The role of hyperthermia in regional alkylating agent chemotherapy

Omar I. Abdel-Wahab, Elizabeth Grubbs, Benjamin L. Viglianti, Tsung Yen Cheng, Tomio Ueno, Sae Hee Ko, Zahid Rabbani, Simon Curtis, Scott K. Pruitt, Mark W. Dewhirst, Doug S. Tyler

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


The role of hyperthermia during regional alkylating agent chemotherapy is controversial. The aim of this study was to determine the exact contribution of hyperthermia to tumor response during isolated limb infusion with L-phenylalanine mustard. Rats bearing rodent fibrosarcoma on the hindlimb underwent isolated limb infusion with saline, saline plus heat, L-phenylalanine mustard, L-phenylalanine mustard under conditions of normothermia, or L-phenylalanine mustard plus hyperthermia. Heat was administered locally using an in-line hot water circulation loop. Treatment with L-phenylalanine mustard at a concentration of 15 or 50 μg/mL was ineffective at producing tumor growth delay (P = 0.24 and 0.41, respectively). Furthermore, thermal enhancement of L-phenylalanine mustard activity was not seen at 15 μg/mL. However, administration of high-dose L-phenylalanine mustard, 50 μg/mL, with increasing amounts of heat yielded increasing tumor growth delay, increased regressions, and decreased proliferative index. Although L-phenylalanine mustard infusion under normothermia yielded a tumor growth delay of 7.1 days, combination L-phenylalanine mustard + hyperthermia treatment produced tumor growth delay of 27.0 days (P < 0.01; with two of five animals showing a complete response). Four hours after isolated limb infusion, 50.9% of cells in tumor treated with L-phenylalanine mustard + hyperthermia experienced apoptosis, whereas only 18.1, 16, and 4.4% of cells underwent apoptosis after treatment with L-phenylalanine mustard, saline + hyperthermia, or saline. The mean concentration of L-phenylalanine mustard within tumor relative to perfusate following isolated limb infusion was found to be similar among all groups at 0.023, 0.025, and 0.032 in animals undergoing isolated limb infusion with L-phenylalanine mustard, L-phenylalanine mustard + normothermia, and L-phenylalanine mustard + hyperthermia, respectively. These data indicate a synergistic cytotoxic effect of L-phenylalanine mustard + hyperthermia in isolated limb infusion, which is not attributable to enhanced tumor drug uptake.

Original languageEnglish (US)
Pages (from-to)5919-5929
Number of pages11
JournalClinical Cancer Research
Issue number17
StatePublished - Sep 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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