Topotecan can compensate for protracted radiation treatment time effects in high grade glioma xenografts.
OBJECTIVE
Several studies reported that prolongation of overall treatment time of fractionated radiotherapy reduces the chance of tumor control. In the present study, we hypothesize that combining topotecan with irradiation could compensate for this detrimental time effect on the radioresponse. Therefore, we investigated the efficiency of different schedules of topotecan (TPT), radiotherapy (RT) or concomitant combination TPT + RT.


METHODS
Experiments were performed in two human high-grade glioma xenograft models (U87 and GBM Nan1). TPT and RT were delivered at a total dose of 3 mg/kg and 40 Gy, respectively. For the TPT + RT groups, TPT was injected 5 min before radiation. Total radiation doses were delivered in 5, 10, 20, or 30 fractions over 1, 2, 4, or 6 weeks, respectively. The efficiency of TPT, RT, and TPT + RT was evaluated by tumor growth delay (TGD).


RESULTS
At this low total dose, and independent of the schedule, no efficacy was found in TPT-treated glioma xenografts. Conversely, radiotherapy-induced antitumor effect decreased with prolongation of treatment time. For TPT + RT combination, antitumor activity was not influenced by schedule, and tumor response was always comparable to those measured for the shortest and the most efficient irradiation schedule (i.e. 1 week). When treatment was delivered over 4 or 6 weeks in U87 glioma xenografts, therapeutic enhancement ratios reached 2.6 and 3.7, respectively. This indicated that the interaction between ionizing radiation and topotecan was synergistic.


CONCLUSIONS
The present study demonstrated that concomitant topotecan can compensate for the detrimental effect of treatment time protraction on radiotherapy efficacy in two malignant glioma xenografts.
Pinel
Sophie
S
Laboratoire de Recherche en Oncologie, Centre A. Vautrin, Vandoeuvre-lès-Nancy, France. pinel.sophie@tiscali.fr
Chastagner
Pascal
P
Merlin
Jean-Louis
JL
Marchal
Christian
C
Taghian
Alphonse
A
Barberi-Heyob
Muriel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D018450:Disease Progression; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D019772:Topotecan