Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model.

Abstract

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.

• Authors: R Wanda Rowe, Frederick R Strebel, Jesse M Proett, Wanleng Deng, Diana Chan, Guangan He, Zahid Siddik, Joan M C Bull
• Journal: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group (Int J Hyperthermia) Vol. 26 Issue 6 Pg. 565-76 ( 2010) ISSN: 1464-5157 [Electronic] England
• PMID: 20707651 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA Adducts
• Organoplatinum Compounds
• Oxaliplatin
• Platinum

Topics

• Adenocarcinoma (metabolism, therapy)
• Animals
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Breast Neoplasms (metabolism, therapy)
• Cell Line, Tumor
• Combined Modality Therapy
• DNA Adducts (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Fever (physiopathology)
• Hyperthermia, Induced (methods)
• Organoplatinum Compounds (administration & dosage, therapeutic use)
• Oxaliplatin
• Platinum (metabolism)
• Rats
• Rats, Inbred F344
• Treatment Outcome