Antineoplastic Agents Flashcards by Blair Tilkens

methotrexate

Cytotoxic, antimetabolite, folic acid analog
Mechanism of action: dihydrofolate reductase inhibitor–>decrease purine synthesis–>decrease dTMP synthesis–>decrease cell proliferation
Uses: acute lymphoblastic leukemia in children, osteosarcomas, choriocarcinoma
Leucovorin= rescue used to reduce toxicity
Toxicities: bone marrow suppression, intestinal epithelial death, hepatic dysfunction, interstitial pneumonitis, nephrotoxicity
Resistance: gene duplication of dihydrofolate reductase, mutations in DHFR reducing affinity for methotrexate, decreased transport into cell

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5-fluorouracil (5-FU)

Cytotoxic, antimetabolite, pyrimidine analog
Mechanism of action: 5-FU metabolize into FdUMP–>inhibits thymidylate synthase–>DNA and RNA damage–>Cell death
Use: colorectal, stomach, breast, head neck cancers
Adverse effects: oral/GI ulcers, bone marrow suppression
Resistance: amplification of thymidylate synthetase
Capecitabine= prodrug with improved oral bioavailability

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cytarabine (cytosine arabinoside, ara-C)

Cytotoxic, antimetabolite, pyrimidine analog
Mechanism of action: Ara-C–>Ara-CMP by CdK–>Ara-dCTP–>into DNA–>inhibits DNA polymerase–>halting DNA elongation
Use: acute myelogenous leukemia (AML)
Toxicity: CNS (no cytidine daminase to inactivate ara-C)= cerebellar syndrome (dysarthria, nystagmus, ataxia, renal, hepatic dysfunction); myelosuppression (leukopenia, thrombocytopenia, anemia)
Resistance: loss of CdK, can’t transport ara-C into cell, cytidine deaminase upregulation

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gemcitabine

Cytotoxic, antimetabolite, purine analog
Mechanism: dFdCyd–> dFDCYd triphosphate by CdK–>into DNA–>inhibit synthesis and function–>inhibits ribonucleotide reductase
Uses: pancreatic, non-small cell lung, ovarian, bladder
Resistance: reduced CdK, increased deoxycytidine

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6-mercaptopurine (6-MP)

6-thioguanine (6-TG)

Cytotoxic, antimetabolite, purine analog
Mechanism: 6-MP and 6-TG–>thio-GMP and thio-IMP by HGPRT–>incorporate into DNA–> damage DNA; also inhibit purine synthesis
Use: acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL)
Adverse effects: life-threatening bone marrow suppression; Thiopurine methyltransferase (TPMT) inactivates 6-MP–>deficient pts have intolerance
Resistance: HGPRT deficiency

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Fludarabine

Cytotoxic, antimetabolite, purine analog
Mechanism: CdK activates to triphosphate form in cell–>incorporate into DNA/RNA–>inhibit DNA polymerase and ribonucleotide reductase–>inhibit RNA function (no protein synthesis)
Use: chronic lymphocytic leukemia (CLL) in combo with cyclophosphamide and rituximab
Resistance: decreased CdK and drug efflux

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Cladribine

Cytotoxic, antimetabolite, purine analog
Mechanism: CdK activates to tri-phosphate form in cells–>incorporate into DNA–> causes strand breaks; inhibits ribonucleotide reductase (RNR)
Use: hairy cell leukemia
Resistance: decrease CdK, drug efflux, increased RNR expression

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Mechlorethamine

Cytotoxic, alkylating agent, nitrogen mustard
Mechanism: Rxn b/t alkyl groups on drug w/ nucleophilic group on protein and nucleic acid–>DNA crosslinking and strand breakage (damage cell in all phases of cycle)
Use: in combo with vincristine, procarbazine, and prednisone (MOPP) for Hodgkin’s lymphoma
Adverse effect: bone marrow suppression, damage to intestinal mucosa, leukemogenic (4 yrs after), toxic to reproductive systems, blistering of veins, pulmonary fibrosis
Resistance: inactivated by glutathione, reduced uptake, accelerated DNA repair, increased MGMT (repairs DNA)

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Cyclophosphamide

Cytotoxic, alkylating agent, nitrogen mustard
Mechanism: Rxn b/t alkyl groups on drug w/ nucleophilic group on protein and nucleic acid–>DNA crosslinking and strand breakage (damage cell in all phases of cycle)
Use: in combo with 5-FU and methotrexate post surgery in breast cancer (CAV), solid tumors and hematological malignancies
Adverse effect: bone marrow suppression, damage to intestinal mucosa, leukemogenic (4 yrs after), toxic to reproductive systems, blistering of veins, pulmonary fibrosis; unique= hemorrhagic cystitis, use mesna to reduce damage
Resistance: inactivated by glutathione, reduced uptake, accelerated DNA repair, increased MGMT (repairs DNA)

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Carmustine (BCNU)

Cytotoxic, alkylating agent, nitrosoureas
Mechanism: Rxn b/t alkyl groups on drug w/ nucleophilic group on protein and nucleic acid–>DNA crosslinking and strand breakage (damage cell in all phases of cycle)
Use: in combo with others for brain tumors (lipophilic –>crosses blood-brain barrier), GI neoplasms, Hodgkin’s lymphoma; wafers placed in tumor cavity after resection of gliomas to kill tumors missed in surgery
Adverse effect: bone marrow suppression, damage to intestinal mucosa, leukemogenic (4 yrs after), toxic to reproductive systems, blistering of veins, pulmonary fibrosis; unique= profound myelosuppression
Resistance: inactivated by glutathione, reduced uptake, accelerated DNA repair, increased MGMT (repairs DNA)

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Cisplastin

Cytotoxic, non-classical alkylating agents (platinum compounds)
Mechanism: DNA cross-linkages without alkyl group
Uses: solid tumors; in combo with vinblastine and bleomycin (PVB) for testicular cancer
Adverse effects: nephrotoxicity, ototoxicity, peripheral neuropathy, emesis, anemia, myelosuppression, anaphylactic-like rxn

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Carboplatin

Cytotoxic, non-classical alkylating agents (platinum compounds)
Mechanism: DNA cross-linkages without alkyl group
Uses: solid tumors; in combo with vinblastine and bleomycin (PVB) for testicular cancer; germ cell, head/neck, esophageal cancers
Adverse effects: LESS nephrotoxicity, ototoxicity, peripheral neuropathy, emesis, anemia, myelosuppression, anaphylactic-like rxn
Used in place of cisplastin if pts can’t tolerate

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Oxaliplatin

Cytotoxic, non-classical alkylating agents (platinum compounds)
Mechanism: DNA cross-linkages without alkyl group
Uses: cancers resistant to cisplastin and carboplastin; in combo with 5-FU and leucovorin for advanced colorectal cancer
Adverse effects: nephrotoxicity, ototoxicity, peripheral neuropathy, emesis, anemia, myelosuppression, anaphylactic-like rxn

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Vinblastine

Cytotoxic, plant derivative, vinca alkaloid
Mechanism: prevent formation of microtubules–>mitotic arrest in metaphase –>killed at metaphase-anaphase cell cycle check point
Use: testicular cancer, lymphomas, 2nd-line therapy of solid tumors
Adverse effects: myelosuppression

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Vincristine

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Paclitaxel

Cytotoxic, plant derivative, taxane
Mechanism: bind beta-tubulin subunit of microtubules–>prevent disassembly of microtubules–>arrest in mitosis–>cell death at metaphase-anaphase cell cycle checkpoint
Use: head and neck, lung, ovaries, breast
Adverse effects: myelosuppression and peripheral neuropathy, hypersensitivity rxn
Filgrastim (granulocyte-colony stimulating factor) reduces myelosuppression
Pretreatment of dexamethasone and antihistamines to prevent hypersensitivity

Docetaxal

Cytotoxic, plant derivative, taxane
Mechanism: bind beta-tubulin subunit of microtubules–>prevent disassembly of microtubules–>arrest in mitosis–>cell death at metaphase-anaphase cell cycle checkpoint
Use: head and neck, lung, ovaries, breast
Adverse effects: myelosuppression, LESS peripheral neuropathy, fluid retention, hypersensitivity rxn
Filgrastim (granulocyte-colony stimulating factor) reduces myelosuppression
Pretreatment of dexamethasone and antihistamines to prevent hypersensitivity

Irinotecan

Topotecan

Cytotoxic, plant derivatives, captothecins
Mechanism: inhibit topoisomerase I–> prevent repair of cuts–>DNA damage (S-phase specific)
Use: colorectal, ovarian, small cell lung cancer
Adverse effects: myelosuppression, diarrhea

Etoposide

Cytotoxic, plant derivatives, class II topoisomerase inhibitor
Mechanism: inhibit topoisomerase I–> prevent repair of cuts–>DNA damage (S-phase specific)
Use: combo therapy for testicular and small cell lung cancer
Adverse effects: myelosuppression, diarrhea

Doxorubicin

Cytotoxic antibiotic, anthracycline (from Streptomyces)
Mechanisms: intercalates DNA–>DNA helix changes shape–>inhibit DNA polymerase; inhibit topoisomerase II–>DNA strand breaks
Use: breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, lung, osteosarcoma, hematological malignancies
Adverse effects: irreversible cardiomyopathy (free radicals), myelosuppression
Epirubicin is analog that has less cardiotoxicity

Bleomycin

Cytotoxic antibiotic
Mechanism: glycopeptide chelates Fe, Cu, and bind DNA–>single and double strand breaks–>arrest in G2 phase
Use: lymphomas, testicular, cervical, head & neck, Hodgkin’s
Adverse effects: pulmonary toxicity (high dose), cutaneous effects, MINIMAL myelosuppression and immunosuppresion

Prednisone

Target agent, glucocorticoids
Mechanism: decrease lymphocyte proliferation
Use: chronic lymphocytic leukemia (CLL), Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma; in combo with vincristine
Adverse effects: glucose intolerance, osteoporosis, psychosis, immunosuppression

Dexamethasone

Target agent, glucocorticoids
Mechanism: decrease lymphocyte proliferation
Use: preferred glucocorticoid for multiple myeloma; in combo with others
Adverse effects: glucose intolerance, osteoporosis, psychosis, immunosuppression

Tamoxifen

Target agent, selective estrogen receptor modulator (SERM)
Mechanism: competitive inhibitor of estrogen receptor
Use: breast cancer tumors expressing estrogen receptor (post-menopausal women)
Adverse effects: increase risk of endometrial cancer, thromboembolism
Resistance: estrogen receptor changes cause reduced affinity

Anastrozole

Target agent, hormone antagonist Mechanism: inhibit aromatase-->decrease estrogen synthesis in post-menopausal women Use: estrogen-sensitive breast tumors in post-menopausal women

Flutamide | Bicalutamide

Target agent, hormone antagonist Mechanism: bind androgen receptor-->inhibit testosterone Use: prostate cancer

Leuprolide | Goserelin

Target agent, hormone agonist Mechanism: desensitization of GnRH receptors-->reduce secretion of LH and FSH from anterior pituitary--> drop in testosterone synthesis Use: prostate cancer

Trastuzumab

Target agent, monoclonal antibody Mechanism: bind extracellular portion of HER-2 receptor-->blocks signaling-->induce antibody dependent cytoxicity Use: combo w/ paclitaxel in pts with HER2 overexpression metastatic breast cancer; gastric, esophageal, lung, and other tumors that over express HER2 Adverse effects: increased cardiac toxicity when used in combo with doxorubicin and anthracyclines, fever, chills, nausea, rashes

Cetuximab

Target agent, monoclonal antibody Mechanism: binds EGFR (tyrosine kinase)-->blocks signaling Use: EGFR-expressing colorectal tumors Resistance: acquire activating mutations in RAS-->test routinely

Bevacizumab

Target agent, monoclonal antibody Mechanism: binds VEGF-->prevent activation of VEGF receptor-->inhibit angiogenesis Use: clear-cell renal cancer, lung, colorectal, breast cancer, glioblastomas Adverse effects: blood vessel injury, bleeding, reduce wound (do NOT use until 4 wks after surgery), hypertension, arterial thrombosis (stroke, MI), colonic perforation

Imatinib (Gleevec)

Target agent, small molecule tyrosine kinase inhibitor Mechanism: binds ABL-->change in conformation-->prevent kinase from binding substrate/phosphate donor; inhibits tyrosine kinase activity of platelet derived growth factor receptor (PDGFR) and c-KIT Use: chronic myelogenous leukemia (CML), tumors driven by activating c-KIT mutations and PDGRF mutations (GI stomal tumors, CML) Adverse effects: GI distress, myelosuppression, hepatoxicity Resistance: point mutations in ABL

Erlotinib

Target agent, small molecule tyrosine kinase inhibitor Mechanism: EGFR inhibitor, ATP competitive inhibitor Use: metastatic nonsmall cell lung carcinoma in pts with EGFR exon 19 deletions or exon 21 substitution mutations Adverse effects: diarrhea, skin rash, anorexia, fatigue Resistance: secondary mutation in EGFR, amplification of MET oncogene

Asparaginase

Target agent Mechanism: hydrolyzes plasma L-asparagine into L-aspartate-->starve tumor cell of L-asparagine Use: childhood acute lymphoblastic leukemia (ALL) Adverse effects: allergic hypersensitivity, respiratory failure, hypotension

Bortezomib

Target agent Mechanism: inhibit proteasome-->inhibit transcription of NF-kappa B-->increase tumor cell death in hypoxic environment; inhibit proteasome-->inhibit degradtion of tumor suppressor and apoptotic initiator p53 Use: multiple myelomas Adverse effects: thrombocytopenia, fatigue, peripheral neuropathy, neutropenia, anemia, vomiting, diarrhea, limb pain, dehydration, nausea, weakness

Temsirolimus

Target agent Mechanism: inhibit mTOR complex 1 (mTORC1)-->reduce protein translation-->promote cell cycle inhibition-->promote apoptosis Use: renal cell carcinoma Adverse effects: skin rash, mucositis, anemia, leukopenia, thrombocytopenia, immunosuppression, hyperglycemia, hypertiglyceridemia Resistance: mTOR forms mTORC2-->increase AKT activity