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ANTIMETABOLITES

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MOA: Body mistakes for nucleotide bases, interfere with production nucleic acids, DNA, RNAEffects rapidly dividing cells (non-specific side effects ex. Bone marrow suppression)Includes pyrimidines, purines, folate antagonists (Kills all rapidly dividing cells-including bone marrow)

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5-Fluorouracil (5-FU)

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Antimetabolite: Fluoropyrimidine - analog of uracil, Prodrug, in presence of folates, interferes with thymidine formation & RNA function, Give reduced folate (leucovorin) to increase cytotoxicity. SE: neutropenia, thrombocytopenia, anemia (IV bolus), hand-foot syndrome (red, dry, blistered), N/V, mucositis, stomatitis-Hand-foot, diarrhea (worse cont. IV infusion & oral)

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Capecitabine

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Antimetabolite: Fluoropyrimidine - oral active pyrimidine analog & prodrug of 5-FU-Greater selectivity tumors than healthy tissue. SE: neutropenia, thrombocytopenia, anemia (IV bolus), hand-foot syndrome (red, dry, blistered), N/V, mucositis, stomatitis-Hand-foot, diarrhea (worse cont. IV infusion & oral)

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Cytarabine (Ara-C)

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Antimetabolite: Cytosine analog - inhibits DNA polymerase & DNA replication. NEUROTOXITY SE - low levels deaminase enzymes in CNS. Toxicity dose-dependent: Higher doses of Ara-C >1g/m2 /dose are more likely to cause CNS toxicity (confusion, dizziness, psych disorders). Bone marrow suppression & cytarabine syndrome. Bone marrow supression- thrombocytopenia (platelets- increase bleeding); anemia (fatique); WBCs-decrease immune response or immune suppression (be careful in crowds, wash hands). Some people have fever, body aches, rash, red eyes, and feel very tired about 6 to 12 hours after getting cytarabine. This is known as cytarabine syndrome. Call the doctor if the fever persists, or if you notice pain in your chest, trouble breathing, or other serious symptoms.

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Gemcitabine

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Antimetabolite: Cytosine analog - inhibits DNA polymerase in DNA and stops DNA synthesis and repair. 20 times higher intracellular conc. than Ara-C

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Azacitidine and Decitabine

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Antimetabolite: Cytosine analog - direct incorporation into DNA apoptosis and hypomethylation of DNA. Toxicity - myelosuppression (infections can occur)

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6-Mercaptopurine (6MP) and 6-Thioguanine

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Antimetabolite: Purine analog- resembles guanine to inhibit purine synthesis. Hepatic toxicity and myelosuppression. Needs Xanthine oxidase to breakdown - XO inhibitor allopurinol = serious toxicity & must dose reduce 6MP

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Fludarabine

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Antimetabolite: Purine analog- purine analog, interferes with DNA polymerase & incorporates into RNA inhibits transcription. Myelosuppression DLT & immunosuppressive on T-cells give prophylactic antibiotics & antivirals to prevent infection

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Cladribine

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Antimetabolite: Purine analog - affects active and resting cells to inhibit DNA synthesis. Risk for infection /they are immunosuppressive

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Pentostatin

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Antimetabolite: Purine analog - inhibits adenosine deaminase. Risk for infection /they are immunosuppressive

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Anti-folates

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MOA - inhibit dihydrofolate reductase (DHFR) to prevent DNA synthesis. Normal DNA synthesis requires folate. Dietary folate must be "reduced" by DHFR to active. Anti-folates inhibit DHFR so prevent DNA synthesis. Effects can be neutralized by supplying reduced folate (leucovorin rescue). Inhibit DHFR, can't break down folate to the reduced form and this prevents DNA synthesis

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Methotrexate

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Antifolate- folic acid analog inhibits DHFR. >50 yrs of use. Transported intracellularly lots MOA resistance. Can test serum MTX levels = clinical tool = target level dosing. Give until MTX levels maintained 0.02mg/L. If need leucovorin rescue for doses >1,000mg/m2, give until MTX levels <0.02mg/L. SE: renal tubular necrosis - give vigorous hydration to reduce chance of renal failure. SE: mucositis, neutropenia, thrombocytopenia, N&V, diarrhea, Stevens-Johnson syndrome. Many drug interactions, NSAIDs may increase risk toxicity. P-Gp- efflux is one reason for MOA resistance. Mucositis- inflammation (consider GI)

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Pemetrexed

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Antifolate - multitargeted antifolate, inhibits thymidine & purine synthesis to resistance. Neutropenic sepsis & hematologic toxicities due to high levels homocysteine & cystathionine (even death). Give folic acid + B12 throughout duration treatment to decrease levels toxic metabolites & reduce risk SE. SE: mucositis, neutropenia, thombocytopenia, N&V

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MICROTUBULE TARGETING AGENTS

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Mitotic inhibitors "spindle poisons", bind to tubulin and inhibit microtubule formation in M phase. Plant derivatives

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Vinca Alkaloids

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Microtubule Targeting Agents - from "vinca" or periwinkle plant. Do not give intrathecally; Vesicant - avoid extravasation

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Vincristine

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Microtubule Targeting Agent: vinca alkaloid - DLT neurotoxic (neuropathy), mild myelosuppression, paralytic ileus (extreme constipation). Max dose 2mg weekly to prevent neurotoxicity

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Vinblastine

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Microtubule Targeting Agent: vinca alkaloid - DLT myelosuppression

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Vinorelbine

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Microtubule Targeting Agent: vinca alkaloid - DLT myelosuppression

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Taxanes

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Microtubule Targeting Agent - MOA bind to tubulin & interfere with microtubule disassembly = nonfunctional microtubules AND inhibit angiogenesis

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Paclitaxel (Taxol ®)

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Microtubule Targeting Agent: Taxane - myelosuppression, neurotoxicity & hypersensitivity rxns, stomatitis, mucositis. Premedicate: dex 20mg po or iv + diphenhydramine 50mg + H2 blocker IV 30 min prior. Derived from bark of Pacific yew

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Docetaxel (Taxotere®)

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Microtubule Targeting Agent: Taxane - myelosuppression & FLUID RETENTION & hypersensitivity rxns. - Pre & postmedicate: dex 8mg po bid day before + 2 days to prevent peripheral edema (& hypersensitivity)

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nab-paclitaxel (Abraxane®)

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Microtubule Targeting Agent: Taxane - bound to albumin, activated by tumor cells. - Comparative effects but less hypersensitivity rxns! - Without cremophor (poss. cause rxns & myelosuppression?)

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Cabazitaxel (Jevtana®)

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Microtubule Targeting Agent: Taxane - FDA approved previously treated docetaxel in prostate pts. *Administer taxanes prior to platinum derivatives to myelosuppression & efficacy*

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Ixabepilone (Ixempra®)

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Microtubule Targeting Agent : Epothilones - binds to microtubules diff. than paclitaxel. Not PGp mediated. Approved metastatic breast cancer. Premed with antihistamines, no steroids needed

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Estramustine (Emcyt®)

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Microtubule Targeting Agent - Inhibits microtubule assembly. Alkylating agent + estradiol - estradiol released after administration, causes toxicity but not effects

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Topoisomerase inhibitors

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- topoisomerase cleaves DNA to unwind, then reseals it ~ inhibitor blocks these effects. Topo I -single strand breaks, Topo II - double strand breaks

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Camptothecins

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Topoisomerase inhibitors - inhibit topo-I

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Ininotecan (Camptosar®)

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Topoisomerase inhibitors: Camptothecin. SE: neutropenia and diarrhea (DLT): treat early with anticholinergics & treat late with loperamide.

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Topotecan (Hycamptin®)

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Topoisomerase inhibitors: Camptothecin. SE: neutropenia and myelosuppression

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Epipodophyllotoxins

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Topoisomerase inhibitors - Inhibit topo-II: S phase cell cycle phase specific ie. Divided doses

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etoposide (Toposar®)

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Topoisomerase inhibitor: Epipodophyllotoxins SE: bone marrow suppression, hepatotoxicity

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teniposide (Vumon®)

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Topoisomerase inhibitor: Epipodophyllotoxins

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Anthracenes (anthracyclines & mitoxantrone)

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Topoisomerase inhibitor -Intercalating topo-II inhibitors (insert themselves between 2 DNA strands & generate reactive oxygen species) Electron reduction to form free radicals cause cardiac damage & extravasation possibly from the leaking effect (also major MOA). Pgp multidrug resistance is a problem

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Anthracylines

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Topoisomerase inhibitors SE: dose-related cardiotoxicity, severe myelosuppression, Greatest risk of irreversible cariotoxicity with cumulative doses >550mg/m2 doxorubicin & aunorubicin, red coloration of fluids

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Doxorubicin (Adriamycin®)

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Topoisomerase inhibitor: Anthracyline - "red devil" - counseling point: looks red, stains red, makes urine red

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Daunorubicin (Cerubidine®)

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Topoisomerase inhibitor: Anthracyline

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Idarubicin (Idamycin®)

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Topoisomerase inhibitor: Anthracyline

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Epirubicin (Ellence®)

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Topoisomerase inhibitor: Anthracylines

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Mitoxantrone

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Topoisomerase inhibitor: anthracene - fewer free radical formation

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ALKYLATING AGENTS

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Oldest, most useful class. Oral agents- may be dispensed from community pharmacy- lots of pt counseling. Cytotoxic, mutagenic, teratogenic, carcinogenic, myelosuppressive, emetogenic, MOA: crosslinking DNA strands to inhibit DNA replication (strands won't separate as usual). Phase non-specific

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Cyclophosphamide (Cytoxan®)

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Alkylating Agent: Nitrogen mustard - alopecia, hemorrhagic cystitis

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Ifosfamide (Ifex®)

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Alkylating Agent: Nitrogen mustard

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Bendamustine (Treanda®)

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Alkylating Agent: Nitrogen mustard - lymphoid cancer tx

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Chlorambucil (Leukeran®)

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Alkylating Agent: Nitrogen mustard - oral, empty stomach

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Mechlorethamine (Mustargen®)

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Alkylating Agent: Nitrogen mustard

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Melphalan (Alkeran®)

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Alkylating Agent: Nitrogen mustard - oral

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Nitrosureas

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Alkylating Agent - high lipophilicity = cross blood brain barrier

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Carmustine (BiCNU®, Gliadel®)

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Alkylating Agent: Nitrosurea - biodegradable wafer imbedded into brain after surgery

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Lomustine (CCNU)

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Alkylating Agent: Nitrosurea - oral

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Triazines and hydrazines

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Alkylating Agents -Inhibit DNA, RNA & protein synthesis

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Dacarbazine (DTIC®)

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Alkylating Agent: Triazines and hydrazines

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Procarbazine (Matulane®)

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Alkylating Agent: Triazines and hydrazines

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Temozolomide (Temodar®)

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Alkylating Agent: Triazines and hydrazines - 100% bioavailable orally on empty stomach. Crosses BBB

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Mitomycin-C

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Alkylating Agent -Natural antitumor antibody

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HEAVY METALS (PLATINUMS)

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Platinum compounds - bind to DNA and crosslink; can cause hypersensitivity

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Cisplatin

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Heavy Metal (Platinum) - nephrotoxic, ototoxicity (sometimes permanent hearing loss), peripheral neuropathy, highly emetogenic; max dose 100mg/m2 Q3wk

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Carboplatin

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Heavy Metal (Platinum) - hematologic toxicities, myelosuppression. Special Dosing- Dose reduce in decreased renal function. Calvert formula dosing. Dose (mg) = AUC x (crCl +25)

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Oxaliplatin

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Heavy Metal (Platinum) - peripheral neuropathy & cold-induced neuropathy; active in colorectal

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Bleomycin

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Misc. Chemotherapy Agent - antitumor antibiotic from fungal streptomyces . Bleomycin-iron complex binds DNA free oxygen radicals single strand DNA breaks. Lung side effects: COPD

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Hydroxyurea

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Misc. Chemotherapy Agent - inhibits ribonucleotide reductase. For rapid decline WBC prior to more potent chemo

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L-asparaginase

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Misc. Chemotherapy Agent - helps to make l-asparagine (amino acid lacking in lymphoid cancers)

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Arsenic trioxide

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Misc. Chemotherapy Agents- differentiating agent to induce progression & apoptosis on cancer & normal cells

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Vorinostat

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Misc. Chemotherapy Agent - HDAC inhibitor causes cell death

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ENDOCRINE THERAPY

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Least toxic of systemic treatments (Esp. breast, prostate, endometrial cancer). MOA: Cancers may regress if "feeding" hormone eliminated or antagonized. Ex. SERM, Aromatase inhibitors. Stops feeding the cancer cells. Corticosteroid hormones - lymphotoxic effects

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DOSING CHEMOTHERAPY

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Often dose using BSA = body surface area. Estimates cardiac output & distribution to liver & kidneys. DuBois BSA (m2)= wt (kg)0.425 x Ht (cm)0.725x0.00718. Mosteller BSA (m2)=({Ht (in) x Wt (lbs)}/3131)1/2. Obese patients: Can use ideal v. actual body wt for obese >2m2

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LABS REQUIRED TO ADMINISTER CHEMO

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WBC > 3,000 cells/mm3 (3x 109L). ANC > 1,500 cells/mm3 (>1.5x109L). Platelets > 100,000 cells/mm3 (100x109L). Chemistry panel - assess renal & hepatic function

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BIOLOGIC AND TARGETED AGENTS

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Cytokines, monoclonal antibodies, growth factors, vaccines. Goal: outcomes, adverse effects. MOA - suppress cell proliferation, progression, survival by stopping intracellular signals. Two ways to do this: Small molecules "nibs" - interfere with downstream intracellular signal by binding target protein inside cell. Monoclonal antibodies "mabs" (MoABs) - bind extracellular receptors to prevent activation downstream signaling pathways (***Nibs- inside the cell ***Mabs-outside cell)

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Monoclonal antibodies

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Biologic and Targeted Agents - consist of immunoglobulin sequences on cell that recognize...Antigens cell death. Growth factor receptor or ligand stop proliferation Nomenclature: _ mab, o= murine (most hypersensitivity rxns), u= human, xi= chimeric, zu= humanized source (least hypersensitivity rxns)

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Monoclonal antibodies: Hypersensitivity reactions

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Mild = fever, chills, nausea, rash Severe = anaphylactic, cardiopulmonary collapse Most common 1st infusion, tumors in bloodstream. Prevention: Premed APAP, antihistamines & lower infusion rates. Treatment: Stop infusion! Give antihistamines, corticosteroids, supportive measures

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BIOLOGIC AND TARGETED AGENTS: Monoclonal antibodies

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MOA (if antigen present on tumor & normal cells = increased AE). Complement dependent cytotoxicity (CDC) = directly activates complement system cell death. Antibody dependent cellular cytotoxicity (ADCC) = MoAB attached to cell & effector cell (NK cell, mono or macrophages) kill cell. Binding leads to signal transmission induce apoptosis. Immunoconjugate - MoAB bound to chemo or radioactive particle = delivers "killing agent" to targeted cell to decrease AE

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Rituximab

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Biologic and Targeted Agent: MoABs that target cell surface glycoproteins - 1st approved anticancer 1997. Targets CD20 antigen on normal & malignant B cells (CDC, ADCC direct apoptosis). FDA approved for relapsed CD20+ B cell non Hodgkin lymphoma. 1st line aggressive & indolent non Hodgkin lymphoma + chemo. CD20+ CLL with chemo. Refractory RA

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Biologic and Targeted Agent/MoABs that target cell surface glycoproteins (others in this class include):

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-ibritumomab tiuxetan & tositumomab (each linked to radioisotopes that target B cells) -alemtuzumab -All have diff. targets & approvals but still target surface proteins

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Biologic and Targeted Agent /MoABs and small molecules that target growth factor receptors and ligands

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Same target; targets in different spots

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Human Epidermal Growth Factor Receptor Family

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Include EGFR, HER-2, HER-3, HER-4; Activated by binding to growth factor ligands uncontrolled cell growth, mets, prevent apoptosis; Activation inhibited by MoABs- competitively bind extracellular receptor to prevent ligand binding; Inhibited internally by small molecular inhibitors - blocks tyrosine kinase receptor domains internally to stop downstream signals stop proliferation, metastases process etc

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cetuximab (Erbitux®)

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BIOLOGIC AND TARGETED AGENTS/ Human Epidermal Growth Factor Receptors - competitively inhibits binding EGFR external receptor to ligands, Inhibits cell growth, apoptosis, inhibits VEGF production. FDA approved combo or monotherapy metastatic colorectal cancer & head and neck. AE: infusion related rxns, acne-like rash, fatigue, GI sxs. Skin reactions for all EGFR inhibitors. Face, upper chest, back - pustular lesions within 1st 2 weeks, resolve after tx, usually slow 28 days. May need to dose reduce if severe. Rash- along I-40

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Panitumumab (Vectibix®)

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Human Epidermal Growth Factor Receptors

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Trastuzumab (Herceptin®)

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Human Epidermal Growth Factor Receptors - Indicated for breast, ovarian, lung, prostate (see breast cancer slides)

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Erlotinib (Tarceva®)

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Human Epidermal Growth Factor Receptors - oral tyrosine kinase inhibitor (binds inside cell) - blocks signal paths in proliferation, mets, & survival of cancer cells (competes with ATP for its binding site on EGFR TK intracellular domain). NSCLC 2nd line, pancreatic cancer +gemcitabine AE: rash, diarrhea, interstitial lung disease. Lots drug interactions: INR warfarin, CYP3A4 DIs

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Lapatinib (Tykerb®)

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Human Epidermal Growth Factor Receptors - oral, combo + capecitabine BC tx. SE: diarrhea, hepatotoxicity, rash, QT prolongation. Most orals have a lot of drug reactions

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Vascular Endothelial Growth Factor

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Angiogenesis = development new blood vessels, Unregulated in several malignancies, Regulated by pro-angiogenic growth factors (VEGF, platelet derived GF, TN factor α, keratinocyte GF), High levels VEGF poor prognosis, high risk mets, Inhibitors VEGF limit or prevent cell growth of tumor, MOST CYTOSTATIC = stop/slow growth & prevent spread, Some destroy existing blood vessels = cytotoxic

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Bevacizumab (Avastin®)

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Vascular Endothelial Growth Factor - human MoAB directed against circulation VEGF. Indicated + 5-FU metastatic colorectal, + carbo+paclitaxel nonsquamous NSCLC. Do not give within 28 days of surgery = bleeding! SE: bleeding, hypertension, thrombotic events (DVT, PE, MI), proteinuria

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Sunitinib

answer

Vascular Endothelial Growth Factor - oral inhibitor VEGF2 & platelet derived growth factor receptor & c-kit. Indicated renal cell, 2nd line GIST. SE: GI (diarrhea), rash, fatigue, hypertension, CHF

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Sorafenib and axitinib

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Vascular Endothelial Growth Factor (new)- orals similar to sunitinib; sorafenib ~more hand-foot syndrome

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Bortezomib

answer

Miscellaneous targeted agents - proteasome inhibitor to induce apoptosis. Indicated MM & mantle cell lymphoma. SE: significant diarrhea >50% pts, asthenia, nausea, neutropenia, peripheral neuropathy. dosed Q72 hours to decrease cumulative toxicity

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Imatinib, dasatinib, nilotinib

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Miscellaneous targeted agents Selective inhibitor TK activity BCR-ABL fusion gene (a product of Philadelphia chromosome CML): Imatinib also causes apoptosis or arrest of growth in hematopoietic cells expressing BCR-ABL.

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Imatinib

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An additional effect of imatinib is its ability in blocking the tyrosine kinase activity of c-KIT (stem-cell factor receptor) and platelet-derived growth factor receptor. Imatinib is a standard treatment option for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and for c-KIT (CD117)-positive gastrointestinal stromal tumors. A major advance observed with imatinib therapy is its ability to eliminate the Philadelphia chromosome in patients receiving therapy resulting in cytogenetic responses (elimination of the genetic defect), thus achieving the goal of all targeted therapies; the attack and elimination of the underlying cancer biology. Prevents downstream activation of cell proliferation. Apoptosis & blocks TK activity of cKIT & platelet derived GF. Eliminates Ph. Chromosome = cytogenetic = eliminated gene defect (underlying cancer biology). SE: fluid retention, liver enzymes, nausea, muscle cramps, HA, rash (steven johnson rare), myelosuppression. DI: CYP3A4, 2D6 inhibitor. 2nd generations have greater effect on mutations except TI35I (ponatinib just approved to target this!)

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Thalidomide, lenalidomide, pomalidomide

answer

Miscellaneous targeted agents Immunomodulatory agents w many MOA including angiogenesis inhibitor, inhibit TN factor, direct cancer cell inhibition. SE thalidomide: somnolence, dizziness, orthostatic hypotension, rash, peripheral neuropathy, neutropenia. SE lenalidomide: less somnolence & neuropathy, more neutropenia, thrombocytopenia, DVT. REMS: System for Thalidomide Education & Prescribing Safety program (STEPS). RevAssist for Revlimid

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Retinoids

answer

Miscellaneous targeted agents Vitamin A plays role in normal cell differentiation. MOA: produces diverse regulatory effects Ex. Cutaneous T cell lymphoma gel or caps (bexarotene)

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Interleukin-2 (Aldesleukin)

answer

Miscellaneous targeted agents Cytokine produced by DNA technology to B & T cell proliferation & initiate multiple immune effects. Many IL-2 receptors on T cells, drug binds, kills tumor. DLT = hypotension, fluid retention, renal dysfunction "capillary leak syndrome"

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Interferons (IFNs)

answer

Miscellaneous targeted agents Proteins produced by nucleated cells & DNA technology with antiviral, antiproliferative, immunoregulatory effects; Α,β,or γ Ex. Interferon α2b (Intron-A) MOA: inhibit angiogenesis, antigen expression on tumor, prolong cell cycle to apoptosis. SE: flu-like symptoms, psychiatric, insomnia, myelosuppression, alopecia; CI in pts with major psych conditions

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Temsirolimus & everolimus

answer

Miscellaneous targeted agents: mTOR inhibitor (mammalian target of rapamycin) - signaling path that protein production & angiogenesis; Inhibitors stop pathway & decrease GF production such as VEGF

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Temsirolimus (Torisel®)

answer

Miscellaneous targeted agents - approved metastatic renal cell. SE: rash, fatigue, N, edema, loss appetite, sCr, LFT, neutropenia, thrombocytopenia, hyperglycemia, hyperlipidemia

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Everolimus (Afinitor®)

answer

Miscellaneous targeted agents: oral approved renal cell

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