Sweatman Cytotoxic Chemotherapy Agents Flashcards by Robert Ellis

3 majors MOA’s through which Chemotherapy drugs work

Action on DNA
Action on Mitotic Spindle
Hormonal Agents

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Action on DNA can be broken up into (2)

damage to DNA

2. inhibition of DNA synthesis

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Action on mittotic spindle can be further subdivided into (1)

Microtubule Inhibition

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Hormonal agents can be broken up into (2)

agonists (prednisone)

2. antagonists (tamoxifen)

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Most toxic pharmaceutic agents

anti-cancer drugs

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DNA damage can be subdivided into 2 types

alkylation (cyclophosphamide)

2. free radical formation (doxorubicin)

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Inhibition of DNA synthesis or function can be divided into two categories

Antimetabolites (methotexate)

2. Topoisomerase (etoposide)

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Anti-cancer drugs that target cells undergoing cycling

Cell-Cycle Specific drugs (CCS)

*cannot kill drugs that are in the G0 phase

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Anti-Cancer drugs that kill tumor cells in both the cycling and resting phases

Cell-Cycle Non-Specific (CCNS)

*can kill cells which are in G0 phase

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CCS drugs are particularly effective when

larger proportion of cells within a tumor are proliferating (cycling)

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Fraction of cells within a tumor hat are actively dividing

Growth fraction

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Log-Kill hypothesis

Chemotherapeutic agents work via First order kinetics–> a constant proportion of cells are killed per log-dose, NOT a constant NUMBER of cells.

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1 log dose will decrease the tumor cell population by

one order of magnitiude (90%)

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rescue therapy

administration of endogenous metabolites to counteract the effects of anticancer drugs on normal tissues

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Vesicant example

mechloethamine (an alkylating agent)

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Vesicant definition

drugs that causes blisters when it contacts tissues–> damaging to the veins if administered in high enough concentrations into small vessels…

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M phase inhibitors

Vinca Alkyloids

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G2 phase inihibotor

Bleomycin

and podophyllotoxins

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G2 and S phase inhibitors

Podophyllotoxins

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S phase inhibitors

Methotrexate

and Podophyllotoxins

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Resistance mechanism especially important for alkylating agents

Increased DNA repair

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MOR important to Bleomycin, CIsplatin, and Anthracyclins

*all of which form electrophillic species

Formation of trapping agents

–>increase production of thiol trapping agents which interact with these drugs

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MOR important to Methotexate

Change in target enzyme
and Increased synthesis of enzyme
*DHFR

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examples of purine antimetabolites

mercaptopurine

thioguanine

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pyrimidine antimetabolites

cytarabine | flourouracil

MOR involving purine/pyrimidine antimetabolites

>decreased activity of tumor cell enzymes to CONVERT PRODUGS INTO CYTOTOXIC METABOLITES

another MOR involving puring/pyrimidine antimetabolites

Increased inactivation of these prodrugs results in decreased effect

MOR involving many Anti-cancer drugs

decreased drug accumulation/increased efflux >upregulation of MDR1 (pGP)

Alkylating agents are CCS or CCNS?

CCNS

Alkylating agents MOA

-->form reactive molecular species that alkylate nucleophillic groups on DNA, particularly N-7 position of guanine-->leads to CROSS LINKING, ABNORMAL BASE PAIRING AND DNA BREAKAGE

RESISTANCE TO ALKYLATING AGENTS OCCURS VIA

INCREASED DNA REPAIR MECHANISMS DECREASED DRUG PERMEABILITY PRODUCTION OF TRAPPING THIOLS

nitrogen mustards (alkylating agents)

cyclophosphamide | mechlorethamine (a vesicant)

CYP450 break down of cyclophosphamide results in

acrolein ( a breakdown product) | CYP450 break down is required for anti-tumor capabilities

Hemorrhagic Cystitis is brought on by ________ and releived by ____________.

acrolein build up following cyclophosphamide tx mesna and intense hydration

biotransformation of cyclophosphamide takes place in the

liver with CYP450's

Conversion of Mechlorethamine takes place

spontaneously in the body to a cytotoxic product

Drug with marked vesicant actions

Mechlorethamine

Alkylating agents: Platinum analogs

Cisplatin-->testicular carcinoma, bladder, lung ovary carboplatin-->similar to cisplatin oxaliplatin--> colon

side effect of cisplatin

tinnitus--> acoustic nerve damage

Alkylating agents: procarbazine characteristics

reactive agent that formd hydrogen peroxide--> generates free radicals--> DNA strand scission

ROS producing cemotherapeutic agent

procarbazine

Anti cancer agent with disulfram-like reactions--> and therefore should not be taken with alcohol

procarbazine | *aldehyde dehydrogenase inhibitor

used to reat chronic myelogenous leukemia

Bisulfram--> an alkylating agent

Antemetabolites are CCS or CCNS

CCS

Antimetab. antagonist of folate

methotrexate

Antimetab. antagonist of purines

mercaptopurine | thioguanine

Antimetab. antagonist of pyrimidines

flourouracil cytarabine gemcitabine

Antimetabolites primarily work on the ______ phase

Synthesis phase

Down side of antimetabolites

immunosupressant

MOA for methotrexate

substrate for and inhibitor of DHFR *ultimately leads to decrease in the synthesis of THYMIDYLATE, PURINE NUCLEOTIDES, AND AMINO ACIDS (INTERFERES WITH NUCLEIC ACID AND PROTEIN METABOLISM

important product derived from breakdown of methotrexate that leads to cytotoxicity-->

polyglutamate derivatives

does methotrexate reach CNS

NO--> but good distribution everywhere else

clearance of methotrexate-->

renal, requires good hydration

toxic effects of methotrexate (bone marrow, skin, gi) can be countered by what?

leucovorin rescue--> folinic acid

6-MP and ^-TG are activated by

hypoxanthien-guaninephosphoribosyl transferases HGPRTases--> to toxic nucleotides that inihibit several enzymes involved in purine metabolism --> resistant tumors have DECREASED HGPRTase activity

Bioavailability of 6-MP and 6-TG

poor due to first pass metabolism

This drug results in thymine-less death

5 FU--flourouracil | -->inhibits thymidylate synthase

Does 5-FU distribute to the cerebrospinal fluid

yes, when given IV

inihibitor of DNA polymerase

Cytarabine (ARA-C)

Of all antimetabilites--> this one is the most specific for the S phase

Cytarabine

deoxycytidine analog that when converted to active diphosphate form inihibits riboneucleotide reductase--> deminishing pool of deoxyribonucleotides--> no DNA synthesis

Gemcitabine

Plant alkaloids are CCS or CCNS

CCS

Name the types of plant alkaloids

vinca alkaloids podophyllotoxins camptothecins taxanes

name the vinca alkaloids

vinlablastine | vincristine

name the podophyllotoxins

etoposide | teniposide

name the camptothecins

topotecan | irinotecan

name the taxanes

paclitaxel | docetaxel

VInca alkyloids MOA

block the formation of mitottic spindle by preventing the assembly of tubulin dimers into microtubules

vinca alkylioids act primarily in what phase

M phase

clearance of vinca alkyloids

billiary excretion

MOA for etoposide

increases degradation of DNA via interaction with topo II | *also inhibits mitochondrial electron transport chain

when are podophyllotoxins most active

late S early G2

MOA for topotecan and irinotecan (campothectins)

inhibit topo I, damage DNA by inihiting an enzyme tha religates single DNA strands during normal DNA repair processes

Pharmacokinetics or irinotecan ( a campothectin)

prodrug converted to its active form in the liver topotectan--> eliminated renally irinotecan--> eliminated in the bowel and feces

How to taxanes work

interfere with mitotic spindle --> prevents MICROTUBUILE DISSASSEMBLY INTO TUBULIN DIMERS

HOW IS PACLITAXEL AND DOCETAXEL ADMINISTERED

NAME THE ANTHRACYCLINS

doxorubicin | daunorubicin

MOA for doxorubicin (anthracyclin)-->

intercalate bw base pairs, inhibit topo II and generate free radicals--> block synthesis of RNA and DNa and cause DNA strand breakage

anti cancer drugs causing increased free radicals

procarbazapine and doxorubicin, daunorubicin, belomycin

Anthracyclins are CCS or CCNS

CCNS

Main toxicity associated with doxorubicin

cardiac toxicity--> EKG changes and possible arrhythmia--> cardiomyopathy and CHF

drug administered to counteract cardiac toxicity of doxorubicin

dexrazoxane--> inhibits iron mediated free radical generation

Belomycin MOA

mixture or GlycoPep's that make free radicals which bidn to DNA and cause strand breakage and inhibit DNA synthesis

Belomycin works mostly in which phase

CCNS drugs that bind to dsDNA and inhibit DNA-dependent RNA synthesis

dactinomycin--> must be given parenterally--> in tact drug and metabolites are excreted in the bile

CCNS drug that is metabolized by the liver to form an alkylating agent that cross-links DNA

MITOMYCIN

ALL these drugs cause bone marrow suppression except

Belomycin Vinblastine VIncristine