Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously a good correlation between etoposide-induced sister chromatid exchanges (SCE) and cytotoxicity. A semisynthetic derivative of podophyllotoxin, etoposide is also called Vepesid (Bristol; code designation VP-16-213, abbreviated VP-16). Since SCE represent DNA recombinational events, we hypothesized that VP-16-induced SCE might result in nonhomologous recombination in which segments of DNA were either deleted or added, leading to an alteration of gene sequences responsible for essential cell proteins. Alterations of such essential genes and consequent interference with formation of their products could consequently lead to cell death. To evaluate whether VP-16 treatment caused sufficient levels of DNA sequence alterations to interfere with gene product formation, we isolated hypoxanthine (guanine) phosphoribosyltransferase (HPRT)-deficient mutants from Chinese hamster V79 cells grown in the presence or absence of VP-16. DNA from 3 spontaneous mutants and 10 VP-16-induced mutants was analyzed by Southern blot hybridization to a full-length hamster HPRT cDNA probe. Most of the VP-16-induced mutants showed partial deletions and/or rearrangements of the HPRT gene. In contrast, spontaneous mutants showed negligible deletions or rearrangements. These results provide strong support for our hypothesis that deletion of genetic sequences may constitute an important component of the mechanism of VP-16-induced cell death.
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PMID:Etoposide (VP-16-213)-induced gene alterations: potential contribution to cell death. 168 41

Etoposide, a topoisomerase II inhibitor, is a chemotherapeutic agent that is used in the treatment of a wide variety of neoplasms, including small cell lung cancer, germ cell cancer, testicular cancer, acute leukemia, and lymphoma. Although it has proven valuable, etoposide is also a known mutagen and has been implicated as a causative agent of treatment-related secondary acute nonlymphocytic leukemia. We have investigated the induction of mutation following etoposide treatment in vivo using the hypoxanthine phosphoribosyltransferase (hprt) T-cell cloning assay in small cell lung cancer patients receiving single-drug etoposide chemotherapy. This report presents results on the monitoring of 12 patients (mean age, 74.8 +/- 6.0 years; range, 66-83 years) before, during, and after chemotherapy. The treatment regimen included up to six cycles of oral etoposide given in twice-daily 50-mg tablets for 10-14 days, separated by 2 weeks of rest. Peripheral blood samples were collected on the first day of each cycle prior to treatment. Patients received one to six etoposide cycles and were followed for 0.7-5.3 months after the start of chemotherapy (total etoposide dose, 1.4-8.4 g). Results from the pooled data show no significant increase in the hprt mutant frequency (pretreatment, 46 x 10(-6) +/- 38 x 10(-6), versus posttreatment, 55 x 10(-6) +/- 46 x 10(-6)), although considerable interpatient variability was observed. Of a total of 424 selected mutants, 228 were analyzed by sequencing hprt cDNA. Spectra of 56 pretreatment and 147 posttreatment mutations revealed significant enhancement of AT-->TA transversions and a concomitant decrease in the number of GC-->TA transversions in posttreatment spectra, when they were compared with pretreatment or control spectra. No evidence for the induction of gross deletions or rearrangements was found in the spectra of mutants that were recovered from patients after etoposide treatment. The lack of enhanced mutant frequency after treatment suggests that the etoposide chemotherapy was not particularly effective in inducing mutation, as measured by the hprt assay. It is proposed that mutated cells are eliminated through apoptosis due to accumulated DNA damage.
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PMID:Mutation frequency and spectrum in lymphocytes of small cell lung cancer patients receiving etoposide chemotherapy. 933 Nov 3