The syntheses of the novel pyrrolo[2,3-d]pyrimidine-based heterocycles as tricyclic analogues of O6-methylguanine are described. Compound 5 is a weak inhibitor of human O6-alkylguanine DNA alkyltransferase.

The management of glioblastoma in the elderly population represents a field growing interest owing longer life expectancy. In this age group, more than young adult, biological is much important chronologic one. date birth should not exclude priori access treatments. Maximal safe resection proved to be first option when performance status and general health good. Adjuvant therapy decision about ...

DNA, isolated from two samples of human liver obtained from a suspected dimethylnitrosamine poisoning, contained 1363 to 1373 micromol of 7-methylguanine per mol of guanine and 273 to 317 micromol of O6-methylguanine per mol of guanine. Liver and kidney DNA obtained from unrelated cases contained no detectable methylated purines. From the DNA methylation levels, it is estimated that the dimethy...

Temozolomide (TMZ) is an example of an alkylating agent, which are known to be effective anticancer drugs for the treatment of various solid tumors, including glioma and melanoma. TMZ acts predominantly through the mutagenic product O6-methylguanine, a cytotoxic DNA lesion. The DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), which functions in the resistance of cancers to TMZ,...

Human lymphoid cell lines contain a DNA repair enzyme which removes the mutagenic alkylation lesion O6-methylguanine from DNA. The enzyme transfers the methyl group to a protein cysteine residue, generating S-methylcysteine, and is inactivated as a consequence of the reaction. Apparently the methylated enzyme represents a dead-end complex. The transfer reaction is very rapid and is completed in...

The application of a 32P-postlabeling assay for 7-methylguanines in DNA was studied either by labeling the imidazole ring-opened dinucleotide derivatives or by using strong-anion-exchange column chromatography for the adduct enrichment from normal nucleotides. Data showed that 7-methylguanines can be efficiently labeled as dinucleotides when in vitro methylated DNA was first imidazole ring-open...

Pulse treatment of DNA with any of several chloroethylnitrosoureas presently in clinical use leads to formation of monoadducts. Further incubation of these monoadducts in the absence of drug leads to DNA interstrand cross-links; however, this cross-link formation is suppressed by a partially purified extract of cultured human leukemic lymphoblasts. The cross-link-suppressing activity copurifies...

An in vitro system in which bacteriophage T7 DNA is replicated and efficiently packaged into procapsids to form viable phage has been used to examine mutagenesis. The fidelity of replication was assayed both by measuring reversion of an amber mutation in an essential gene and by generation of temperature-sensitive mutants among the phage produced in vitro. Under standard reaction conditions, th...