Antineoplastic Agents Flashcards
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
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
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
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
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
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
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
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)
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)
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)
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
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
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
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
Vincristine
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: less myelosuppression, neurotoxicity (numbness, tingling, motor weakness)
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
