title: Interleukin-2: hope in cases of cisplatin-resistant tumours.
abstract: To establish whether or not local low-dose recombinant interleukin-2 (rIL-2) therapy might result in therapeutic benefit for ovarian cancer patients treated with cisplatin, the antitumour effects of rIL-2 and of combined treatment with cisplatin and rIL-2 in a mouse ovarian tumour (MOT) model were studied. In addition, some possible mechanistic aspects underlying the observed antitumour responses were analysed. MOT cells were injected i.p. into syngeneic, immunocompetent, female C3HeB mice. Tumour-bearing mice received i.p. treatment with cisplatin, rIL-2 or both. The MOT tumour appeared to be hardly responsive to treatment with cisplatin only or rIL-2 only. In contrast, combined local treatment with low doses of cisplatin (1 and 5 mg/kg body weight) and rIL-2 (60000 U/day) resulted in an effective antitumour response in MOT-bearing mice. Complete rejection of the i.p. (local) tumour occurred in up to 60% of the cases. In vitro studies showed that cisplatin and rIL-2 do not have cumulative direct toxic effects on MOT cells. Mice cured after combined treatment with cisplatin and rIL-2 were not able to reject a rechallenge with tumour cells, indicating that these mice had not developed immunity to the tumour. Analysis of tumour-associated leucocytes, however, showed that combined treatment with cisplatin and rIL-2 did result in enhanced non-specific cytolytic activity of peritoneal leucocytes. We have thus demonstrated that, in the MOT model, combined local treatment with low doses of cisplatin and of rIL-2 is far more effective than therapy with cisplatin alone. Non-specific cytotoxicity of leucocytes appears to be involved in antitumour responses induced by combined treatment with cisplatin and rIL-2. These results suggest that, in human ovarian carcinoma, much better results may be obtained with the combined treatment of cisplatin and low (non-toxic) doses of rIL-2 than with cisplatin only. This may also apply to cisplatin-resistant ovarian carcinoma.
authors.affiliation: Department of Functional Morphology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands. m.bernsen@pathol.azn.nl
authors.forename: M R
authors.initials: MR
authors.lastname: Bernsen
authors.forename: A W
authors.initials: AW
authors.lastname: Van Der Velden
authors.forename: L A
authors.initials: LA
authors.lastname: Everse
authors.forename: H F
authors.initials: HF
authors.lastname: Dullens
authors.forename: W
authors.initials: W
authors.lastname: Den Otter
authors.forename: A P
authors.initials: AP
authors.lastname: Heintz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D019008:Drug Resistance, Neoplasm; D005260:Female; D007376:Interleukin-2 / Q000627:therapeutic use*; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018243:Teratocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D002945:Cisplatin