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

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Clin Cancer Res. 2006 Jan 1;12(1):289-97.

a novel regional chemotherapeutic agent against melanoma:
hyperthermia-induced enhancement of temozolomide cytotoxicity.
Ko SH, Ueno T, Yoshimoto Y, Yoo JS, Abdel-Wahab OI, Abdel-Wahab Z, Chu E, Pruitt SK, Friedman HS, Dewhirst MW, Tyler DS.
Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA.
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.
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.
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.