4 - Cancer Chemotherapy 2014

8/10/2019 4 - Cancer Chemotherapy 2014

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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

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4 - Cancer Chemotherapy 2014