Cancer Chemotherapy

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6 types of resistance to Anticancer Drugs

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1.) increased DNA repair
2.) formation of trapping agents
3.) changes in target enzymes
4.) decreased activation of prodrugs
5.) inactivation of anticancer drugs
6.) decreased drug accumulation

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mechanism of resistance to cisplatin and other alkylating agents

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increased rate of DNA repair

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mechanism of resistance to bleomycin, cisplatin, and anthracyclines

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increased production of thiol trapping agents which interact with with anticancer drugs that form reactive electrophilic species

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mechanism of resistance to methotrexate

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changes in drug sensitivity of dihydrofolate reductase

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mechanism of resistance to mercaptopurine, thioguanine, cytarabine, fluorouracil

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decreased activity of tumor cell enzymes needed to convert the prodrugs to cytotoxic metabolites

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mechanism of resistance to purine and pyrimidine antimetabolites

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increased enzymes that can inactivate the drugs

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mechanism for decreased drug accumulation

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increased expression of a normal gene for a cell surface glycoprotein; transport molecule is involved in accelerated efflux of many anticancer drugs in resistant cells

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nitrogen mustards (alkylating agents)

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chlorambucil
cyclophosphamide
mechlorethamine

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alkylating agents nitrosoureas

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carmustine, lomustin

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alkylating agent (alkyl sulfonates)

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busulfan

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partial alkylating agents

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cisplatin, decarbazine, procarbazine

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alkylating agent classification and MOA

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- CCNS drugs
- form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine
- leads to cross linking of bases, abnormal base pairing, and DNA strand breakage

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pharmacokinetics of cyclophosphamide

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hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for antitumor activity

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breakdown product of cyclophosphamide

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acrolein

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clinical use of cyclophosphamide

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leukemia, non-Hodgkin's lymphoma, breast and ovarian cancers, neuroblastoma

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Toxicity of cyclophosphamide

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GI distress, myelosuppression, alopecia

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adverse effect of acrolein formation

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hemorrhagic cystitis that can be decreased by vigorous hydration and use of mercaptoethanesulfonate (mesna)

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bad side effects of cyclophosphamide

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cardiac dysfunction, pulmonary toxicity, SIADH

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MOA and pharmacokinetics of mechlorethamine

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spontaneously converts in the body to a reactive cytotoxic product

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clinical use of mechlorethamine

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Hodgkin's and non-Hodgkin's lymphoma

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toxicity of mechlorethamine

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GI distress, myelosuppression, alopecia, sterility

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three platinum analogs

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cisplatin, carboplatin, oxaliplatin

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pharmacokinetics of platinum analogs

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cisplatin is IV- distributes to most tissues and cleared unchanged form by the kidney

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clinical uses of platinum analogs

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cisplatin- component of regimens for testicular carcinoma and bladder, lung, and ovarian cancer
oxaliplatin- advanced colon cancer

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toxicity of cisplatin

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GI distress and mild hematotoxicity and is neurotoxic (peripheral neuritis and acoustic nerve damage, and nephrotoxic

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reduction of renal damage from cisplatin

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mannitol with forced hydration

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toxicity of carboplatin

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less nephrotoxic and less likely to cause tinnitus and hearing loss but has greater myelosuppression

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oxaliplatin toxicity

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neurotixicity

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mechanism of action of procarbazine

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reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA strand scission

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pharmacokinetics of procarbazine

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orally active and penetrates most tissues including CSF
-eliminated via hepatic metabolism

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clinical use of procarbazine

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component of regimens for Hodgkin's and non-Hodgkin's lymphoma, and brain tumors

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toxicity of procarbazine

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myelosuppressant and causes GI irritation, CNS dysfunction, peripheral neuropathy, and skin reactions

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enzymes inhibited by procarbazine

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monoamine oxidase, and those in hepatic drug metabolism; disulfiram-like reactions have occured with ethanol

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characteristics of busulfan

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- used in CML
- causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation

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characteristics of carmustine and lomustine

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highly lipid-soluble drugs used as adjuncts in the management of brain tumors

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characteristics of dacarbazine

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- regimens for Hodgkin's lymphoma
- causes alopecia, skin rash, GI distress, myelosuppression, phototoxicity, flu-like syndrome

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antagonists of folic acid

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methotrexate

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antimetabolites that are antagonists of purines

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mercaptopurine, thioguanine

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antimetabolites that are antagonists of pyrimidines

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fluorouracil, cytarabine, gemcitabine

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MOA of antimetabolites

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- CCS drugs acting primarily in the S phase of the cell cycle
- immunosuppressant actions

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MOA of methotrexate

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- inhibits dihydrofolate reductase
- decrease in synthesis of thymidylate, purine nucleotides, and AAs and interferes with nucleic acid and protein metabolism

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pharmacokinetics of methotrexate

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- oral and IV administration
- good tissue distribution except to CNS
- not metabolized
- clearance dependent on renal function
- adequate hydration is needed to prevent crystallization in renal tubules

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clinical use of methotrexate

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choriocarcinoma, acute leukemias, non-Hodkin's and primary CNS lymphomas, breast CA, head and neck CA, bladder CA

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side use of methotrexate

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rheumatoid arthritis psoriasis and ectopic pregnancy

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toxicity of methotrexate

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- bone marrow suppression and toxic effects on skin and GI mucosa (mucositis)
- hepatotoxicity and pulmonary infiltrates and fibrosis (long term use)

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leucovorin rescue

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toxic effects of methotrexate diminished by administration of folinic acid (leucovorin)

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MOA of mercaptopurine and thioguanine

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- purine antimetabolites
- activated by HGPRTases to toxic nucleotides that inhibit purine metabolism enzymes

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pharmacokinetics of mercaptopurine and thioguanine

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- low bioavailability because of first-pass metabolism by hepatic enzymes
- metabolism of 6-MP by xanthine oxidase is inhibited by allopurinol and febuxostat

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clinical use of mercaptopurine and thioguanine

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acute leukemias and CML

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toxicity of mercaptopurine and thioguanine

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- bone marrow suppression (dose limiting)
- hepatic dysfunction

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MOA of fluorouracil

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converted in cells to 5-fluoro-2-deoxyuridine-5-monophosphate (5-FdUMP) which inhibits thymidylate synthase and leads to thymineless death of cells
- incorporation of FdUMP into DNA inhibits DNA synthesis and function
- incorporation of FUTP into RNA interferes with RNA processing and function

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pharmacokinetics of fluorouracil

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widely distributed, including into CSF
- elimination via metabolism

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clinical use of fluorouracil

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bladder, breast, colon, anal, head and neck, liver, ovarian cancer
- topically for keratoses and superficial basal cell carcinoma

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toxicity of fluorouracil

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GI distress, myelosuppression, alopecia

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MOA of cytarabine (ARA-C)

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- pyrimidine antimetabolite
- activated by kinases to AraCTP, inhibitor of DNA polymerase
- most specific for the S phase of the cell cycle

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MOA of gemcitabine

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- deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form
- minhibits ribonucleotide reductase and diminishes pool of deoxyribonucleoside triphosphates needed for DNA synthesis
- gemcitabine triphosphate can be incorporated into DNA where it causes chain termination

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pharmacokinetics of gemcitabine

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metabolism

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clinical use of gemcitabine

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- pancreatic cancer, non-small cell lung cancer, bladder cancer, non-Hodkin's lymphoma

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toxicity of gemcitabine

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myelosuppression, neutropenia, pulmonary toxicity

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vinca alkaloids

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vinblastine, vincristine, vinorelbine

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MOA of vinca alkaloids

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- block formation of mitotic spindle by preventing assembly of tubulin dimers into microtubules
- act primarily in M phase of cancer cell cycle

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resistance to vinca alkaloids

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increased efflux from tumor cells via membrane drug transporter

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pharmacokinetics of vinca alkaloids

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- must be given parenterally
- penetrate most tissues except CSF
- cleared via biliary excretion

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clinical use of vincristine, vinblastine, and vinorelbine

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vincristine: acute leukemias, lymphomas, Wilms tumor, neuroblastoma
vinblastine: lymphomas, neuroblastoma, testicular carcinoma, Kaposi's sarcoma
vinorelbine- non-small cell lung cancer and breast cancer

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mechanism of action of etoposide and teniposide

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etoposide- semisynthetic derivative of podophyllotoxin, induces DNA breakage through inhibition of topoisomerase II
- most active in the late S and early G2 phases of cell cycle- teniposide similar

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pharmacokinetics of etoposide and teniposide

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well absorbed after oral administration and distributes to most body tissues
- elimination via kidneys- dose reductions needed in those with kidney problems

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clinical use of etoposide and teniposide

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- combination drug regimens for lymphoma, lung, germ cell, gastric cancers

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toxicity of etoposide and teniposide

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- GI irritants
-alopecia and bone marrow suppression

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mechanisms of topotecan and irinotecan

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camptothecins
- DNA damage by inhibiting topoisomerase I
- damage DNA by inhibiting and enzyme that cuts and relegates single DNA strands during normal DNA repair processes

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pharmacokinetics of topotecan and irinotecan

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irinotecan- prodrug that is converted in liver to an active metabolite
topotecan- eliminated renally
irinotecan- eliminated in bile and feces

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clinical use of topotecan and irinotecan

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topotecan- second-line therapy for advanged ovarian cancer and small cell lung cancer
- irinotecan- metastatic colorectal cancer

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toxicity of topotecan and irinotecan

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- myelosuppression and diarrhea

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MOA of paclitaxel and docetaxel

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- interfere with mitotic spindle
- prevent microtubule disassembly into tubulin monomers

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pharmacokinetics of paclitaxel and docetaxel

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given IV

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clinical use of paclitaxel and docetaxel

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- breast, ovarian, lung, gastroesophageal, prostate, bladder, head and neck cancers

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toxicity of paclitaxel and docetaxel

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paclitaxel: neutropenia, thrombocytopenia, peripheral neuropathy, possible hypersensitivity reactions during infusion
docetaxel: neurotoxicity and bone marrow suppression

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anthracyclines

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doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone

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MOA of anthracyclines

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- intercalate between base pairs, inhibit topoisomerase II, and generate free radicals
- block synthesis of RNA and DNA and cause DNA strand scission
- membrane disruption occurs
- CCNS drugs

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pharmacokinetics of anthracyclines

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- doxorubicin and daunorubicin- IV
- metabolized in the liver, products are excreted in bile and urine

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Clinical use of anthracyclines

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doxorubicin- Hodgkin's and non-Hodgkin's lymphoma, myelomas, sarcomas, breast, lung, ovarian, and thyroid cancer
- main use of daunorubicin is in acute leukemias
- idarubicin: use in AML
epirubicin: breast and gastroesophageal CA
mitoxantrone: AML, non-Hodgkins lymphoma, breast and gastroesophageal CA

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toxicity of anthracyclines

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-bone marrow suppression, GI distress, severe alopecia
- most distinctive adverse effect- cardiotoxicity- initial electrocardiographic abnormalities
- slowly developing, dose-dependent cardiomyopathy and congestive heart failure

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dexrazoxane use

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- inhibitor of iron-mediated free radical generation, protects against dose-dependent form of cardiotoxicity

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MOA of bleomycin

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- mixture of glycopeptides that generate free radicals, which bind to DNA< cause strand breaks, and inhibit DNA synthesis
- CCS drug active in G2 phase of tumor cell cycle

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pharmacokinetics of bleomycin

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- parenteral administration
- inactivated by tissue aminopeptidases, some renal clearance

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clincal use of bleomycin

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- Hodgkin's lymphoma and testicular cancer
- lymphomas and squamous cell carcinomas

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bleomycin toxicity

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- pulmonary dysfunction (pneumonitis, fibrosis)- slow development and is dose limiting
- hypersensitivity reactions common
- mucocutaneous reactions common (alopecia, blister formation, hyperkeratosis)

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MOA and pharmacokinetics of mitomycin

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- CCNS drug that is metabolized by liver enzymes to form alkylating agent that cross-links DNA
- given IV and is rapidly cleared via hepatic metabolism

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clinical use of mitomycin

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- hypoxic tumor cells and used in combo regimens for adenocarcinomas of cervix, stomach, pancreas, and lung

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mitomycin toxicity

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severe myelosuppression and is toxic to heart, liver, lung, and kidney

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imantinib

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- inhibits tyrosine kinase activity of bcr-abl oncogene in CML
- also used to treat GI stromal tumors that express c-kit tyrosine kinase- inhibited

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toxicity of imatinib

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diarrhea, myalgia, fluid retention, CHF

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Trastuzumab

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monoclonal antibody that recognizes surface protein in breast cancer cells that overexpress HER-2/neu receptor for epidermal growth factor

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toxicity of trastuzumab

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- nausea and vomiting, chills, fevers, headache
- cardiac dysfunction, CHF

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cetuximab

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- chimeric monoclonal antibody directed to extracellular domain of EGFR
- used in combo with irinotecan and oxaliplatic for metastatic colon cancer and in combo with radiation for head and neck cancer

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toxicity of cetuximab

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skin rash and hypersensitivity infusion reaction

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panitumumab

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- human monoclonal antibody against the EGFR's tyrosine kinase domain
- rash and diarrhea

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gefitinib and erlotinib

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- small molecule inhibitors of EGFR's tyrosine kinase domain
- second line agents for non-small cell lung cancer

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bevacizumab

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-monoclonal antibody that binds to VEGF and prevents it from hitting receptors
- colorectal, breast, non-small cell lung, renal cancer

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VEGF

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critical role in angiogenesis required for tumor metastasis

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adverse effects of bevacizumab

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HTN, infusion reactions, arterial thrombosis, impaired wound healing, GI perforation, proteinuria

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rituximab

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monoclonal antibody that binds to a surface protein in non-Hodgkin's lymphoma cells and induces complement-mediated lysis, direct cytotoxicity, and induction of apoptosis

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use of rituximab

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low-grade lymphomas
- hypersensitivity reactions and myelosuppression

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interferons

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endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions

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alpha-interferons use

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- hairy cell leukemia, early CML, T-cell lymphomas

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toxic effects of interferons

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myelosuppression and neurologic dysfunction

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asparaginase

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-enzyme that depletes serum asparagine
- used in treatment of T-cell auxotrophic cancers that require exogenous asparagine for growth

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asparaginase toxicity

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hypersensitivty reactions, acute pancreatitis, and bleeding

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prednisone

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glucocorticoid used in combination therapy for leukemias and lympohomas

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tamoxifen

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- selective estrogen receptor modulator
- blocks the binding of estrogen to receptors of estrogen-sensitive cancer cells in breast tissue

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when to use tamoxifen

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receptor-positive breast carcinoma and has preventive effect in women at high risk for breast cancer

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tamoxifen side effects

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increases risk of endometrial hyperplasia and neoplasia

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adverse effects of tamoxifen

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nausea, vomiting, hot flushes, vaginal bleeding, and venous thrombosis

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flutamide

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androgen receptor antagonist used in prostatic carcinoma

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adverse effects of flutamide

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gynecomastia, hot flushes, hepatic dysfunction

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toremifene

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new estrogen receptor antagonist in advanced breast CA

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leuprolide, goserelin, nafarelin

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GnRH agonists, effective in prostatic carcinoma

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leuprolide toxicity

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bone pain, gynecomastia, hematuria, impotence, testicular atrophy

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anastrozole and letrozole

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inhibit aromatase (enzyme that catalyzes conversion of androstenedione to estrone)

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toxicity of anastrozole and letrozole

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nausea, diarrhea, hot flushes, bone and back pain, dyspnea, peripheral edema