Antineoplastic Drugs

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Alkylating agents target

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DNA - specifically guanine >>adenosine, cytosine

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what happens to DNA + alkylating agent?

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cross linking, mispairing, depurination, ring cleavage

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R to alkylating agents?

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incr. in P-glycoprotein, incr. in competing nucleophiles, incr. in DNA repair enzymes

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Nitrogen mustards are

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alkylating agents

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Nitrogen mustards specific examples

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Mechlorethamine, Chlorambucil, Melphalan, Cyclophosphamide, Ifosfamide

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Mechlorethamine given

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IV, topical only

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Mechlorethamine is a...

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Vesicant (blistering agent when leaks out of blood vessels)

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Chlorambucil

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least toxic, slowest acting mustard

oral

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Chlorambucil indication

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chronic lymphocytic leukemia (CLL)

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Melphalan

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IV

treats multiple myeloma, ovarian & breast cancer

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Cyclophosphamide

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oral and iv

longest half half (7 hours)

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Cyclophosphamide and Ifosfamide are

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prodrugs (require activation in liver by cytochrome P450 system)

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cyclophosphamide and ifosfamide toxic metabolite

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acrolein

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cyclophosphamide is part of

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CHOP regime

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cyclophosphamide, ifosfamide important S/E

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Hemorrhagic cystitis (prevented by mesna)

Immunosuppressant

Secondary acute leukemias (AML)

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Busulfan MOA

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alkylating agent; cross links DNA

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Busulfan indications

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CML, combo w/ cyclophosphamide for allogeneic BMTs

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busulfan delayed toxicity

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pulmonary toxicity!!

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Nitrosoureas

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Carmustine, Lomustine

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Nitrosoureas MOA

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alkylate & carbamoylate (destroys proteins)

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Nitrosoureas can

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pass through the BBB

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Nitrosoureas important S/E

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pulmonary toxicity (pulm. fibrosis)

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Carmustine & Lomustine indications

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brain tumors

Hodgkins, other lymphomas

colorectal cancer

multiple myeloma

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Dacarbazine, Temozolomide, Bendamustine are

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nonclassic alkylating agents

PRODRUGS

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Bendamustine MOA

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alkylating agent & inhibits mitotic checkpoints and induces mitotic catastrophe

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Temozolomide can

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cross the BBB

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Temozolomide indications

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brain tumors esp. malignant gliomas

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Dacarbazine indications

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melanoma, Hodgkin's dz, sarcoma

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Platinum coordination complexes

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Cisplatin, Oxaliplatin, Carboplatin

all IV drugs

"alkylating-like agents"

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Platinum coordination complexes MOA

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Pt-guanine DNA crosslinking; inhibit DNA & RNA polymerase

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Cisplatin S/E

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N/V, renal toxicity, ototoxicity, peripheral neuropathy

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Oxaliplatin S/E

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some N/V, reversible cold-induced peripheral neuropathy

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Carboplatin

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few S/E except severe bone marrow suppression

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Cisplatin and Carboplatin indications

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testicular cancer, head & neck cancer, ovarian cancer, lung cancer, bladder cancer

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Oxaliplatin indication

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Colorectal cancer (much different than cisplatin & carboplatin)

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Antimetabolites

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Folic acid, purine & pyrimidine analogs

DNA enzyme inhibitors

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Folic acid analogues

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methotrexate, pemetrexed, pralatrexate

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Metrotrexate MOA

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S phase specific

inhibits dihydrofolate reductase, resulting in reduction of one carbon transfers (anti-DNA synthesis)

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high dose of methotrexate requires

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leucovorin rescue

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Methotrexate S/E

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Renal toxicity!!

bone marrow, GI, liver, radiation recall

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high dose IV methotrexate indication

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osteogenic sarcoma (requires leucovorin rescue)

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Methotrexate indications

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immunosuppressive agent

RA

acute psoriasis

corticosteroid-dependent asthma

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Pemetrexed

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antifolate analog

inhibits thymidylate synthetase but also DHFR, GARFT, AICARFT

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GARFT, AICARFT enymes

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involved in de novo purine biosynthesis (inhibited by pemetrexed)

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Pemetrexed and pralatrexate require

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folic acid and vit. b12 to reduce toxicities

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Pralatrexate MOA

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targets DHFR and thymidylate synthetase

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Pyrimidine analogues

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5-fluorouracil, Capecitabine, Cytarabine, Gemcitabine

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5-fluorouracil MOA

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PRODRUG

converted to FdUMP, inhibits thymidylate synthetase!

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5-FU S/E

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cerebellar ataxia, hand and foot syndrome

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5-FU is enhanced by

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leucovorin (makes drug + thymidylate synthetase a more stable complex)

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5-FU can

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cross the BBB (used w/ cisplatin)

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Capecitabine MOA

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oral prodrug of 5-FU

inhibits thymidylate synthetase

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Capecitabine S/E

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less myelosuppression!!

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Cytarabine

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prodrug, S phase specific

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Gemcitabine

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inhibits both DNAp and ribnucleotide reductase

longer half life (inhibits deaminases)

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Gemcitabine S/E

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dose-limiting myelosuppression

relatively well tolerated

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Purine analogues

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6 mercaptopurine, 6-thioguanine, fludarabine, cladribine

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activation of purine analogues

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requires HGPRT - transfers PRPP on to purines

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6 mercaptopurine MOA

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competes w/ hypoxanthine for HGPRT

derivative (6-TIMP) competes w/ IMP for AMP and GMP formation

inhibits purine biosynthesis, nucleotide interconversion, biosynthesis of nucleic acids

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6 mercaptopurine S/E

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tumor lysis syndrome (treat w/ allopurinol or rasburicase)

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6 mercaptopurine drug interactions

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allopurinol (inhibits xanthine oxidase) will incr. toxicity

metabolized by 6-thiopurine methyltransferase (genetic deficiencies cause toxicities)

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azathioprine

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prodrug, metabolized to 6-mercaptopurine

used as immunosuppressant, treat RA

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6-thioguanine MOA

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damages DNA after incorporation into DNA, inhibits synthesis of AMP & GMP

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6-thioguanine drug interaction

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NOT degraded by xanthine oxidase = NO drug interaction w/ allopurinol

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Fludarabine MOA

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inhibits DNAp and ribonucleotide reductase

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Cladribine MOA

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incorporated into DNA, inhibits DNA synthesis & repair, induces DNA strand breaks

resistant to breakdown by adenosine deaminase

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Cladribine S/E

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myelosuppression, nephrotoxicity, neurotoxicity

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Purine analogues general indication

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leukemias

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Ribonucleotide reductase inhibitor

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Hydroxyurea

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Hydroxyurea S/E

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hyperpigmentation of skin, radiation recall

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Vinca alkaloids

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Vinblastine, Vincristine, Vinorelbine

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Vinca MOA

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disruption of microtubules for mitosis, thus inhibit the mitosis phase of the cell cycle

aggregate the free tubulin dimers so can't form polymer of MTs

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Vincristine S/E

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neurotoxicity (severe), bone marrow suppression (mild), alopecia

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Vinorelbine S/E

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in b/t vincristine and vinblastine

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Vinblastine S/E

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severe bone marrow suppression, mild neurotoxicity, alopecia

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Taxanes

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Paclitaxel, nanoparticle albumin-bound (NAB) paclitaxel, docetaxel

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Paclitaxel MOA

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cause build up of microtubules rather than allowing free tubulin dimers to form

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Paclitaxel S/E

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bone marrow suppression, hypersensitivity (unless pretreated w/ corticosteroid & antihistamines)

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Topoisomerase II inhibitors

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etoposide

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Etoposide MOA

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inhibit topoisomerase II DNA repair enzymes, resealing of DNA strand breaks

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Etoposide indication

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testicular cancer

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Etoposide S/E

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secondary leukemias, radiation recall, BM suppression

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Etoposide combo w/

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bleomycin & cisplatin

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Topoisomerase I inhibitors

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Topotecan and irinotecan

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Irinotecan indication

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metastatic cancer of colon or rectum

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Irinotecan S/E

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severe diarrhea, myelosuppression

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Anthracyclines

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doxorubicin, idarubicin, epirubicin

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Anthracycline MOA

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intercalates into DNA - distorts structure so RNAp cannot use DNA as a template, also binds topoisomerase II

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Doxorubicin S/E

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vesicant, discolors urine red, cardiotoxic rxn dependent on iron (forms superoxide anion causing free radical rxns)

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Bleomycin MOA

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glycopeptide; binds to DNA forming a complex w/ iron and oxygen which breaks DNA

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Bleomycin S/E

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pulmonary fibrosis (pulm. toxicity)

very little BM toxicity!!! (good for combo therapy)

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bleomycin indication

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testicular cancer (w/ etoposide)

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L-asparaginase, pegasparagase MOA

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enzyme; asparagine -> aspartic acid

ultimately limits protein synthesis in cancer cells requiring lots of asparagine for growth

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L-asparaginase, pegasparagse indications

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acute lymphocytic leukemia!

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L-asparaginase, pegasparagase S/E

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hypersensitivity, coagulation deficiencies (thrombosis), CNs neurotoxicity, liver & kidney damage, pancreatitis

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Asparaginase is different because

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lack of toxicity for BM, GI and hair follicles

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agents for Acute promyelocytic leukemia (APL)

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Arsenic Trioxide, Tretinoin (all-trans-retinoic-acid)

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Arsenic trioxide MOA

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induce differentiation of promyelocytic leukemia cells and induces apoptosis

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Arsenic trioxide S/E

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QT prolongation leading to ventricular arrhythmia

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Tretinoin MOA

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induces differentiation of acute promyelocytic cells to normal myelocytic cells

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Tretinoin S/E

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QT prolongation, Vit A toxicity

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benefit of hormonal agent, signal transduction inhibitors & targeted drgs

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may lack BM suppression, stomatitis, alopecia, severe N/V

some have specific severe toxicities

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Glucocorticoid receptor specific hormones

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Prednisone, Dexamethasone

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Prednisone & dexamethasone MOA

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binds glucocorticoid R, binds to DNA sequences (glucocorticoid response elements) = repress or activate txn for specific genes

result = apoptosis to lymphocytes

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Prednisone & dexamethasone S/E

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truncal obesity, moon facies, osteoporosis, susceptibility to infections

must withdraw drug slowly to prevent adrenal insufficiency

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EGFR-tyrosine kinase inhibitors

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Cetuximab, Panitumumab, Gefitinib, Ibrutinib

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Cetuximab MOA

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monoclonal Ab that competitively inhibits EGFR receptor

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Cetuximab indications

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Colorectal cancer (primarily), head and neck cancer

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Cetuximab S/E

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severe infusion rxns (hypoT, urticaria), acne-like rash, interstitial lung dz

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Panitumumab

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same as cetuximab; full human Ab w/ rare infusion rxns and interstitial lung dz

colorectal cancer!!

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Gefitinib and Erlotinib MOA

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metabolized by CYP3A4

cytosolic inhibitor of EGFR-TK, prevents autophosphorylation of receptor

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Gefitinib and Erlotinib indications

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non-small cell lung cancer

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Gefitinib and Erlotinib S/E

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interstitial lung dz, GI perforation

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Ibrutinib MOA

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blocks Bruton's tyrosine kinase on B-cell receptor

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Ibrutinib indications

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MCL and CLL

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BCR-ABL Tyrosine kinase inhibitors (CML drugs)

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Imatinib, Nilotinib, Dasatinib

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Imatinib MOA

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competitive inhibitor of inactive form of ATP binding site on c-abl, c-KIT, and PDGFR TKs

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all CML drugs are

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metabolized by CYP3A4

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Imatinib indications

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CML!!

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Nilotinib MOA

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binds to inactive form of BCR-ABL, higher binding affinity

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Nilotinib S/E

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less severe than imatinib, but w/ prolongation of QT interval

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Dasatinib MOA

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binds to inactive and active form of BCR-ABL, higher binding affinity

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Dasatinib S/E

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higher myelosuppression, prolongation of QT interval

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RAS/Map Kinase pathway inhibitors

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Sorafenib, Sunitinib, Pazopanib, Vandetanib, Lenvatinib, Cabozantinib, Vemurafenib, Dabrafenib

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Sorafenib MOA

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inhibits phosphorylation and activation of multiple tyrosine kinases, preventing angiogenesis, growth and metastasis

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Sorafenib indication

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advanced renal cell carcinoma

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Sorafenib, Sunitinib PK

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metabolized by CYP3A4

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Sunitinib MOA

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inhibits phosphorylation and activation of multiple tyrosine kinases, preventing angiogenesis, growth and metastasis

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Sunitinib indication

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advanced renal cell carcinoma, gastrointestinal stromal tumors

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Sunitinib S/E

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cardiac dysfunction, fatigue, hyperT

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Pazopanib indication

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advanced renal cell carcinoma

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Vandetanib, lenvatinib, cabozantinib indication

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advanced medullary thyroid cancer

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Vemurafenib, dabrafenib MOA

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low MW inhibitor of BRAF-V600E mutated forms of BRAF serine threonine kinase

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Vemurafenib, dabrafenib indication

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metastatic melanoma w/ BRAF-V600E mutation

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Vemurafenib, dabrafenib S/E

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hypersensitivity, secondary malignancies, cardiac QT prolongation

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Vemurafenib, dabrafenib + ______ for melanoma?

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Dacarbazine

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mTOR kinase inhibitors

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temsirolimus, everolimus

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Temsirolimus MOA

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inhibits mTOR (mammalian target of rapamycin) - leads to G1 arrest and apoptosis

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Temsirolimus, everolimus indication

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advanced renal cell carcinoma

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Temsirolimus, everolimus S/E

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hypersensitivity, immunosuppression, hyperglycemia, hyperlipidemia, hypertriglyceridemia, pulm toxicity

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Anaplastic lymphoma kinase (ALK) inhibitor

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Crizotinib

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Crizotinib indication

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advanced non-small cell lung cancer w/ specific fusion protein

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Crizotinib MOA

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inhibits anaplastic lymphoma kinase positive cancer cells

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Crizotinib S/E

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QT prolongation

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Proteasome inhibitors

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Bortezomib (parenteral), Carfilzomib (oral)

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Bortezomib, carfilzomib MOA

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inhibits 26S proteasome; proteins accumulate = increased apoptosis and incr. sensitivity to lethal radiation, anticancer drugs

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Bortezomib, carfilzomib indications

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multiple myeloma, mantle cell lymphoma

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Bortezomib, carfilzomib S/E

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GI, BM suppression, diarrhea, peripheral neuropathy, cardiotoxicity, fever

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Angiogenesis inhibitors

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Bevacizumab, Thalidomide, Lenalidomide, Pomalidomide

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Bevacizumab MOA

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monoclonal Ab binds to VEGF = don't form new blood vessels

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Bevacizumab indications

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metastatic cancer of colon or rectum (w/ 5FU), nonsquamous non-small cell lung cancer (with carboplatin, paclitaxel)

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Bevacizumab S/E

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GI perforation, pulm. hemorrhage, kidney damage, hyperT crisis, thromboembolism

NO myelosuppression or resistance devo

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Thalidomide MOA

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inhibits FGF, VEGF, TNF-alpha (suppress angiogenesis), co-stimulates T cells

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Thalidomide indication

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multiple myeloma (and leprosy)

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Thalidomide S/E

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neuropathy, constipation, thromboembolism

POWERFUL teratogen

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Lenalidomide, Pomalidomide MOA

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enhanced inhibition of TNF-alpha, co-stimulates T cells to suppress angiogenesis

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Lenalidomide, Pomalidomide indication

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multiple myeloma

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Lenalidomide, Pomalidomide S/E

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teratogen, myelosuppression, thrombocytopenia, thromboembolism

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Rituximab MOA

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binds Ag CD20 on B-cell precursors and mature B-lymphocytes = apoptosis, immune attack

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Rituximab indication

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B-cell NHL, CLL, combined with CHOP regime

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Rituximab S/E

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infusion-related, cardiac events, lymphopenia, reactivates HBV, TB infections, immunosuppression

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Ibritumomab tiuxetan

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anti-CD20 antibody linked to chelator (high affinity site for Indium-111 or Yttrium-90

B cells killed by radiation

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Ibritumomab tiuxetan indication

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NHL

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Tositumomab MOA

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anti-CD20 Ab unlinked and linked with 131-I

B cells killed by immune attack

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Tositumomab S/E

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hypothyroidism, severe BM suppression, hypersensitivity, infusion rxn, GI toxicity, teratogen

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Ofatumumab and obinutuzumab

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anti-CD20 on B cells of chronic lymphocytic leukemia

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Ofatumumab and obinutuzumab indication

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B-CLL for pts with failed alkylating agent and fludarabine therapy

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Obinutuzumab often combined w/

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chlorambucil for CLL Rx

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Ipilimumab MOA

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blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) on T cells to activate T-cell mediated anti-tumor immune response

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Ipilimumab indication

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metastatic melanoma, in combo w/ dacarbazine

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Pembrolizumab, mivolumab MOA

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anti- programmed death cell receptor on T-cells

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Pembrolizumab, mivolumab indication

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malignant melanoma

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Pembrolizumab, mivolumab S/E

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anemia, musculoskeletal, skin, edema

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Brentuximab vedotin

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CD30 directed drug conjugate linked to microtubule disrupting agent and protease linker = apoptosis and cell cycle arrest

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Brentuximab vedotin indication

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Hodgkin's lymphoma after failure of autologous SC transplant or 2 prior multi-agent chemo regimens

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Histone deacetylase (HDAC) inhibitors

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Vorinostat, romidepsin, panobinostat

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Vorinostat, romidepsin, panobinostat MOA

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increases acetylation of histones = increases gene txn of regulatory proteins = cell-cycle arrest and apoptosis

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Vorinostat, romidepsin, panobinostat indication

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cutaneous T-cell lymphoma, multiple myeloma

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Vorinostat, romidepsin, panobinostat S/E

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GI, anemia, thrombocytopenia, PE, cardiotoxicity

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Immunostimulants

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Interferon alfa-2a, Interferon alba-2b, Aldesleukin