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Titolo:
Differential degradation rates of inactivated alkyltransferase in blood mononuclear cells and tumors of patients after treatment with O-6-benzylguanine
Autore:
Liu, L; Spiro, TP; Qin, XS; Majka, S; Haaga, J; Schupp, J; Willson, JKV; Gerson, SL;
Indirizzi:
Case Western Reserve Univ, Div Hematol & Oncol, Cleveland, OH 44106 USA Case Western Reserve Univ Cleveland OH USA 44106 Cleveland, OH 44106 USA Univ Hosp Cleveland, Dept Med, Div Hematol & Oncol, Cleveland, OH 44106 USA Univ Hosp Cleveland Cleveland OH USA 44106 Oncol, Cleveland, OH 44106 USA Univ Hosp Cleveland, Ireland Canc Ctr, Cleveland, OH 44106 USA Univ Hosp Cleveland Cleveland OH USA 44106 c Ctr, Cleveland, OH 44106 USA
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 8, volume: 7, anno: 2001,
pagine: 2318 - 2324
SICI:
1078-0432(200108)7:8<2318:DDROIA>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN COLON CANCER; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; DNA ALKYLTRANSFERASE; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA; PHOSPHORYLATION; PROTEIN; O6-METHYLGUANINE; UBIQUITINATION; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
21
Recensione:
Indirizzi per estratti:
Indirizzo: Gerson, SL Case Western Reserve Univ, Div Hematol & Oncol, BRB-3,10900 Euclid Ave, Cleveland, OH 44106 USA Case Western Reserve Univ BRB-3,10900 Euclid Ave Cleveland OH USA 44106
Citazione:
L. Liu et al., "Differential degradation rates of inactivated alkyltransferase in blood mononuclear cells and tumors of patients after treatment with O-6-benzylguanine", CLIN CANC R, 7(8), 2001, pp. 2318-2324

Abstract

O-6-Alkylguanine-DNA alkyltransferase (AGT) repairs O-6-alkylating DNA adducts generated by alkylating therapeutic agents. Therefore, AGT activity may be an important marker of tumor and normal tissue sensitivity to chemotherapeutic agents and a predictor for the success of chemotherapeutic regimens. It is rapidly inactivated by O-6-benzylguanine (BG) that mimics its substrates, O-6-methylguanine and O-6-chloroethylguanine DNA adducts. In a Phase I clinical trial, BG was given in increasing doses (from 10 to 120 mg/m(2)) by 1-h infusion. We previously reported depletion of AGT activity, and in this report, we demonstrate the relationship between degradation of BG-inactivated AGT protein and the depletion of AGT activity in peripheral bloodmononuclear cells (PBMCs) and tumor samples obtained by computed tomography-guided cutting needle biopsy from patients prior to BG and either 2 or 18h after BG. In PBMCs, BG inactivated AGT activity by over 95-100% at the end of a 1-h infusion, and depletion was maintained for 18 h. In contrast, AGT protein remained almost unchanged for up to 18 h after BG, suggesting that inactivated AGT proteins remain immunoreactive and are not rapidly degraded in PBMCs. In patient tumor biopsies, AGT activity was depleted similar to 90% 2 h after BG. Tumor AGT protein levels were reduced to similar to 40% of pretreatment values when detected by either Western blot or immunohistochemistry staining. In tumor samples obtained 18 h after BG, >95% inactivation of tumor AGT activity was observed at BG doses of 36-80 mg/m(2), and complete depletion of tumor AGT activity occurred at 120 mg/m(2) BG. However, residual AGT protein (5-10% of baseline) was detectable in all tumor samples. Therefore, the degradation of BG-inactivated AGT protein appeared to be much more rapid in tumors than that in PBMCs, which may impact on AGT regeneration rates as well. Because degradation of BG-inactivated AGT takes place slowly, antibody-based measurements of AGT protein correlate poorly with depletion of AGT activity immediately after BG. Thus, biochemical activity measurements remain the appropriate monitor of AGT during therapeutic modulation. These data provide the first and conclusive evidence of differential degradation rates of inactivated AGT in PBMCs and tumors of patients after treatment with BG and suggest that immunoreactive AGT measurements in PBMCs are a poor surrogate for AGT activity in tumor tissue.

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Documento generato il 10/07/20 alle ore 09:09:15