Pharmacology: Test 4: Cancer Chemotherapy Lec 71-73

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Class I agents

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all cells killed regardless state of proliferation

ex: nitrogen mustard, non-spec alkylating agents

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class II agents

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cell cycle specific

ex: vinblastine, methotrexate

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Class III

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non-cycle specific but more effective against proliferating cells

ex: daunorubicin

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Major mech of resistance against chemo?

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MDR- due to non-specific membrane glycoproteins that actively pumps drug out, even drugs that a structurally unrelated. BIG in NATURAL drugs.

also: transport defects, somatic mutation (6-thioguanine resistance), gene amplification (methotrexate resistance).

Fight resistance w/: combo, following protocols, cell recruitment and cell synchronization.

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Alkylating agents: Nitrogen Mustards

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contain bis-2-chloroethyl grp.

MOA: alkylation of DNA at N-7 position of GUANINE. That DNA is then subject to depurination >> single and double stranded breaks

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Alkylating agents: Nitrogen Mustards: MELPHALAN

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orally stable, phenylalanine derivative

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Alkylating agents: Nitrogen Mustards: CHLORAMBUCIL

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similar to melphalan

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Alkylating agents: Nitrogen Mustards: CYCLOPHOSPHAMIDE

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must be activated by p450 to ALDOPHOSPHAMIDE >>> then hydrolyzed to active phosphoramide mustard.

Liver converts aldophosphamide to inactive metabolites >>> less hepatotoxicity, and side effects.

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Alkylating agents: Nitrogen Mustards: CYCLOPHOSPHAMIDE -- Toxicities

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pulm. fibrosis, CYSTITIS, WATER RETENTION.

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Alkylating agents: Nitrogen Mustards: IFOSFAMIDE

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cyclophosphamide derivative; good acitivity against TESTICULAR CANCER.

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Alkylating agents: Ethylenimines: THIOTEPA

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has reactive ehtylenimonium ring already formed.

for BREAST AND OVARIAN CANCER.

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Alkylating agents: Alkylsulfonates: BUSULFAN

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bifunctional methanesulfonate.

good oral absorption, tox: myelosupression, pul fibrosis, INCREASED PIGMENTATION.

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Alkylating agents: Nitrosoureas: CARMUSTINE (BCNU), LOMUSTINE (CCNU)

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These two drugs are choloroethyl nitroureas vs methylnitroureas.

They cause: alkylation, DNA cross linking and carbamoylation of proteins.

LIPID SOLUBLE >> LONG acting, cross BBB; used in MALIGNANT GLIOMAS.

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Alkylating agents: Nitrosoureas: CARMUSTINE (BCNU), LOMUSTINE (CCNU) -- toxicities

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DELAYED but severe hematopoietic depression, pulm fibrosis, renal insufficiency.

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Alkylating agents: Triazenes: DACARBAZINE (DTIC)

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activated by microsomal enzymes. RNA and PROTEIN Synth. INHIBITED > DNA synth.

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Alkylating agents: Triazenes: TEMOZOLOMIDE

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similar to dacarbazine, but doesn't require enzymatic activation. used for ANAPLASTIC ASTROCYTOMA.

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Alkylating agents: CISPLATIN (platinol)

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platinum coord. comples with cis-dichloro form active in cancer chemo.

Against: TESTICULAR, OVARIAN, HEAD & NECK.

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Alkylating agents: CISPLATIN (platinol) -- mech of action

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dissoc. of Cl- leaving positively charged complex >>> DNA-DNA and DNA-prot. crosslinking.

BINDING to plasma protein

OXALIPTAN: a cisplatin analogue

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Alkylating agents: CISPLATIN (platinol) -- Toxicity

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NEPHROTOXICITY... CARBOPLATIN doesn't have this toxicity.

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Alkylating agents: PROCARBAZINE

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a non-spec alkylator (DNA, RNA, Protein). It is activated metabolically and metabolized by the liver to REACTIVE COMPOUNDS.

Useful in HODGKIN'S DZ

Tox: MAO-i, carcinogenicity, myelosupression

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Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE

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most potent plant-derived antitumor.

MAO: bind 1:1 ration to tubulin, leading to depolyermization, and disruption of microtubule structures >>> spindle fiber formation and mitosis inhibited, cytoskeletal movement disrupted

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Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE -- toxicities

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Vincristine: NEUROTOXICITIES, ADH release stim.,

Vinblastine: myelosupression, mucositis.

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Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE --- VINORELBINE

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semisynthetic deriv. of vinblastine with increase spec. for microtubules and less neurotoxicity

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Natural Products: Taxanes: PACLITAXEL

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from bark of western yaw tree.

Tx of BREAST, OVARIAN where anthracycline or cisplastin has failed

MOA: stabilizes assembly of microtubules by inhibiting disassembly... blocking mitotic reorganization.

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Natural Products: Taxanes: PACLITAXEL -- Toxicities

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may induce CARDIAC ARRHYTHMIAS, mucositis, neutropenia

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Natural Products: Taxanes: DOCETAXEL

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a semisynth. analgoue of paclitaxel.

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Natural Prodcuts: Epipodophyllotoxins: ETOPOSIDE (VP-16), TENIPOSIDE (VM-26).

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semisynth. glycosidic deriv. of podophyllotoxin derived from mandrake plant.

Tx: HODGKIN'S DZ, HISTIOCYTIC LYMPHOMA, SMALL CELL LUNG CARCINOMA.

MOA: inhibition of Topoisomerase II.

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Natural Products: Campothecin Derivatives: IRINOTECAN, TOPOTECAN

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Irinotecan: prodrug, effective against METASTATIC COLORECTAL CANCER.

Topotecan: effective for tx of OVARIAN, AND SCC OF LUNG

MOA: inhibiton of Topoisomerase I

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Natural Products: Campothecin Derivatives: IRINOTECAN, TOPOTECAN -- Toxicities

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usual, but especially in pts who are homozygous for 28 allele of uridine diphosphate glucuronosyltransferase 1A1 gene.

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Anticancer Antibiotics: Dactinomycin (actinomycin D)

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MOA: intercalates between adjacent G:C base pairs.

At low conc., RNA synth is inhibited.

At high both RNA and DNA synth are inhibited.

Tox: radiation sensitization

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Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE

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MOA: DNA intercalation, introduction of single strand breaks.

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Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE -- Toxicities

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CARDIOTOXICITY, leading to arrhythmias and digitalis unresponsive CHF. This is due to formation of reactive specifies leading to lipid peroxidation.

Cardiac tissue spec. sensitive to damage b/c it lack of catalase and SOD, also the drug declines glutathione peroxidase.

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Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE -- Dealing with cardiac toxicities?

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use Dexrazoxane, an iron chelator, to inhibit free radical formation to reduce cardiac damage.

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Anticancer Antibiotics: BLEOMYCIN

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peptide antibiotic, with DNA binding region and iron binding region.

MOA: S peptide binds DNA, bringing A2-Fe2+ complex into a position, which facilitates oxidation leading to depurination and depyrimidation.

This all results in SS and DS DNA breaks

The drug makes free radicals, so anywhere there is high Oxygen tension, the drug is found in higher concentration i.e skin, lung, tumor.

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Anticancer Antibiotics: BLEOMYCIN -- Resistance and Toxicity

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Resistance: increased activation of bleomycin hydrolase, increase DNA repair enzyme and cellular uptake.

Toxicity: PNEUMONITIS, skin lesions.

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Antimetabolites: METHOTREXATE (MTX)

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MOA: MTX is a folic acid analogue that is competitive inhibitor of enzyme, dihydrofolate reductase (DHFR). This blocks conversion of FH2 to FH4, causing folate depletion which is necessary to perform single carbon transfers.

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Antimetabolites: METHOTREXATE (MTX) -- What does it inhibit then?

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Due to folate depletion:

1. dUMP to dTMP inhibited. (pyrimidine biosynth)

2. glycinamide ribonucleotide to N-formyl glycinamide ribonucleotide

3. 5-aminoimidazole-4-carboxamide ribonucleotide to 5-formaminoimidazole-4-carboxamide ribonucleotide.

2 and 3 involved in purine ring synth.

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Antimetabolites: METHOTREXATE (MTX) -- Pharmacology

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RENAL excretion only.

low dose oral or high dose IV.

TIGHTLY BOUND TO PROTEINS.

actively transported into cells and found as MTX-polyglutamates.

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Antimetabolites: METHOTREXATE (MTX) -- Resistance & toxicities

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INCREASED DHFR ACTIVITY (gene amplification), and reduce transport


In low dose to high dose:

myelosupression, renal, haptic, neuro and teratogenicity.

significant incidence of LEUKOENCEPHOLOPATHY after intrathecal administration, espec. if used in combo with CRANIAL RADIATION.

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Antimetabolites: METHOTREXATE (MTX) -- aborting the toxicity

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can be done by administring LEUCOVORIN, which provides cells with reduce folate, bypassing inhibited reductase.

Leucovorin can also be used to potentiate the acitivity of 5-FU.

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Pyrimidine analogues:

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they are analogues of uridine or cytidine which: block synthesis of nucleic acid, and/or metabolized to active inhibitors of nucleic acid biosynthesis and/or incorporated into nucleic acid resulting in disruption.

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Pyrimidine analogues: 5-Fluorouracil

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pyrimidine analogue, in which 5th position ring has a fluorine atom.

MOA: 5-FU metabolized to 5-FdUMP (a dTMP analogue).

5-FdUMP potent suicide inhibitor of thymidylate synthase (TS).

5-FUTP incorporated into RNA resulting in defective transcripts.

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Pyrimidine analogues: 5-Fluorouracil -- resistance and toxicities

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Overexpression of TS, or decreased affinity of 5-FdUMP due to mutation.

tox incl. chronic conjunctivitis, mylosuppression and GI distress.

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Pyrimidine analogues: Other fluoropyrmidines

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Capecitabine: a 5-FU prodrug who's final action is catalyzed by thymidine phosphorylase, an enzyme elevated in certain tumors. Used to tx: METASTATIC BREAST, COLON CANCER

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Pyrimidine analogues: Cytosine arabinoside

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a cytidine analogue, in which ribose is replaced by arabinose.

For tx of: HEMATOLOGIC MALIGNANCIES.

MOA: Ara C converted to Ara CTP by deoxycytidine kinase.

Ara CTP is potent inhibitor of DNA Pol, and incorporation resultis in defective ligation and premature termination.

Overall, STOPS DENOVO SYNTHESIS OF DNA.

GEMCITABINE has good acitivity against breast, non-small cell lung cancer, pancreatic carcinoma and ovarian carcinoma.

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Pyrimidine analogues: Other pyrimidine analogues

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AZACITIDINE: inhibited DNA methyl-transferase resulting in hypomethylation... tx of MYELODYSPLASTIC SYNDROME.

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Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE

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MOA: convert hypoxanthine-guanine-phophoribosyl transferase (HPRT) to nucleoside monophosphates.

The phosphorylated forms inhibit:

feedback inhibit de novo purine synthesis

competitively inhibit biosynth. reaction.

coverted to triphosphates that are incorporated into DNA and RNA.

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Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE -- Pharmacology

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Metabolism of 6-MP: S-methylation by TPMPT, and oxidation by Xanthine Oxidase (XO) to 6-thiouric acid.

POLYMORPHISMS in TPMT can result in variable effeciveness/toxicity i.e. gouty syndrome.

metabolism of 6-TG: via S-methylation

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Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE -- Mech of Resistance

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overexpression of TPMT, HPRT mutation.

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Purine Analogues: HYDROXYUREA

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inhibits ribonucleotide reductase, inhibits DNA synthesis, and blocks cells at the **G1/S** Boundary

adverse effect: bone marrow supression.

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Enzymes: ASPARAGINASE

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catalyze asparagine to aspartate.

MOA: in cells, esp lymphoid cells, levels of asparagine synthetase are very low, so asparagine is an essential amino acid to them. Asparaginase causes deprivation and hence inhibition of PROTEIN SYNTHESIS.

Tox: REDUCTION in secreted proteins i.e. clotting factors, insulin, albumin; also causes hypersensitivity reactions.

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Tyrosine Kinase Inhibitors: IMATINIB MESYLATE (GLEEVEC)

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competitively blocks ATP-binding site of c-abl kinase.

c-abl kinase is unregulated in CML due to its transloction to bcr region of chromose 22.

Tx of CML and Ph+ ALL.

Also inhibits c-kit and PDGF-assoc tyrosine kinase.

also approved for GI stromal tumor.

Side effects: **CHF,

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Tyrosine Kinase Inhibitors: ERLOTINIB, GEFITINIB

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inhibits EGF receptor-associated tyrosine kinase.

tx of non-SCC of lung (in non-smokers) and pancreatic cancer.

Also assoc. w/ increase risk of CHF.

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Antibodies: CETUXIMAB

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antibody against EGF receptor in HEAD AND NECK AND METASTATIC COLORECTAL CANCER.

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Antibodies: TRASTUZUMAB (HERCEPTIN)

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induces antibody-dependant cell mediated cytotoxicity.

tx of p185-her2-positive breast cancer.

side effects: cardiotoxicity esp. w/ anthracyclins.

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Antibodies: BEVACIZUMAB

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against VEGF receptors, inhibits angiogenesis

tx of LUNG AND MET. COLON CANCER.

assoc. with thromboembolic events.

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Antibodies: RITUXIMAB

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anti-CD20 antibody, promotes complement mediated cell lysis of malignant B cells in CD-20 pos, non-Hodgkin's B Cell Lymphoma

Use can result in HBV reactivation.

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Antibodies: GEMTUZUMAB OZOGAMICIN

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against myeloid cell surface antigen CD33. The ab is cojucated to DNA-cleaving antibiotic calicheamicin.

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biologic response modifiers: VORINOSTAT

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histone deacetylase inhibitor

tx of cutaneous T cell lymphoma

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biologic response modifiers: BORTEZOMIB

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proteosome inhibitor, for tx of multiple myeloma and mantle cell lymphoma.

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biologic response modifiers: ALL-TRANS-RETINOIC ACID (VIT A)

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first line tx for PROMYELOCYTIC LEUKEMIA.