Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.
This study investigated whether the therapeutic index of regional melanoma therapy using parenteral temozolomide could be improved by chemomodulation with O6-benzylguanine (O6BG), an inhibitor of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). Using a nude rat s.c. human melanoma xenograft model of the extremity, tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10% DMSO in PBS (control), temozolomide alone, or temozolomide in conjunction with single or multiple doses of i.p. O6BG. Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional temozolomide alone (350 mg/kg), systemic temozolomide with O6BG, or vehicle combined with O6BG showed no significant tumor responses compared with controls. Whereas use of regional temozolomide alone at a higher dose (750 mg/kg) showed some degree of tumor response, regional temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with temozolomide regional chemotherapy leads to a significant improvement in melanoma antitumor responses. Clinical trials using chemotherapy modulation may improve response rates in future regional infusion and perfusion drug trials.
Department of Surgery, Duke University Medical Center, Box 3118, Durham, NC 27710, USA.
Tomio
T
Ueno
Sae Hee
SH
Ko
Elizabeth
E
Grubbs
Yasunori
Y
Yoshimoto
Christi
C
Augustine
Zeinab
Z
Abdel-Wahab
Tsung-Yen
TY
Cheng
Omar I
OI
Abdel-Wahab
Scott K
SK
Pruitt
Henry S
HS
Friedman
Douglas S
DS
Tyler
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D003849:Deoxyguanosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007269:Injections, Intra-Arterial; D008545:Melanoma / Q000188:drug therapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012878:Skin Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; C088636:O(6)-benzyl-2'-deoxyguanosine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine; D000077204:Temozolomide