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61 Cards in this Set

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Class I agents
all cells killed regardless state of proliferation

ex: nitrogen mustard, non-spec alkylating agents
class II agents
cell cycle specific

ex: vinblastine, methotrexate
Class III
non-cycle specific but more effective against proliferating cells

ex: daunorubicin
Major mech of resistance against chemo?
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.
Alkylating agents: Nitrogen Mustards
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
Alkylating agents: Nitrogen Mustards: MELPHALAN
orally stable, phenylalanine derivative
Alkylating agents: Nitrogen Mustards: CHLORAMBUCIL
similar to melphalan
Alkylating agents: Nitrogen Mustards: CYCLOPHOSPHAMIDE
must be activated by p450 to ALDOPHOSPHAMIDE >>> then hydrolyzed to active phosphoramide mustard.

Liver converts aldophosphamide to inactive metabolites >>> less hepatotoxicity, and side effects.
Alkylating agents: Nitrogen Mustards: CYCLOPHOSPHAMIDE -- Toxicities
pulm. fibrosis, CYSTITIS, WATER RETENTION.
Alkylating agents: Nitrogen Mustards: IFOSFAMIDE
cyclophosphamide derivative; good acitivity against TESTICULAR CANCER.
Alkylating agents: Ethylenimines: THIOTEPA
has reactive ehtylenimonium ring already formed.

for BREAST AND OVARIAN CANCER.
Alkylating agents: Alkylsulfonates: BUSULFAN
bifunctional methanesulfonate.

good oral absorption, tox: myelosupression, pul fibrosis, INCREASED PIGMENTATION.
Alkylating agents: Nitrosoureas: CARMUSTINE (BCNU), LOMUSTINE (CCNU)
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.
Alkylating agents: Nitrosoureas: CARMUSTINE (BCNU), LOMUSTINE (CCNU) -- toxicities
DELAYED but severe hematopoietic depression, pulm fibrosis, renal insufficiency.
Alkylating agents: Triazenes: DACARBAZINE (DTIC)
activated by microsomal enzymes. RNA and PROTEIN Synth. INHIBITED > DNA synth.
Alkylating agents: Triazenes: TEMOZOLOMIDE
similar to dacarbazine, but doesn't require enzymatic activation. used for ANAPLASTIC ASTROCYTOMA.
Alkylating agents: CISPLATIN (platinol)
platinum coord. comples with cis-dichloro form active in cancer chemo.

Against: TESTICULAR, OVARIAN, HEAD & NECK.
Alkylating agents: CISPLATIN (platinol) -- mech of action
dissoc. of Cl- leaving positively charged complex >>> DNA-DNA and DNA-prot. crosslinking.

BINDING to plasma protein

OXALIPTAN: a cisplatin analogue
Alkylating agents: CISPLATIN (platinol) -- Toxicity
NEPHROTOXICITY... CARBOPLATIN doesn't have this toxicity.
Alkylating agents: PROCARBAZINE
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
Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE
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
Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE -- toxicities
Vincristine: NEUROTOXICITIES, ADH release stim.,

Vinblastine: myelosupression, mucositis.
Natural Products: Vinca Alkaloids: VINCRISTINE, VINBLASTINE --- VINORELBINE
semisynthetic deriv. of vinblastine with increase spec. for microtubules and less neurotoxicity
Natural Products: Taxanes: PACLITAXEL
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.
Natural Products: Taxanes: PACLITAXEL -- Toxicities
may induce CARDIAC ARRHYTHMIAS, mucositis, neutropenia
Natural Products: Taxanes: DOCETAXEL
a semisynth. analgoue of paclitaxel.
Natural Prodcuts: Epipodophyllotoxins: ETOPOSIDE (VP-16), TENIPOSIDE (VM-26).
semisynth. glycosidic deriv. of podophyllotoxin derived from mandrake plant.

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

MOA: inhibition of Topoisomerase II.
Natural Products: Campothecin Derivatives: IRINOTECAN, TOPOTECAN
Irinotecan: prodrug, effective against METASTATIC COLORECTAL CANCER.

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

MOA: inhibiton of Topoisomerase I
Natural Products: Campothecin Derivatives: IRINOTECAN, TOPOTECAN -- Toxicities
usual, but especially in pts who are homozygous for 28 allele of uridine diphosphate glucuronosyltransferase 1A1 gene.
Anticancer Antibiotics: Dactinomycin (actinomycin D)
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
Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE
MOA: DNA intercalation, introduction of single strand breaks.
Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE -- Toxicities
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.
Anticancer Antibiotics: Anthracyclins: DAUNORUBICIN, DOXORUBICIN, MITOXANTRONE -- Dealing with cardiac toxicities?
use Dexrazoxane, an iron chelator, to inhibit free radical formation to reduce cardiac damage.
Anticancer Antibiotics: BLEOMYCIN
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.
Anticancer Antibiotics: BLEOMYCIN -- Resistance and Toxicity
Resistance: increased activation of bleomycin hydrolase, increase DNA repair enzyme and cellular uptake.

Toxicity: PNEUMONITIS, skin lesions.
Antimetabolites: METHOTREXATE (MTX)
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.
Antimetabolites: METHOTREXATE (MTX) -- What does it inhibit then?
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.
Antimetabolites: METHOTREXATE (MTX) -- Pharmacology
RENAL excretion only.

low dose oral or high dose IV.

TIGHTLY BOUND TO PROTEINS.

actively transported into cells and found as MTX-polyglutamates.
Antimetabolites: METHOTREXATE (MTX) -- Resistance & toxicities
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.
Antimetabolites: METHOTREXATE (MTX) -- aborting the toxicity
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.
Pyrimidine analogues:
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.
Pyrimidine analogues: 5-Fluorouracil
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.
Pyrimidine analogues: 5-Fluorouracil -- resistance and toxicities
Overexpression of TS, or decreased affinity of 5-FdUMP due to mutation.

tox incl. chronic conjunctivitis, mylosuppression and GI distress.
Pyrimidine analogues: Other fluoropyrmidines
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
Pyrimidine analogues: Cytosine arabinoside
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.
Pyrimidine analogues: Other pyrimidine analogues
AZACITIDINE: inhibited DNA methyl-transferase resulting in hypomethylation... tx of MYELODYSPLASTIC SYNDROME.
Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE
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.
Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE -- Pharmacology
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
Purine Analogues: 6-MERCAPTOPURINE, 6-THIOGUANINE -- Mech of Resistance
overexpression of TPMT, HPRT mutation.
Purine Analogues: HYDROXYUREA
inhibits ribonucleotide reductase, inhibits DNA synthesis, and blocks cells at the **G1/S** Boundary

adverse effect: bone marrow supression.
Enzymes: ASPARAGINASE
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.
Tyrosine Kinase Inhibitors: IMATINIB MESYLATE (GLEEVEC)
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,
Tyrosine Kinase Inhibitors: ERLOTINIB, GEFITINIB
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.
Antibodies: CETUXIMAB
antibody against EGF receptor in HEAD AND NECK AND METASTATIC COLORECTAL CANCER.
Antibodies: TRASTUZUMAB (HERCEPTIN)
induces antibody-dependant cell mediated cytotoxicity.

tx of p185-her2-positive breast cancer.

side effects: cardiotoxicity esp. w/ anthracyclins.
Antibodies: BEVACIZUMAB
against VEGF receptors, inhibits angiogenesis

tx of LUNG AND MET. COLON CANCER.

assoc. with thromboembolic events.
Antibodies: RITUXIMAB
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.
Antibodies: GEMTUZUMAB OZOGAMICIN
against myeloid cell surface antigen CD33. The ab is cojucated to DNA-cleaving antibiotic calicheamicin.
biologic response modifiers: VORINOSTAT
histone deacetylase inhibitor

tx of cutaneous T cell lymphoma
biologic response modifiers: BORTEZOMIB
proteosome inhibitor, for tx of multiple myeloma and mantle cell lymphoma.
biologic response modifiers: ALL-TRANS-RETINOIC ACID (VIT A)
first line tx for PROMYELOCYTIC LEUKEMIA.