Journal
INTERNATIONAL JOURNAL OF HYPERTHERMIA
Volume 26, Issue 6, Pages 565-576Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/02656736.2010.483635
Keywords
breast cancer; cell death; hyperthermia; immune stimulation; low dose chemotherapy; oxaliplation; schedule; thermal therapy; thermochemotherapy; tumour cure
Funding
- National Institutes of Health [NCI R01 CA 43090, NCI R01 CA127263]
- Susan G. Komen Breast Cancer Foundation
- University of Texas Hyperthermia Research Laboratory
- Sanofi-Aventis
- NATIONAL CANCER INSTITUTE [R01CA127263, R01CA043090] Funding Source: NIH RePORTER
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Purpose: Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity. Materials and methods: The effect of mild heat (40 degrees C) on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumour cell line. In vivo oxaliplatin was administered at various doses and times before, during and after fever-range thermal therapy (6 h at 40 degrees C) to rats bearing an MTLn3 mammary adenocarcinoma. Tumour growth, survival, and toxicity were measured to determine treatment outcome. Results: Heating halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24 h before thermal therapy were completely immunologically cured, while a further 11% regressed their primary tumour but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumour efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 h before fever-range whole body thermal therapy. Conclusions: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumours in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.
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