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


METHODS
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.


CONCLUSIONS
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.
Ko
Sae Hee
SH
Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA.
Ueno
Tomio
T
Yoshimoto
Yasunori
Y
Yoo
Jin Soo
JS
Abdel-Wahab
Omar I
OI
Abdel-Wahab
Zeinab
Z
Chu
Edward
E
Pruitt
Scott K
SK
Friedman
Henry S
HS
Dewhirst
Mark W
MW
Tyler
Douglas S
DS
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000187:drug effects; D008546:Melanoma, Experimental / Q000628:therapy*; D051381:Rats; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D019394:Ki-67 Antigen; D003606:Dacarbazine; D000077204:Temozolomide