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Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.

Publication ,  Journal Article
Ko, SH; Ueno, T; Yoshimoto, Y; Yoo, JS; Abdel-Wahab, OI; Abdel-Wahab, Z; Chu, E; Pruitt, SK; Friedman, HS; Dewhirst, MW; Tyler, DS
Published in: Clin Cancer Res
January 1, 2006

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 degrees C), or hyperthermic (43 degrees 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.

Duke Scholars

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

January 1, 2006

Volume

12

Issue

1

Start / End Page

289 / 297

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Temozolomide
  • Rats
  • Oncology & Carcinogenesis
  • Melanoma, Experimental
  • Ki-67 Antigen
  • Immunohistochemistry
  • Hyperthermia, Induced
  • Humans
  • Dacarbazine
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ko, S. H., Ueno, T., Yoshimoto, Y., Yoo, J. S., Abdel-Wahab, O. I., Abdel-Wahab, Z., … Tyler, D. S. (2006). Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity. Clin Cancer Res, 12(1), 289–297. https://doi.org/10.1158/1078-0432.CCR-05-0210
Ko, Sae Hee, Tomio Ueno, Yasunori Yoshimoto, Jin Soo Yoo, Omar I. Abdel-Wahab, Zeinab Abdel-Wahab, Edward Chu, et al. “Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.Clin Cancer Res 12, no. 1 (January 1, 2006): 289–97. https://doi.org/10.1158/1078-0432.CCR-05-0210.
Ko SH, Ueno T, Yoshimoto Y, Yoo JS, Abdel-Wahab OI, Abdel-Wahab Z, et al. Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity. Clin Cancer Res. 2006 Jan 1;12(1):289–97.
Ko, Sae Hee, et al. “Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.Clin Cancer Res, vol. 12, no. 1, Jan. 2006, pp. 289–97. Pubmed, doi:10.1158/1078-0432.CCR-05-0210.
Ko SH, Ueno T, Yoshimoto Y, Yoo JS, Abdel-Wahab OI, Abdel-Wahab Z, Chu E, Pruitt SK, Friedman HS, Dewhirst MW, Tyler DS. Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity. Clin Cancer Res. 2006 Jan 1;12(1):289–297.

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

January 1, 2006

Volume

12

Issue

1

Start / End Page

289 / 297

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Temozolomide
  • Rats
  • Oncology & Carcinogenesis
  • Melanoma, Experimental
  • Ki-67 Antigen
  • Immunohistochemistry
  • Hyperthermia, Induced
  • Humans
  • Dacarbazine