Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea) is a new chloroethylnitrosourea (CENU) being used in phase II clinical trials of disseminated melanoma. Clinical results show that tumour regression has only been observed in 25% of melanomas treated by CENUs. Tumour resistance to CENU is known to be mainly due to a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT). The poor remission rate of melanoma with CENUs is attributed to the fact that metastases contain high MGMT levels. Previously, we have shown that O6-benzyl-N2-acetylguanosine (BNAG), an MGMT inhibitor, can be combined with cystemustine by intravenous administration, and increases the antitumour effect of cystemustine in resistant human melanoma. In the work presented here, we investigated the in vitro pharmacological effect of this combination on the DNA of human melanoma cells (M3Dau cells). A quantitative polymerase chain reaction (QPCR) assay was used to measure DNA damage in a fragment (2.7 kb) of the hprt gene. The results show that treatment with BNAG enhances the number of lesions in the DNA of cystemustine-treated resistant malignant melanocytes, which may account for the high tumour-cell toxicity of the combination of cystemustine and BNAG.
Melanoma Res 1998 Apr
PMID:Melanoma-cell toxicity of cystemustine combined with O6-benzyl-N2-acetylguanosine. 961 Aug 64

In vivo hypoxanthine-guanine phosphoribosyltransferase (HPRT)-deficient T cells (MT) from melanoma patients are enriched for T cells with in vivo clonal amplifications that traffic between blood and tumor tissues. Melanoma is thus a model cancer to test the hypothesis that in vivo MT from cancer patients can be used as immunological probes for immunogenic tumor antigens. MT were obtained by 6-thioguanine (TG) selection of lymphocytes from peripheral blood and tumor tissues, and wild-type T cells (WT) were obtained analogously without TG selection. cDNA sequences of the T cell receptor beta chains (TRB) were used as unambiguous biomarkers of in vivo clonality and as indicators of T cell specificity. Public TRB were identified in MT from the blood and tumor of different melanoma patients. Such public TRB were not found in normal control MT or WT. As an indicator of T cell specificity for melanoma, the >2600 MT and WT TRB, including the public TRB from melanoma patients, were compared to a literature-derived empirical database of >1270 TRB from melanoma-reactive T cells. Various degrees of similarity, ranging from 100% conservation to 3-amino acid motifs (3-mer), were found between both melanoma patient MT and WT TRBs and the empirical database. The frequency of 3-mer and 4-mer TRB matching to the empirical database was significantly higher in MT compared with WT in the tumor (p=0.0285 and p=0.006, respectively). In summary, in vivo MT from melanoma patients contain public TRB as well as T cells with specificity for characterized melanoma antigens. We conclude that in vivo MT merit study as novel probes for uncharacterized immunogenic antigens in melanoma and other malignancies.
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PMID:In vivo 6-thioguanine-resistant T cells from melanoma patients have public TCR and share TCR beta amino acid sequences with melanoma-reactive T cells. 2118 40