Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.

2.50
Hdl Handle:
http://hdl.handle.net/10541/93410
Title:
Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.
Authors:
Vassal, G; Boland, I; Terrier-Lacombe, M J; Watson, Amanda J; Margison, Geoffrey P; Vénuat, A M; Morizet, J; Parker, F; Lacroix, C; Lellouch-Tubiana, A; Pierre-Kahn, A; Poullain, M G; Gouyette, A
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.
Affiliation:
Laboratory of Pharmacotoxicology and Pharmacogenetics (Centre National de la Recherche Scientifique URA 147, Institut Gustave-Roussy, Villejuif, France. gvassal@igr.fr
Citation:
Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity. 1998, 4 (2):463-8 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
Feb-1998
URI:
http://hdl.handle.net/10541/93410
PubMed ID:
9516937
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorVassal, Gen
dc.contributor.authorBoland, Ien
dc.contributor.authorTerrier-Lacombe, M Jen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorVénuat, A Men
dc.contributor.authorMorizet, Jen
dc.contributor.authorParker, Fen
dc.contributor.authorLacroix, Cen
dc.contributor.authorLellouch-Tubiana, Aen
dc.contributor.authorPierre-Kahn, Aen
dc.contributor.authorPoullain, M Gen
dc.contributor.authorGouyette, Aen
dc.date.accessioned2010-03-02T17:18:32Z-
dc.date.available2010-03-02T17:18:32Z-
dc.date.issued1998-02-
dc.identifier.citationActivity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity. 1998, 4 (2):463-8 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid9516937-
dc.identifier.urihttp://hdl.handle.net/10541/93410-
dc.description.abstractFotemustine 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.en
dc.language.isoenen
dc.subjectBrain Canceren
dc.subjectAntitumour Drug Screening Assaysen
dc.subjectCultured Tumour Cellsen
dc.subjectUterine Cervical Canceren
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshBrain Neoplasms-
dc.subject.meshCarmustine-
dc.subject.meshCerebellar Neoplasms-
dc.subject.meshDNA Glycosylases-
dc.subject.meshDNA Repair-
dc.subject.meshDrug Screening Assays, Antitumor-
dc.subject.meshFemale-
dc.subject.meshGlioma-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMedulloblastoma-
dc.subject.meshMice-
dc.subject.meshMiddle Aged-
dc.subject.meshN-Glycosyl Hydrolases-
dc.subject.meshNeoplasm Transplantation-
dc.subject.meshNitrosourea Compounds-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshOrganophosphorus Compounds-
dc.subject.meshTransplantation, Heterologous-
dc.subject.meshTumor Cells, Cultured-
dc.titleActivity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.en
dc.typeArticleen
dc.contributor.departmentLaboratory of Pharmacotoxicology and Pharmacogenetics (Centre National de la Recherche Scientifique URA 147, Institut Gustave-Roussy, Villejuif, France. gvassal@igr.fren
dc.identifier.journalClinical Cancer Researchen
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