Comparison of efficacy and toxicity profile between intraperitoneal and intravenous topotecan in human ovarian cancer xenografts.
OBJECTIVE
To compare the therapeutic and toxic profile of topotecan given intraperitoneally with intravenously in human ovarian cancer xenografted into athymic nude mice.


METHODS
Eighty female Balb-c/nu-nu mice were randomized assigned into eight groups (n=10). Xenografts resulted from intramesentery injection of cultured human ovarian cancer cells SKOV3 in athymic mice. Onset of intraperitoneal treatment with either topotecan or cisplatin (7.5 mg/kg) was on day 7. Animals scheduled for topotecan i.p. received intraperitoneal application of topotecan (1.5 mg/kg x 2, 3.0 mg/kg x 2, 6.0 mg/kg x 2 or 10.0 mg/kg x 1). Animals scheduled for topotecan i.v. received intravenous administration of topotecan (6.0 mg/kg x 2 or 10.0 mg/kg x 1). Two weeks after drug application animals were killed. Tumor growth inhibition were assessed and compared with untreated mice and cisplatin intraperitoneally administered mice. Acute toxicity was determined by loss of body weight. Cell cycle division and apoptosis after drug administration was determined by flow cytometric analysis.


RESULTS
In a panel of ten tumour xenografts, intraperitoneal topotecan was significantly more effective than intravenous administration. The toxicity profile suggested a better tolerability in terms of weight loss after intraperitoneal administration than cisplatin control. Topotecan 10.0 mg/kg i.p. per day (1 day) schedule was an optimal treatment for ovarian cancer and well tolerated by mice with no signs of acute toxicity. Topotecan and cisplatin induce cells G0-G1 arrest and apparent apoptosis. No significant difference among mice treated with topotecan intraperitoneally or intravenously or cisplatin was observed in term of apoptosis and cell cycle perturbation.


CONCLUSIONS
The results may have implications for the future design of clinical studies on intraperitoneal application of topotecan. It suggests that apoptosis and cell cycle perturbation play an limited role in the mechanism of topotecan administration.
Yi
Xiao-fang
XF
Department of Gynecology, The Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China.
Fan
Shi-ming
SM
Yao
Ming
M
Feng
You-ji
YJ
D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009852:Omentum; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D019772:Topotecan