Optimizing a novel regional chemotherapeutic agent against melanoma

Hyperthermia-induced enhancement of temozolomide cytotoxicity

Sae Hee Ko, Tomio Ueno, Yasunori Yoshimoto, Jin Soo Yoo, Omar I. Abdel-Wahab, Zeinab Abdel-Wahab, Edward Chu, Scott K. Pruitt, Henry S. Friedman, Mark W. Dewhirst, Douglas Tyler

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Purpose: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. Experimental Design: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5°C), or hyperthermic (43°C) conditions. Results: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. Conclusion: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide.

Original languageEnglish (US)
Pages (from-to)289-297
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

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temozolomide
Induced Hyperthermia
Melanoma
Extremities
Fever
Growth
Neoplasms
Therapeutics
Nude Rats

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Optimizing a novel regional chemotherapeutic agent against melanoma : Hyperthermia-induced enhancement of temozolomide cytotoxicity. / Ko, Sae Hee; Ueno, Tomio; Yoshimoto, Yasunori; Yoo, Jin Soo; Abdel-Wahab, Omar I.; Abdel-Wahab, Zeinab; Chu, Edward; Pruitt, Scott K.; Friedman, Henry S.; Dewhirst, Mark W.; Tyler, Douglas.

In: Clinical Cancer Research, Vol. 12, No. 1, 01.01.2006, p. 289-297.

Research output: Contribution to journalArticle

Ko, SH, Ueno, T, Yoshimoto, Y, Yoo, JS, Abdel-Wahab, OI, Abdel-Wahab, Z, Chu, E, Pruitt, SK, Friedman, HS, Dewhirst, MW & Tyler, D 2006, 'Optimizing a novel regional chemotherapeutic agent against melanoma: Hyperthermia-induced enhancement of temozolomide cytotoxicity', Clinical Cancer Research, vol. 12, no. 1, pp. 289-297. https://doi.org/10.1158/1078-0432.CCR-05-0210
Ko, Sae Hee ; Ueno, Tomio ; Yoshimoto, Yasunori ; Yoo, Jin Soo ; Abdel-Wahab, Omar I. ; Abdel-Wahab, Zeinab ; Chu, Edward ; Pruitt, Scott K. ; Friedman, Henry S. ; Dewhirst, Mark W. ; Tyler, Douglas. / Optimizing a novel regional chemotherapeutic agent against melanoma : Hyperthermia-induced enhancement of temozolomide cytotoxicity. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 1. pp. 289-297.
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AU - Yoo, Jin Soo

AU - Abdel-Wahab, Omar I.

AU - Abdel-Wahab, Zeinab

AU - Chu, Edward

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