Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model.
OBJECTIVE
Studies were conducted to test whether fever-range whole body thermal therapy would boost the efficacy of oxaliplatin chemotherapy without substantial toxicity.


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.
Rowe
R Wanda
RW
University of Texas Medical School, Division of Oncology, Houston, Texas 77030, USA.
Strebel
Frederick R
FR
Proett
Jesse M
JM
Deng
Wanleng
W
Chan
Diana
D
He
Guangan
G
Siddik
Zahid
Z
Bull
Joan M C
JM
D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018736:DNA Adducts / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000503:physiopathology*; D006979:Hyperthermia, Induced / Q000379:methods*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010984:Platinum / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum