Cancer Chemotherapy Drugs

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Mechlorethamine

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Alkylating Agent (Bis(chloroethyl)amines)
--anti-cancer drug
--MOA: formation of cyclic immonium or carbonium ion intermediate that reacts with tissue nucelophiles --> alkylation of DNA bases --> interfere w/ nucleic acid synthesis/function --> antitumor

--part of MOPP regimen in treating Hodgkin's
--Mainly IV use
--Adverse effects: Strong vesicant (causes blistering of skin), myelosuppression, nausea, vomiting, reproduction issues

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Cyclophosphamide

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Alkyltaing agent - Bis(chloroethyl)amine
--anti-cancer drug
--effective immunosuppressant
--MOA: "prodrug" converted by liver P450 system --> alkylates DNA bases.
--"ring" has to open before it becomes active
--Adverse Effects: Myelosuppression, nausea, vomiting, reproductive effects, hemorrhagic cystitis (bleeding of bladder) so make sure patient is hydrated to wash out any active metabolites

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Melphalan

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Alkylating agents - Bis(chloroethyl)amine
--anticancer therapy
--MOA: alkylates DNA bases (DNA damage)
--Treats multiple myeloma

--common toxicities include myelosuppression, GI effects, reproductive effects, carcinogenesis

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Carmustine
Lomustine

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--nitrosourea alkylating agents
--anti-cancer drugs

--have high lipid solubility --> so crosses BBB (used for brain tumors)
--can cross BBB

--can cause delayed myelosuppression - WBC decrease 4 weeks later
Adverse Effects: nausea, vomiting, reproductive problems

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Streptozocin

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--alkylating agent - nitrosurea
--anti-cancer drug
--reactive metabolite alkylates DNA bases --> DNA damage
--Adverse Effects: renal damage, myelosuppression (only in 20% but severe when it does happen), nausea, vomiting, reproductive problems

--used to treat pancreatic islet cell carcinoma

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Procarbazine

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--alkylating agent - Nonclassical
--anti-cancer drug
--Inhibits DNA, RNA and protein synthesis
--used as part of MOPP- treatment of Hodgkin's Dz

--may cause myelosuppression, CNS depression

--may cause disulfiram-like effect after drinking EtOH
--is a weak MAO inhibitor so pts should not ingest foods containing Tyramine --> can cause increase in BP

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Cisplatin

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--platinum compound
--anti-cancer drug
--splats (binds) onto DNA and inhibits function

--similar mechanism to that of alkylating agents
--Highly emetogenic (lots of puking!!! splats!)
--may cause nephrotoxicity and ototoxicity
--may cause peripheral neuropathy, electrolyte disturbances, and anaphylactic-like rxns

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Carboplatin
Oxaliplatin

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--platinum compounds
--anti-cancer drugs
--Analogs of cisplatin
--binds to DNA and inhibits its function

--carboplatin causes dose-limiting myelosuppression but has less renal and GI toxicity

--oxaliplatin causes dose-limiting peripheral neuropathy

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Methotrexate

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--folic acid analog - Antifolate
--anti-cancer drug
--inhibits dihydrofolate reductase (DHFR) --> decreases tetrahydrofolate (FH4) --> inhibits synthesis of DNA, RNA, protein synthesis
--Resistance: decreased cellular uptake, increased efflux, increased syn of DHFR, altered DHFR, decreased formation of polyglutamates
--Oral, IV, intrathecal

--other uses other than cancer include rheumatoid arthritis and psoriasis
--Adverse Effects: myelosuppression, nausea, vomiting, liver damage, mucositis

--leucorvin is the antidote for excessive MTX dose

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Pemetrexed

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--folic acid analog
--anti-cancer drug
--inhibits thymidylate synthase and dihydrofolate reductase --> decreased DNA, RNA, protein synthesis

--Adverse Effects: myelosuppression, GI, Rash

--For rescue: supplement with folic acid and vitB12 to avoid toxic effects - reduce toxicity without interfering with clinical efficacy

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6-Mercaptopurine

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--purine analog
--anti-cancer drug
--Prodrug --> active nucleotides interfere with multiple reactions in purine synthesis. (Inhibits purine synthesis)
--analog is also incorporated into DNA and RNA causing strand instability

--metabolized by TPMT so pts that are slow metabolizers --> toxicity

--if given with allopurinol (which inhibits xanthine oxidase which also metabolizes analog), 6-MP dose must be reduced

--can cause myelosuppression, liver toxicity, immunosuppression

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Fludarabine phosphate

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--purine analog
--anti-cancer drug

--a nucleotide that is dephosphorylated extracellularly and then re-phosphorylated to an active nucleotide in the cell.
--active nucleotide inhibits DNA synthesis/repair, inhibits ribonucleotide reductase, is incorporated in DNA and induces apoptosis

--myelosuppression, immunosuppression

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Cladribine

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--purine analog
--anti-cancer drug
--incorporated into DNA, decreased DNA synthesis and repair
--Adverse Effects: myelosuppression, immunosuppression

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Alkylating Agents

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Bis(chloroethyl)amines, Nitrosoureas, alkyl sultonate, ethyleneimine, triazenes, methylhydrazine derivative, platinum analogs.
--All damage DNA
--Active metabolite reacts with tissue nucleophiles and alkylates tissue molecules -->alkylation of DNA bases = antitumor effect
--Resistance involves DNA repair
--Toxicities: myelosuppression, adverse GI and reproductive effects

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Busulfan

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Alkylating Agent - alkyl sulfonate
--causes DNA strand cross-linking --> DNA damage
--Used for CML - chronic myelogenous leukemia
Adverse Effects: myelosuppression, nausea, vomiting, reproductive problems, pulmonary fibrosis

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Antimetabolites

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--Folic Acid Analog (Methotrexate) - Interferes with nucleotide synthesis or degradation
--Purine Analog (6-mercaptopurine) - interferes with nucleotide synthesis or degradation
--Pyrimidine Analog (5-FU, Cytrabine, Gemcitabine) - interferes with DNA synthesis

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Leucovorin

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Antidote for methotrexate (MTX)
--antidote for excessive does of MTX
--Used as part of high dose MTX regimen
--Leucovorin rescue - rescues the normal cells

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5-Fluorouracil

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--Pyrimidine analog
--Anti-cancer drug
--FdUMP inhibitor of thymidylate synthase --> decreased thymidylate and decreased DNA synthesis
--analog also incorporated into DNA and RNA
--Adverse Effects: myelosuppression, GI issues, Neurotoxicity (Nervous system stuff)

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Gemcitabine

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Pyrimidine analog
--Anti-cancer drug
MOA: inhibition of ribonucleotide reductase, incorporation into DNA, inhibition of DNA synthesis/repair
--Adverse Effects: Myelosuppression, GI

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Cytarabine

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Pyrimidine analog
--anti-cancer drug
MOA: inhibitoin of DNA synthesis/repair, incorpation into DNA, inhibition of DNA chain elongation
--Adverse Effects: Myelosuppression, GI , Neurotoxicity

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Dactinomycin

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Antitumor Antibiotic
--Anti-cancer drug'
--binds DNA and interferes with RNA synthesis
--IV
Adverse Effect: Myelosuppression, GI, alopecia, tissue damage if extravasated.

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Doxorubicin

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Antitumor Antibiotic
--anti-cancer drug
MOA: inhibition of topoisomerase II (involved in uncoiling of DNA), intercalation into DNA, free radical formation, and binding to membranes
--IV, hepatic metabolism
--Adverse Effects: Myelosuppression, nausea, stomatitis, alopecia, tissue damage if extravasated,
--Cardiotoxicity:
----Chronic form - cardiomyopathy, manifested by heart failure related to cumulative dose. with treatment for months/years
---Acute form - ECG abnormalities, arrhythmias pericarditis-myocarditis

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Daunorubicin

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Antitumor Antibiotic
--anti-cancer drug
MOA: inhibition of topoisomerase II (involved in uncoiling of DNA), intercalation into DNA, free radical formation, and binding to membranes
--IV, hepatic metabolism
--Adverse Effects: myelosuppression, cardiac toxicity, nausea, tissue damage if extravasated, alopecia (hair loss)

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Bleomycin

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Antitumor Antibiotic
--Anti-cancer drug
--mixture of glycopeptides
--binds to DNA --> strand breaks. thought to involve formation of iron complex and generation of free radicals
--eliminated in urine
--Adverse Effects: Pulmonary (cough, dyspnea, pulmonary infiltrate, pulmonary fibrosis), skin (erythema, tenderness), Allergic reactions

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Mitomycin

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Antitumor Antibiotic
--anti-cancer drug
--reduced to an alkylating agent which then binds to DNA and alkylates DNA bases
--Adverse Effects: Nausea, myelosuppression, hemolytic uremic syndrome, pulmonary toxicity

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Vinblastine

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Vinca alkaloid
--Anti-cancer drug
--inhibition of mitosis. (M-phase specific)
-- binds to tubulin inhibiting polymerization to microtubules --> mitotic arrest (undergo apoptosis)
--IV, hepatic metabolism
--Adverse Effects: myelosuppression, irritation with extravasation, nausea and vomiting, alopecia

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Vinchristine

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Vinca alkaloid
--Anti-cancer drug
--inhibition of mitosis. (M-phase specific)
-- binds to tubulin inhibiting polymerization to microtubules --> mitotic arrest (undergo apoptosis)
--IV, hepatic metabolism
--Adverse Effects: myelosuppression (milder than vinblastine), neurotoxicity (peripheral neuropathy, constipation), irritation with extravasation, alopecia

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Paclitaxel

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Taxane
--Anti-cancer drug
--binds microtubules --> promotes formation of microtubules (enhances polymerization)--> inhibition of mitosis
--IV, extensive hepatic elimination
--Adverse effects: Hypersensitivity rxns, myelosuppression, peripheral neuropathy, arrhythmias

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Etoposide

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Epipodophyllotoxin
--anti-cancer drug
--inhibits topoisomerase II (uncoils DNA) --> DNA strand breaks
--Adverse Effects: Myelosuppression, nausea and vomiting, alopecia, allergic reactions, leukemias have been reported.

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Irinotecan

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Camptothecin
--Anti-cancer drug
-- Inhibits topoisomerase I causing DNA damage.
Adverse Effects: Diarrhea, nausea and vomiting, myelosuppression

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Topotecan

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Camptothecin
--Anti-cancer drug
-- Inhibits topoisomerase I causing DNA damage.
Adverse Effects: myelosuppression, GI stuff

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Asparaginase

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Anti-cancer enzyme
--enzyme (from bacteria) which catalyzes hydrolysis of circulating L-asparagine to aspartic acid and NH3
--depletes asparagine in certain leukemic cells which have insufficient asparagines synthetase --> decreased protein synthesis
--Adverse Effects: allergic reactions, hepatotoxicity, clotting factor changes --> risk of bleeding or clotting, neurotoxicity, pancreatitis, hyperglycemia

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Imatinib

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Anti-cancer drug
--inhibition of Bcr-Abl tyrosine kinase --> inhibition of proliferation and induction of apoptosis
--Oral, hepatic CYP metabolism
--Adverse Effects: nausea, vomiting, diarrhea, fluid retention/edema, muscle cramps, anemia, neutropenia, thrombocytopenia, hepatotoxicity

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Cetuximab

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Growth factor receptor inhibitor
--Anti-cancer drug
--monoclonal antibodies that bind to extracellular domain of EGFR (epidermal growth factor receptor) --> inhibit cell proliferation, cell survival, invasion, metastasis
--EGFR is overexpressed in some tumors
--Adverse Effects: Infusion reaction, rash, hypomagnesemia, interstitial lung disease.

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Gefitinib

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Growth Factor receptor inhibitor
--Anti-cancer drug
--Inhibits tyrosine kinase domain of EGFR --> inhibits cell proliferation, cell survival etc
--Oral, hepatic metabolism
--Diarrhea, rash, interstitial lung disease, potential drug interactions

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Erlotinib

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Growth Factor receptor inhibitor
--Anti-cancer drug
--Inhibits tyrosine kinase domain of EGFR --> inhibits cell proliferation, cell survival etc
--Oral, hepatic metabolism
--Diarrhea, rash, interstitial lung disease, potential drug interactions

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Bevacizumab

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Growth factor receptor inhibitor
--Anti-cancer drug
--monoclonal antibody that binds to vascular endothelial growth factor (VEGF) --> prevents VEGF action on its receptors --> inhibits vascular growth, cell survival, cell proliferation, etc
--Adverse effects: hypertension, infusion reaction, GI perforation, would healing complications, bleeding, arterial thromboembolic events, proteinuria

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Sorafenib

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Growth factor receptor inhibitor
--Anti-cancer drug
--inhibits multiple receptor tyrosine kinases including VEGF receptors and PDGF receptors
--Oral, metabolized by CYP3A4
--Adverse Effects: hypertension, fatigue, bleeding, hand-foot syndrome

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Sunitinib

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Growth factor receptor inhibitor
--Anti-cancer drug
--inhibits multiple receptor tyrosine kinases including VEGF receptors and PDGF receptors
--Oral, metabolized by CYP3A4
--Adverse Effects: hypertension, fatigue, bleeding, cardiac dysfunction, possibly heart failure

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All-trans-retinoic acid

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Anti-cancer drug
--induction of differentiation into cells that cannot proliferate
--Adverse Effects: Vitamine A toxicity, Retinoic acid syndrome (dyspnea, fever, weight gain, hypotension, and pulmonary infiltrates)

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Arsenic trioxide

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Anti-cancer drug
--induction of differentiation into cells that cannot proliferate
--Adverse effects: QT prolongation, arrhythmias, syndrome similar to retinoic acid syndrome (dyspnea, fever, weight gain, hypotension, and pulmonary infiltrates)

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Bortezomib

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Anti-cancer drug
--Proteasome Inhibitor
--Adverse Effects:peripheral neuropathy, GI, hypotension, thrombocytopenia, neutropenia

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Hydroxyurea

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Anti-cancer Drug
--Inhibits ribonucleotide reductase decreasing DNA synthesis
--Adverse Effects: myelosuppression, GI, dermatologic rxns

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Rituximab

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Anti-cancer Antibody
--Antigen = CD20
--Used for B-cell non-Hodgkin's lymphoma

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Trastuzumab

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Anti-cancer Antibody
--Antigen = HER-2/neu
--Used for breast cancer

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Information from Cancer chemotherapy Clinical correlation

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All you need to know from this lecture is:
1) B-Raf is mutated in melanomas.
2) CTLA4 turns off T cells, making it a good target for chemotherapy drugs. So block CTLA4 --> T cells turned on and activated against melanoma.