Intratumoral infusion of topotecan prolongs survival in the nude rat intracranial U87 human glioma model.
Topotecan is a topoisomerase (topo) I inhibitor with promising activity in preclinical studies. We hypothesized that low-dose intratumoral delivery of topotecan would be highly effective for gliomas. Human glioma cell lines (U87, U138 and U373) displayed different sensitivities to topotecan (IC50 range: 0.037 microM to 0.280 microM) in cell culture. The most resistant of the glioma cell lines (U87) was implanted stereotactically into the brains of nude rats. Twelve days later, at which time tumor diameter measured 2 to 2.5 mm, animals were randomized to three groups: group I, intratumoral topotecan infused via osmotic pump (n = 12); group II, intratumoral saline infusion (n = 7); and group III, no treatment (n = 10). Animals were sacrificed when signs of deterioration developed, or at 60 days. Animals in group I had a mean survival time (MST) of > 55 days (range = 40-60); whereas, those in groups II and III had MST of 26.1 (range = 21-31) and 26.5 (range = 20-30) days, respectively. The differences in survival between group I and each of the other groups were statistically significant (p < 0.0001; Logrank Mantel-Cox). None of the animals that survived 60 days had histological evidence of residual tumor at sacrifice. Measurement of topotecan levels in normal brain revealed cytotoxic concentrations up to 4.5 mm from the site of infusion. This study demonstrates that intratumoral topotecan delivered via an osmotic pump prolongs survival in the U87 human glioma model.
Pollina
J
J
Department of Neurosurgery, S.U.N.Y., Buffalo School of Medicine and Biomedical Sciences, New York, USA.
Plunkett
R J
RJ
Ciesielski
M J
MJ
Lis
A
A
Barone
T A
TA
Greenberg
S J
SJ
Fenstermaker
R A
RA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007263:Infusions, Parenteral; D051381:Rats; D011923:Rats, Nude; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan