Antineoplastics: antimetabolites, dna elongation inhibitors, antifolates

nucleotides, chain elongation

MOA of antimetabolites:

- inhibit enzymes that synthesize ________

- some arrest _____ _______ by incorporation into DNA

purine and pyrimidine antagonists

what are the 2 subclasses of antimetabolites?

thymidylate synthase

pyrimidine antagonists inhibit _____ _____, the enzyme that carries out the rate limiting step in dTMP synthesis, which eventually leads to cell death

AMP, GMP

purine antagonists inhibit the biosynthesis of ____ and ____

5FU, floxuridine, capecitabine

what are the 3 examples of pyrimidine antagonists?

5FU

5FU

(pyrimidine antagonist -- antimetabolite)

ROA: IV, topical

SAR: needs to be activated for 5-F-dUMP (which can be recognized by TS)

MOA: thymidylate synthase inhibitor

- gives false substrate that binds + enters reaction, then stops it

- 5-F-dUMP, 5-10THF, and TS form a ternary complex that cannot eliminate a proton + causes irreversible inhibition of TS

indication: palliative treatment of colorectal, breast, stomach, and pancreatic cancers

- topical: actinic or solar keratosis

ADME: rapidly cleared, 20% excreted unchanged in urine, most metabolized in liver by dihydropyrimidine dehydrogenase

- pts w genetic deficiency of DPD = inc risk of life threatening consequences

floxuridine

floxuridine

(pyrimidine antagonist -- antimetabolite)

ROA: IV, regional arterial infusion

MOA: converted to 5-F-dUMP in vivo (active form) which then causes irreversible inhibition of TS

indication: GI adenocarcinoma metastatic to liver

AE: use w extreme caution in impaired renal or hepatic function

- can be removed by dialysis

- lower risk of N/V

- PK not impacted by DPD

capecitabine

capecitabine

(pyrimidine antagonist -- antimetabolite)

ROA: oral

MOA: prodrug converted to 5-F-dUMP in vivo which then irreversibly inhibits TS

indication: first-line for colorectal cancer

- alone/combo w docetaxel for metastatic breast cancer

AE: myelosuppression, N/V, severe diarrhea , potentially disabling disorder of "hand and foot syndrome"

DDI: warfarin (lethal)

ADME: rapid absorption, negative food effect, variable Cmax and AUC

5FU

which is associated with genetic polymorphisms of DPD?

a. 5FU

b. floxuridine

c. capecitabine

floxuridine

which can be removed by dialysis?

a. 5FU

b. floxuridine

c. capecitabine

capecitabine

which pyrimidine antagonist is first line therapy for colorectal cancer?

hand and foot syndrome

what is a potentially fatal side effect associated with capecitabine?

warfarin

what drug does capecitabine have a lethal DDI warning with?

capecitabine

which can be given orally?

a. 5FU

b. floxuridine

c. capecitabine

5-F-dUMP

all pyrimidine antagonists need to be activated in vivo to what?

6MP, 6TG

what are the 2 examples of purine antagonists?

6MP

6MP (6-mercaptopurine)

(purine antagonist - antimetabolite)

ROA: oral

MOA: inhibits de novo synthesis of AMP and GMP by inhibiting glutamine amino phosphoribosyl (rate limiting enzyme) and is then incorporated into RNA and DNA

- lower risk of mutagenesis and 2º malignancy

indication: acute lymphatic and myelogenous leukemia

resistance:

- active uptake via nucleoside transporters

- deficiency in activating HGPRT enzyme

AE: myelosuppression, hepatotoxic at high doses

- genetic deficiency of TPMT = inc risk of purinethol toxicity

6TG

6TG (6-thioguanine)

(purine antagonist - antimetabolite)

ROA: oral

MOA: inhibits de novo synthesis of AMP and GMP by inhibiting glutamine amino phosphoribosyl (rate limiting enzyme) and is then incorporated into RNA (active form) and DNA

indication: nonlymphatic leukemias

AE: TPMP deficiency = serious myelosuppression

oral

what is the ROA for 6-MP and 6-TG?

cytarabine, gemcitabine, fludarabine

what are the 3 examples of dna polymerase + chain elongation inhibitors?

cytarabine

cytarabine

(dna polymerase + chain elongation inhibitor)

ROA: IV, in combo

MOA: prodrug that needs to have triphosphate attached for activation, which is then incorporated into growing DNA + preventing chain elongation

- also inhibits DNA/RNA polymerases + nucleotide reductase

- active in S phase

indication: acute nonlymphatic leukemia

- intrathecal admin: meningeal leukemia

SAR: differs from cytidine bc there is an arabinose instead of ribose

gemcitabine

gemcitabine

(dna polymerase + chain elongation inhibitor)

ROA: IV

SAR: active = triphosphate form

MOA: DNA polymerase inhibitor

- incorporated into elongating DNA , then only 1 NT can be added eventually leading to cell death

- diphosphate form inhibits ribonucleotide reductase

indication: 1st line for adenocarcinoma of the pancreas

- (+) carboplatin = advanced ovarian cancer

- (+) paclitaxel = 1st line for metastatic breast cancer

- (+) cisplatin = 1st line for NSCLC

ADME: longer t1/2 than cytarabine due to gem-difluoromethylene group

fludarabine

fludarabine

(dna polymerase + chain elongation inhibitor)

ROA: IV

SAR: marketed as phosphate to inc aqueous solubility for IV admin

- triphosphorylated to active triphosphate (2-fluoro-ara-ATP) in vivo

MOA: DNA polymerase inhibitor

- ribonucleotide reductase inhibitor

indication: b-cell chronic lymphocytic leukemia

- cells w high levels of deoxycytidine kinase will respond well this agent

AE: "aids in a bottle" due to significant immunosuppressant activity

ADME: relatively resistant to degradative action of adenosine deaminase

triphosphate

in what form are all dna polymerase + chain elongation inhibitors active?

gemcitabine

which has a longer t1/2:

a. cytarabine

b. gemcitabine

gemcitabine

what is the 1st line treatment for adenocarcinoma of the pancreas?

fludarabine

which agent is associated with the AE "aids in a bottle"?

a. cytarabine

b. gemcitabine

c. fludarabine

both

antifolates inhibit the synthesis of:

a. purines

b. pyrimidines

c. both

methotrexate

methotrexate

(antifolate)

ROA: PO, IV

MOA:

- DHFR inhibitor = blocks dTMP synthesis

- inhibits GAR transformylase, a key enzyme in synthesis of purine nucleotides

- works in S phase

SAR: undergoes intracellular FPGS-catalyzed polyglutamation, which adds several anionic carboxylate groups

indication: breast, lung, head, and neck cancers

- non-hodgkin's lymphoma

- psoriasis, RA

- off label: MS

AE: toxicity occurs at high doses

- use leucovorin as rescue therapy

note: cancer cells become resistant over time

leucovorin

what should be used for methotrexate toxicity?

methotrexate, pemetrexed

what are the 2 examples of antifolates?

pemetrexed

pemetrexed

(antifolate)

ROA: IV

MOA: inhibits synthesis of pyrimidine and purine nucleotides via inhibition of DHFR and GAR transformylase

indication: NSCLC, malignant pleural mesothelioma (combo w cisplatin)

ADME: dose-proportional Cmax and AUC, 81% ppb

AE: myelosuppression, neutropenia, nausea, mucositis