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Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 1998 Feb; Vol. 4 (2), pp. 463-8. - Publication Year :
- 1998
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Abstract
- Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors. Because new drugs are required for the treatment of medulloblastoma in children, we evaluated the preclinical antitumor activity of fotemustine in four s.c. medulloblastoma xenografts, in comparison with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Both drugs were administered as a single i.p. injection to nude mice bearing advanced-stage tumor. Fotemustine displayed significant antitumor activity in three of four medulloblastoma xenografts; two, IGRM34 and IGRM57, were highly sensitive, with 37 and 100% tumor-free survivors, respectively, more than 120 days after treatment at the highest nontoxic dose (50 mg/kg). Fotemustine was also highly active in a malignant glioma xenograft (IGRG88; five of six tumor-free survivors on day 177). Fotemustine proved to be significantly more active than BCNU in IGRM34 and the glioma xenograft IGRG88. The DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) was detected in all tumor xenografts, ranging in activity from 6 to 892 fmol/mg protein. The high in vivo sensitivity to fotemustine and BCNU observed in three xenografts was clearly associated with a low ATase activity (> 20 fmol/mg), whereas the two poorly sensitive or refractory medulloblastoma xenografts showed high ATase activity (> 500 fmol/mg). Alkylpurine-DNA N-glycosylase activity was detected in all tumor xenografts but at levels ranging only from 513 to 1105 fmol/mg/h; no consistent relationship was found between alkylpurine-DNA N-glycosylase activity and the in vivo sensitivity to the two chloroethylnitrosoureas. The improved activity and tolerance of fotemustine in comparison with BCNU in pediatric medulloblastoma xenografts strongly support the clinical development of this agent in children with brain tumors, in which ATase should be examined as a potential prognostic indicator.
- Subjects :
- Animals
Antineoplastic Agents toxicity
Antineoplastic Agents, Alkylating pharmacology
Carmustine pharmacology
DNA Repair
Drug Screening Assays, Antitumor
Female
Humans
Male
Mice
Middle Aged
Neoplasm Transplantation
Nitrosourea Compounds toxicity
Organophosphorus Compounds toxicity
Transplantation, Heterologous
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Brain Neoplasms drug therapy
Brain Neoplasms enzymology
Cerebellar Neoplasms drug therapy
Cerebellar Neoplasms enzymology
DNA Glycosylases
Glioma drug therapy
Glioma enzymology
Medulloblastoma drug therapy
Medulloblastoma enzymology
N-Glycosyl Hydrolases metabolism
Nitrosourea Compounds pharmacology
O(6)-Methylguanine-DNA Methyltransferase metabolism
Organophosphorus Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 4
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 9516937