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Preclinical and phase I study of oxaliplatin and topotecan in combination in human cancer
- Publication Year :
- 2002
-
Abstract
- Background: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. Materials and methods: We studied the effect of a sequential schedule of oxaliplatin on day 1 and topotecan on days 2–5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. Results: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m 2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m 2 on days 2–5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m 2 caused a doselimiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m 2 , at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. Conclusions: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m 2 and topotecan 1.25 mg/m 2 , possibly in ovarian cancer
- Subjects :
- Adult
Male
endocrine system diseases
Maximum Tolerated Dose
Organoplatinum Compounds
Colorectal cancer
oxaliplatin
topotecan
cancer therapy
medicine.medical_treatment
Drug Evaluation, Preclinical
Phases of clinical research
Apoptosis
Pharmacology
Mice
Antineoplastic Combined Chemotherapy Protocols
medicine
Tumor Cells, Cultured
Animals
Humans
Aged
Ovarian Neoplasms
Chemotherapy
Mice, Inbred BALB C
biology
Dose-Response Relationship, Drug
business.industry
Topoisomerase
Cell Cycle
Cancer
Hematology
Middle Aged
medicine.disease
Oxaliplatin
Oncology
biology.protein
Topotecan
Female
business
Ovarian cancer
Colorectal Neoplasms
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....54982622b39f4f1901e3869b068fabfa