Unit 1 - Principles of Cancer Chemotherapy Flashcards Preview

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Flashcards in Unit 1 - Principles of Cancer Chemotherapy Deck (68):

when is chemotherapy indicated?

cancers that are not amenable to surgery or radiation therapy
-also used as supplemental treatment to prevent metastasis following surgery and radiation treatment


what order kinetics does killing of cancer cells by chemotherapy follow?

first-order kinetics
-kills a constant fraction of cancer cells, instead of a constant number of cells


what are the 4 possible cancer outcomes?

1. death without treatment
2. cure with surgery and/or radiation therapy
3. first-order cure/remission with chemotherapy
4. palliation and eventual resistance/toxicity and death with chemotherapy


what are the principles of combination drug selection?

1. drugs used have individual anticancer activities
2. different mechanisms of action
3. different toxicities (dose-limiting)
4. need several cycles of drugs
5. should have additive or synergystic effects


what are advantages of chemotherapy drug combinations?

1. provide maximal cell killing within range of tolerated toxicity
2. effective VS heterogeneous cell populations present in tumors (b/c of different drug resistances)
3. reduces changes of development of resistant clones


what are drugs in ABVD?

doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine


what are drugs in CHOP

cyclophosphamide, hydroxydoxorubicin, vincristine (oncovine), prednisone


what are drugs in MOPP?

mechlorethamine, vincristine (oncovine), procarbazine, prednisone


what are drugs in CMF?

cyclophosphamide, methotrexate, 5-fluorouracil


what are drugs in FEC?

5-fluorouracil, epirubicin, cyclophosphamide


what are 2 limitations of cancer chemotherapy?

1. drug resistance - some tumors are inherently resistant to anticancer drugs
-others acquire drug resistance after prolonged administration of drug, but this is minimized by short-term, intensive, intermittent therapy with drug combos
2. toxicity - affect normal cells undergoing rapid proliferation (BM, GI mucosa, hair follicles)


what are possible mechanisms of drug resistance?

1. decreased cellular uptake
2. abnormal transport of drug (rapid efflux by P-glycoprotein)
3. increased cellular inactivation (binding/metabolism)
4. altered target PRO
5. reduced affinity for drug
6. enhanced repair of DNA damage


what are common side effects of chemotherapy and why?

1. BM toxicity: neutropenia, thrombocytopenia, anemia
-long-term treatment has leukemia and myelodysplasia
2. GI toxicity: nausea, vomiting, stomatitis
3. hair follicle toxicity: alopecia


what are the 7 classes of anticancer drugs?

based on mech of action
1. alkylating agents
2. antimetabolites
3. DNA intercalating agents
4. microtubule inhibitors
5. topoisomerase inhibitors
6. hormones and antagonist
7. miscellaneous agents


describe alkylating agents?

transfer alkyl group to DNA and promote X-linking of DNA strands resulting in DNA damage
-active against prolfierating and resting cells (cell cycle non-specific drugs)
-first chemotherapeutic agents used clinically to treat cancer patients


what is the mechanism of action for alkylating agents? major sites of action?

produce strong electrophiles through formation of carbonium or ethyleneimonium ion intermediates, which form covalent linkages by alkylation of nucleophilic moieties present in DNA
-major site: N7 position of guanine > N1/3 of adenine, N3 of cytosine, O6 of guanine > associated phosphate atoms and proteins


toxicity of alkylating agents?

1. BM toxicity (neutropenia, thrombocytopenia, anemia)
2. mucosal toxicity (oral mucosal ulceration, intestinal denudation
3. nausea and vomiting
4. toxic effects on reproductive systems (amenorrhea in women, male sterility)
5. increased risk of secondary leukemia (highly carcinogenic)


why can there be resistance to alkylating agents?

1. decreased permeability or uptake of drugs
2. increased rates of metabolism of activated forms to inactive species
3. enhanced activity of DNA repair pathways
4. increased production of glutathione that inactivates alkylating agents through conjugations


explain nitrogen mustards and some examples?

bifunctional alkylating agents that undergo spontaneous conversion to active metabolites in body fluids, or are enzymatically converted to active metabolites in liver
-include mechlorethamine, cyclophosphamide and ifosfamide


what are therapeutic uses and toxicity of mechlorethamine?

nitrogen mustard used primarily in treatment of Hodgkin's disease, and as component of MOPP
-used topically to treat cutaneous T-cell lymphoma

causes severe nausea, vomiting, and myelosuppression (leucopenia and thrombocytopenia)


what are therapeutic uses and toxicity of cyclophopshamide and ifosfamide

nitrogen mustard prodrugs activated by hepatic cytochrome P450 enzymes --> phosphoramide mustard
-taken orally and have relatively long plasma half life compared to others

-cyclophosphamide: most widely used alkylating agent with broad spectrum (alone or combo for acute/chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast, lung, ovarian cancer)
-ifosamide treats sarcoma and testicular cancer

causes nausea, vomiting, myelosuppression, and hemorrhagic cystitis (local irritation of bladder due to toxic metabolite acrolein in urine; minimized with MESNA)


what is an example of nitrosoureas, its therapeutic uses, and toxicity?

carmustine and lomustine are alkylating agents that are highly lipophilic and able to cross BBB
-used to treat brain tumors

cause profound myelosuppression, severe nausea/vomiting, renal toxicity, and pulmonary fibrosis


what is an example of triazenes, their therapeutic uses and toxicity?

dacarbazine and temozolomide are alkylating agents
-D: prodrug that needs metabolic activation by cytochromes in liver and administered by IV
--part of ABVD to treat Hodgkin's disease and malignant melanoma
-T: undergoes nonenzymatic conversion to methylhydrazine at physiologic pH, administered orally
--for malignant gliomas and standard agent in combo with radiation therapy

causes nausea/vomiting, myelosuppression (neutropenia, thrombocytopenia), flu-like symptoms (fever, fatigue)


what are platinum analogs and general info?

cisplatin, carboplatin, and oxaliplatin are all alkylating agents and inorganic platinum derivatives
-don't form carbonium ion intermediates like the other alkylating agents, but covalently bind to nucleophilic sites on DNA
-converted to active cytotoxic forms by reacting with water to form + hydrated intermediates to react with DNA guanine to form intrastand and interstand X-links


explain the therapeutic uses and toxicity of cisplatin, carboplatin, and oxaliplatin

alkylating platinum analogs
Cis: wide range of neoplasms (testicular, ovarian, cervical, bladder, head/neck, lung), and often in combos
-renal toxicity (renal tubular damage/necrossi_ is dose-limiting toxicity), but also ototoxicity (hearing loss), severe nausea and vomiting, peripheral motor and sensory neuropathy at high doses, mild/moderate myelosuppression
Car: approved for ovarian cancer
-myelosuppresion (thrombocytopenia) toxicity
Ox: used in combo with 5-FU for treating gastric and colorectal cancer
-peripheral sensory neuropathy (cold-induced acute peripheral neuropathy) and neutropenia toxicity


explain antimetabolite therapy mechanisms?

structural analogs of folic acid or of purine/pyrimidine bases in DNA
-inhibit and/or compete for enzymes needed for nt synthesis (S-phase --> cell cycle specific drugs)


what are 2 folate analogs?

methotrexate and pemetrexed


what is methotrexate mechanism, terapeutic uses, and toxicity?

MTX - folate analog antimetabolite that inhibites DHFR (normally converts dietary folate to THF)
-treats childhood ALL and choriocarcinoma
-part of combo therapy for Burkitt's lymphoma and carcinomas of breast, ovary, head/neck, bladder
-administered intrathecally (can't pass BBB) to treat meningeal leukemia and meningeal metastases
-high dose MTX used for osteosarcoma

-BM toxicity (myelosuppression, spontaneous hemorrhage)
-GI toxicity (oral ulceration, stomatitis)
-renal toxicity (high doses causing crystallization in urine and renal damage)
-hepatotoxicity (long-term use causes fibrosis or cirrhosis)
-cause defective oogenesis, spermatogenesis, or lead to abortion


what is leucovorin used for?

fully activated form of folic acid that is taken up more readily by normal cells than tumor cells
-used in treatment of MTx toxicity


what is mechanism of MTX resistance?

1. reduced drug uptake by neoplastic cells
2. increased production of DHFR (gene amplification)
3. decreased affinity of DHFR for MTX


what is pemetrexed?

multi-targeted folate analog antimetabolite
-rapidly metabolized to active polyglutamine forms that inhibit THF-dependent enzymes in purine/pyramidine synthesis
-activity VS colon cancer, mesothelioma, non-small cell lung cancer, pancreatic cancer


what is 5-FU, mechanism, therapeutic uses and toxicity?

pyramidine analog antimetabolite prodrug activated by ribosylation and phosphorylation
-5-FdUMP inhibits thymidylate synthetase
-5-FdUTP incorporated into RNA

-given via IV due to severe toxicity to GIT and rapid metabolic degradation in gut/liver
-combo therapy for breast, colorectal, gastric, head/neck, cervical, pancreatic
-topical application for basal cell carcinoma

causes anorexia, nausea, mucosal ulcerations, stomatitis, diarrhea, thrombocytopenia, anemia, hand-foot syndrome (erhythema/sensitivity of palms/soles), cardiac toxicity (acute chest pain)


what is capecitabine?

a new, oral form of 5-FU pyrimidine analog antimetabolite
-prodrug converted to 5'dFdU for metastatic breast cancer and colorectal cancer


what is cytarabine mechanism, therapeutic use, and toxicity?

ara-C; pyrimadine analog antimetabolite
-natural ribose of 2'-deO2C is replaced by D-arabinose
-ara-CMP converted to triphosphate Ara-CTP that competes with dCTP for incorporation into DNA by DNA polymerase, resulting in premature DNA chain termination (but only in S-phase)

-most effective for AML, and also ALL and blast phase CML

causes severe myelosuppression (leukopenia, thrombocytopenia, anemia) and GIT toxicity (ulceration, stomatitis, diarrhea)


what is gemcitabine mechanism, therapeutic use, and toxicity?

dFdC; analog of deoxycitidine and active through cell cycle (not just S-phase)
-phosphorylated to dFdCMP, then converted to dFdCD/TP to inhibit ribonucleotide reductase and incorporate into DNA to end DNA synthesis

firstline treatment for pancreatic carcinoma; effective in non-small cell lung cancer, ovarian, bladder, esophageal, and head/neck

causes myelosuppression (leukopenia, thrombocytopenia, anemia) and flu-like symptoms


what is 6-mercaptopurine mechanism, therapeutic use, and toxicity?

6-MP is purine analog antimetabolite that reduces purine levels to inhibit DNA and RNA synthesis in tumor cells
-prodrug metabolized by HGPRT to make TIMP
--inhibits first step of de novo synthesis, blocks formation of AMP, and is incorporated in D/RNA to inhibit synthesis

used to maintain remission in ALL patients

causes BM suppression, hepatotoxicity if prolonged


what is the significance of 6-MP and allopurinol?

allopurinol inhibits xanthine oxidase, thus elevating 6-MP plasma levels
-thus must decrease dose of 6-MP if individual is taking allopurinol for hyperuricemia


what is the mechanism of resistance for 6-MP?

1. reduced metabolic conversion of 6-MP to active nucleotide due to decreased HGRPT expression
2. decreased drug transport


what are DNA intercalating agents overall? examples?

anti-tumor antibiotics
-derived from Streptomyces strains
-bind to DNA through intercalation between specific bases (usually G-C) to block DNA and/or RNA synthesis
-causes DNA strands to break, interfering with cell replication
-includes dactinomycin (actinomycin D), daunorubicin, doxorubicin, epirubicin, idarubicin, bleomycin


mechanism, therapeutic uses, and toxicity for dactinomycin

AKA actinomycin D; first antibiotic (DNA intercalating agent) used in cancer therapy
-intercalates between G-C base pairs of DNA to form stable dactinomycin-DNA complex
--interferes with DNA-dependent RNA polymerase, causing inhibition of DNA transcription and creating single strand breaks
-used to treat pediatric tumors (Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma)
-causes anorexia, nausea, vomiting, and possible severe hematopoietic suppression with pancytopenia


mechanism, therapeutic uses, and toxicity for daunorubicin

anthracycline antibiotics (DNA intercalating agent) with broad spectrum of clinical usefulness in hematologic and solid tumors
-along with idarubicin, used to treat AML
-causes irreversible dose-limiting cardiotoxicity (cardiomyopathy), myelosuppression (neutropenia), stomatitis, GI disturbances, and alopecia


mechanism, therapeutic uses, and toxicity for doxorubicin

anthracycline antibiotics (DNA intercalating agent) with broad spectrum of clinical usefulness in hematologic and solid tumors
-treats sarcomas, breast/lung carcinomas, and malignant lymphomas
-causes irreversible dose-limiting cardiotoxicity (cardiomyopathy), myelosuppression (neutropenia), stomatitis, GI disturbances, and alopecia


mechanism, therapeutic uses, and toxicity for epirubicin

anthracycline antibiotics (DNA intercalating agent) with broad spectrum of clinical usefulness in hematologic and solid tumors
-used in FEC combo for metastatic breast and gastric cancer
-causes irreversible dose-limiting cardiotoxicity (cardiomyopathy), myelosuppression (neutropenia), stomatitis, GI disturbances, and alopecia


what is the significance of dexrazoxane?

Fe-chelator that blocks FR and protects against cardiotoxicity caused by the DNA intercalating agents daunorubicin, doxorubicin, epirubicin, and idarubicin


mechanism, therapeutic uses, and toxicity for bleomycin

DNA intercalating agent that's a mix of 2 Cu-chelating peptides (works in G2 phase)
-forms FR in rpesence of Fe and O2, inducing ss and dsDNA breaks
-used as PEB and ABVD combo for testicular tumors and Hodgkins, respectively
--also effective VS squamous cell carcinomas and lymphomas
-minimally myelo/immunosuppressive, so often used in combo therapy regimens
--pulmonary toxicity (pulmonary fibrosis), cutaneous toxicity, hyperthermia


what are microtubule inhibitors? examples?

inhibit mitosis and cause metaphase arrest by interfering with microtubule function
1. vinca alkaloids (vinblastine and vincristine; prevent assembly, so continued disassembly)
2. taxanes (paclitaxel and docetaxel; prevent disassembly, so continued assembly)


mechanism, therapeutic uses, and toxicity for vinca alkaloids

vinblastine and vincristine: natural alkaloids (periwinkle) that bind to tubulin and block ability of tubulin to polymerize into microtubules, thus arresting in M phase --> cell death
-vinblastine: used with bleomycin and cisplatin to treat metastatic testicular tumors; part of ABVD for Hodgkin's
--myelosuppression, nausea, vomiting
-vincristine: used with glucocorticoids to treat ALL (MOPP); also treats Hodgkin's and non-Hodgkin's lymphomas
--dose-limiting neurotoxicity (peripheral neuropathy), but relatively low toxicity in BM


why is there resistance to vinca alkaloids?

amplification of P-glycoproteins or tubulin mutation causes decreased binding


mechanism, therapeutic uses, and toxicity for taxanes?

plant alkaloids (yew) that bind to tubulin to promote polymerization (prevent depolymerization for Xm desegregation during mitosis)
-against metastatic breast, ovarian, lung, head/neck cancers (doce for hormone-refractory prostate cancer)
-causes neutropenia, peripheral neuropathy, and hypersensitivity reactions


what are topoisomerase inhibitors? examples?

cause permanent strand breaks by preventing resealing of nicked DNA strands by topoisomerase
1. epipodophyllotoxins (etoposide, teniposide)
2. camptothecin analogs (irinotecan and topotecan)


mechanism, therapeutic uses, and toxicity for epipodophyllotoxins?

inhibit topoisomerase II to cause DNA damage
-etoposide has braod spectrum of activity; for testicular carcinoma, lung cancer, non-Hodgekin's lymphoma
-teniposide for ALL
-both have dose-limiting myelosuppression (neutropenia) and oral mucositis


mechanism, therapeutic uses, and toxicity for camptothecin analogs?

inhibit topoisomerase I to cause accumulation of ssDNA breaks
-irinotecan: treat advanced colorectal cancer, and lung, ovarian, cervical, brain tumors
-topotecan: treat ovarian and small cell lung cancer)
-both cause severe neutropenia and diarrhea


what are the hormone therapies for lymphomas and leukemias?

glucocorticoids have cytotoxic effects on lymphocytes by inhibiting mitosis
-well tolerated and don't induce myelosuppression
-prednisone: treat ALL with vinocristine; Hodgkin's and non-Hodgkin's with MOPP/CHOP; multiple myeloma and CLL
-dexamethasone: used with radiation therapy to reduce edema related to brain and spinal cord tumors


where is hormonal therapy useful?

lymphomas/leukemias (glucocorticoids)
breast cancer (estrogen antagonists)
prostate cancer (androgen antagonists)


what are the types of hormone therapy for breast cancer? examples?

estrogen antagonists
1. SERMs (selective estrogen-receptor modulators: tamoxifen)
2. SERDs (selective estrogen-receptor downregulators: fulvestrant)
3. aromatase inhibitors (aminoglutethamide, anastrozole


mechanism, therapeutic uses, and toxicity for tamoxifen?

SERM that is most widely used anti-estrogen therapy
-readily absorbed following oral administration
-competes with estradiol to bind to ER, causing non-functional hormone receptor complex
-stabilizes/increases ER expression
-used to treat ER+ metastatic breast cancer, or adjuvant therapy following primary breast tumor excision
--used to prevent breast cancer in high-risk patients (family history)
-hot flushes, hair loss, nausea, vomiting
--increases risk of endometrial cancer and thromboembolic events


mechanism, therapeutic uses, and toxicity for fulvestrand?

SERD that binds to ER with higher affinity than tamoxifen
-inhibits dimerization of ER and increases degradation (reduces number of ER molecules in cells)
-for postmenopausal women with ER+ metastatic breast cancer


mechanism, therapeutic uses, and toxicity for aminoglutethamide

first generation aromatase inhibitor that is relatively weak with significant toxicity
-beneficial effects against breast cancer, but being replaced by new third generations


mechanism, therapeutic uses, and toxicity for anastrozole

third generation aromatase inhibitor that is potent and selective
-first line therapy for ER+ breast cancer treatment in postmenopausal women


what are the hormone therapies for prostate cancer? examples?

1. leuprolide (LUPRON) or goserelin (ZOLADEX): GnRH analogs to inhibit release of FSH/LH, causing decreased testicular testosterone
2. flutamide, bicalutamide: nonsteroidal androgen-receptor blockers that compete with natural hormone for binding to androgen receptor to prevent translocation in nucleus


mechanism, therapeutic uses, and toxicity for hydroxyurea

inhibits ribonucleoside diphosphate reductase, which catalyzes conversion of rnt to drnts (rate-limiting step in DNA biosynthesis)
-used to treat myeloproliferative neoplasms (polycythemia vera and essential thrombocythemia)
-approved to treat SCD


mechanism, therapeutic uses, and toxicity for retinoids

all-trans retinoic acid (ATRA) treats acute promyelocytic leukemia by inducing differentiation in leukemic promyelocytes and remissions in APL patients


mechanism, therapeutic uses, and toxicity for aresenic trioxide

heavy metal toxin effective in treating relapsed APL


mechanism, therapeutic uses, and toxicity for thalidomide

used to treat multiple myeloma and myelodysplastic syndromes


mechanism, therapeutic uses, and toxicity for interferons

IFN-alpha used to treat neoplastic diseases
-approved for hairy-cell leukemia, CML (but has been replaced), AIDS-related Kaposi's sarcoma


mechanism, therapeutic uses, and toxicity for tyrosine kinase inhibitors

1. imatinib (Gleevec) - inhibitor of Abl kinase, PDGFR, c-kit
-first line therapy for CML, also treats gastrointestinal tumors
2. Gefitinib (Iressa), Erlotinib (Tarceva) - inhibit epidermal growth factor receptor (EGFR) tyrosine kinase
-approved for non-small cell lung cancer


mechanism, therapeutic uses, and toxicity for monoclonal antibodies

1. rituximab - targets CD20 B-cell antigen to treat Non-Hodgkin's lymphoma
2. trastuzumab (Herceptin) - humanized against HER2/NEU (ErbB2) to treat HER2/neu-overexpressing metastatic breast cancer
3. cetuximab - against EGFR1 (ErbB1) to treat EGFR+ metastatic colorectal cancer


what can cause multi-drug resistance? what can prevent it?

increased expression of cell surface glycoproteins involved in drug efflux (such as P-GP)
-drug transporters use ATP to drive drugs out of cancer cells
-verapamil (Ca++ channel antagonist) inhibits transporters