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Titolo:
METHYL DNA-ADDUCTS, DNA-REPAIR, AND HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE MUTATIONS IN PERIPHERAL WHITE BLOOD-CELLS FROM PATIENTSWITH MALIGNANT-MELANOMA TREATED WITH DACARBAZINE AND HYDROXYUREA
Autore:
PHILIP PA; SOULIOTIS VL; HARRIS AL; SALISBURY A; TATES AD; MITCHELL K; VANDELFT JHM; GANESAN TS; KYRTOPOULOS SA;
Indirizzi:
WAYNE STATE UNIV,DEPT INTERNAL MED,DIV HEMATOL & ONCOL,509 HUDSON BLDG,3990 JOHN R ST DETROIT MI 48201 UNIV OXFORD,CHURCHILL HOSP,IMPERIAL CANC RES FUND,CLIN ONCOL UNIT OXFORD OX3 7LJ ENGLAND NATL HELLEN RES FND,INST BIOL RES & BIOTECHNOL,LAB CHEM CARCINOGENESIS GR-11635 ATHENS GREECE LEIDEN STATE UNIV,DEPT RADIAT GENET & CHEM MUTAGENESIS 2312 AV LEIDENNETHERLANDS TNO,NUTR & FOOD RES 2280 HV RIJSWIJK NETHERLANDS
Titolo Testata:
Clinical cancer research
fascicolo: 2, volume: 2, anno: 1996,
pagine: 303 - 310
SICI:
1078-0432(1996)2:2<303:MDDAHP>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; LEUKOCYTE DNA; O-6-METHYLGUANINE; LYMPHOCYTES; EXPOSURE; GLYCOSYLASE; INVIVO; ASSAY; 7-METHYLGUANINE; OLIGONUCLEOTIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
37
Recensione:
Indirizzi per estratti:
Citazione:
P.A. Philip et al., "METHYL DNA-ADDUCTS, DNA-REPAIR, AND HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE MUTATIONS IN PERIPHERAL WHITE BLOOD-CELLS FROM PATIENTSWITH MALIGNANT-MELANOMA TREATED WITH DACARBAZINE AND HYDROXYUREA", Clinical cancer research, 2(2), 1996, pp. 303-310

Abstract

Dacarbazine (DTIC) is a DNA-methylating drug used in the treatment ofmalignant melanoma, Among the DNA dducts induced by DTIC are N7-methylguanine (N7-meG) and O-6-methylguanine (O-6-meG). The latter adduct, in particular, may be important in the mutagenic as well as the cytotoxic activity of DTIC, Repair of O-6-meG is carried out by the enzyme O-6-alkylguanine-DNA-alkyltransferase (AGT) by a process which results in its autoinactivation, N7-meG is lost from DNA partly spontaneously and partly by enzymatic depurination followed by excision repair of the resulting apurinic site, The purpose of this study was to determine the in vivo kinetics of formation and repair of O-6-meG and N7-meG andthe changes in AGT in peripheral WBCs with repeated doses of DTIC, and to determine the effects on these processes of concomitant administration of hydroxyurea, In addition, we examined the induction of mutations at the HPRT gene locus, Thirty-four patients with malignant melanoma received 1.0 g/m(2) DTIC i.v. every 3 weeks, Hydroxyurea was added to the second and subsequent doses of DTIC in 19 patients. The concentrations of O-6-meG, N7-meG, and AGT in peripheral blood lymphocytes were determined up to 24 h after each of the first two doses of DTIC, Mutations at the HPRT gene locus were determined using the T-cell clonalassay, Peak O-6-meG levels were detected 1 and 4 h after the first and second dose of DTIC, respectively. AGT concentrations declined to 56.7% (range, 40.3-76.9%) and 55.0% (range, 45.4-58.9%) of pretreatment levels 24 h after the first and second doses of DTIC, respectively, and were still approximately 25% below their initial levels just prior to administration of the second dose of DTIC. An increase in formation of O-6-meG was observed at all time points after the second dose of DTIC (P = 0.0001), which was not affected by cotreatment with hydroxyurea (P > 0.5). There was a negative correlation between pretreatment AGTlevels and the O-6-meG concentration at 24 h after therapy (r = -0.554, P = 0.014). N7-meG levels peaked at 6 h after DTIC therapy and werenot significantly influenced by the cycle number, Cotreatment with hydroxyurea tended to be associated with lower levels of N7-meG (P = 0.08). There was no correlation between either O-6-meG or N7-meG levels and the grade of neutropenia, On the basis of a limited series of bloodsamples analyzed, there was no firm evidence that chemotherapy with DTIC resulted in induction of HPRT mutations in lymphocytes. In conclusion, repeated administrations of DTIC resulted in higher concentrations of O-6-meG, probably due to reduction in cellular AGT, Hydroxyurea did not significantly influence the kinetics of O-6-meG, and N7-meG adduct formation. There was no significant induction of HPRT gene mutations with DTIC, This study suggests that sequencing of DTIC doses shouldbe evaluated using the time course of cellular AGT depletion and DNA adduct formation to achieve higher cytotoxic efficiency.

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Documento generato il 24/09/20 alle ore 23:41:52