Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.4.2.8 (
hypoxanthine-guanine phosphoribosyltransferase
)
2,527
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Decomposition of the antitumor agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (
DTIC
,
Dacarbazine
) produces several potentially toxic compounds, the concentration of which depend on incubation parameters such as pH, temperature and illumination. The action of
DTIC
on chinese hamster ovary (CHO) cell clone formation in the dark (7-8-day incubation) reflects the slow formation of 2-azahypoxanthine. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT,
EC 2.4.2.8
)-deficient cells are resistant to
DTIC
under these conditions, reflecting their inability to utilize 2-azahypoxanthine. The toxicity of
DTIC
in conventional survival experiments (1-2-h exposure to drug) is dependent upon illumination and is highly influenced by the pH of the medium. Toxicity of
DTIC
in these experiments appears to reflect rapid accumulation of the immediate photodecomposition product of the drug, 4-diazoimidazole-5-carboxamide (DZC), since HGPRT-deficient cells are not resistant to
DTIC
under these conditions. The biologically initiated pathway of
DTIC
action (enzymatic hydroxylation) has little, if any, role in the action of this agent toward cultured CHO cells.
...
PMID:Mechanisms of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (Dacarbazine) cytotoxicity toward Chinese hamster ovary cells in vitro are dictated by incubation conditions. 374 46
Dacarbazine
(
DTIC
) is a DNA-methylating drug used in the treatment of malignant melanoma. Among the DNA dducts induced by
DTIC
are N7-methylguanine (N7-meG) and O6-methylguanine (O6-meG). The latter adduct, in particular, may be important in the mutagenic as well as the cytotoxic activity of
DTIC
. Repair of O6-meG is carried out by the enzyme O6-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 O6-meG and N7-meG and the 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/m2
DTIC
i.v. every 3 weeks. Hydroxyurea was added to the second and subsequent doses of
DTIC
in 19 patients. The concentrations of O6-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 clonal assay. Peak O6-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 O6-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 AGT levels and the O6-meG concentration at 24 h after therapy (r = -0.554, P = 0.014). N7-meG levels peaked at 6 h after
DTIC
therapy and were not 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 O6-meG or N7-meG levels and the grade of neutropenia. On the basis of a limited series of blood samples 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 O6-meG, probably due to reduction in cellular AGT. Hydroxyurea did not significantly influence the kinetics of O6-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 should be evaluated using the time course of cellular AGT depletion and DNA adduct formation to achieve higher cytotoxic efficiency.
...
PMID:Methyl DNA adducts, DNA repair, and hypoxanthine-guanine phosphoribosyl transferase mutations in peripheral white blood cells from patients with malignant melanoma treated with dacarbazine and hydroxyurea. 981 73
