title: Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.
abstract: 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.
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Sae Hee
authors.initials: SH
authors.lastname: Ko
authors.forename: Tomio
authors.initials: T
authors.lastname: Ueno
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshimoto
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Yoo
authors.forename: Omar I
authors.initials: OI
authors.lastname: Abdel-Wahab
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdel-Wahab
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.forename: Scott K
authors.initials: SK
authors.lastname: Pruitt
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: 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
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019394:Ki-67 Antigen; D003606:Dacarbazine; D000077204:Temozolomide