Purine Analogs Flashcards

6-MP, 6-TG, Penoststin, Cladribine, Fluarabine

purine analogs that have valuable roles in cancer therapy

Purine analogs can also function as:

immunosuppression in auto-immune disease and organ transplant as well as serve as antiviral chemotherapy

Most important point of attack in purine analogs is:

reaction of glutamine and PRPP to form 5-phosphoribosylamine, the first committed step in the de novo pathway

IMP dehydrogenase inhibition leads to:

Inhibition of GMP

Adenylosuccinate synthetase inhibition leads to:

Inhibition of AMP

A purine analog in which sulfur replaces the oxygen atom of purine,

then used as an antineoplastic AGENT primarily for treatment of acute lymphoblastic leukemia

6-MP and 6-TG mechanisms of resistance

deficiency or lack of the activating enzyme HGPRT (leads to decreased drug transport)

Alteration in inhibition of ribosylamine 5-phosphate synthase which leads to:

altered recognition of DNA breaks and mismatches induced by 6-MP

6-MP and 6-TG toxicities

reversible bone marrow depression (primary), nausea/vomiting and anorexia (rare cases of stomatitis and diarrhea

Jaundice and hepatic enzyme elevations occur in up to:

one-third of adult patients treated with 6-MP and usually resolve in discontinuation of therapy

6-MP and its derivative azathioprine predispose

to opportunistic infection

Oral ingestion of 6-MP and 6-TG is:

incomplete since it is subject to first-pass metabolism by xanthine oxidase in the liver

What does food or oral antibiotics do to 6-MP and 6-TG?

decreases absorption

Low levels of erythrocyte TPMT activity are associated with:

increased drug toxicity in individual patients and a lower risk of relapse

Fludarabine MOA

Leads to extracellular dephosphorylation (nucleoside fludarabine)

Fludarabine inhibits

DNA polymerase, DNA primase, DNA ligase and ribonucleotide reductase where it acts a chain terminator when incorporated into DNA

Fludarabine resistance:

Decreased activity of deoxycytidine kinase, increased drug efflux, increased RNR activity

Fludarabine Toxicities

Myelosuppression in 50% patients, and nausea and vomiting in a minor fraction of patients

Pentostatin (2’-deoxycoformycin) MOA

transition-state analog of adenosine deaminase (ADA) (inhibits ADA, incorporated into DNA and results in strand breakage)

Pentostatin also inhibits:

RNA synthesis which results in intracellular accumulation of adenosine and deoxyadenosine nucleosides

Pentostatin Toxicities

Myelosuppression, GI symptoms, skin rash and abnormal liver function

What does adenosine and deoxyadenosine nucleosides inhibit?

ribonucleotide reductase and S-adenosyl homocysteine hydrolase