoxifen
Early and metastatic breast CA Chemopreventive for high risk patients Competitive agonist inhibitor of estrogen Estrogen sensitive tumors
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Flutamide / Bicalutamide
Used in combination with RT for treatment ofProstate CA, early an metastatic
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Leuprolide/ Goserelin
Analogs of GnRH When given in depot, these lead to a transient
release of FSH and LH Castration levels of testosterone For prostate CA
Flushes, impotence and gynecomastia
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Miscellaneous
Imatinib: tyrosine kinase inhibitor; CML Asparaginase Hydroxyurea: CML, blast crisis in AML,
myelosuppression limits the dose Mitotane: analog of DDT, adrenocortical CA
Bone Marrow growth Factors: Erythropoeitin:chemotherapy related anemia
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Anti VEGF
Cetuximab Bevacizumab Inhibits the tyrosine kinase domain of
epidermal growth factor