Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.
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.
Vassal
G
G
Laboratory of Pharmacotoxicology and Pharmacogenetics (Centre National de la Recherche Scientifique URA 147, Institut Gustave-Roussy, Villejuif, France. gvassal@igr.fr
Boland
I
I
Terrier-Lacombe
M J
MJ
Watson
A J
AJ
Margison
G P
GP
Vénuat
A M
AM
Morizet
J
J
Parker
F
F
Lacroix
C
C
Lellouch-Tubiana
A
A
Pierre-Kahn
A
A
Poullain
M G
MG
Gouyette
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D002330:Carmustine / Q000494:pharmacology; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045647:DNA Glycosylases; D004260:DNA Repair; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008875:Middle Aged; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009607:Nitrosourea Compounds / Q000494:pharmacology* / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C076131:DNA-3-methyladenine glycosidase II; C054368:fotemustine; D002330:Carmustine