PMID- 16546988
OWN - NLM
STAT- MEDLINE
DCOM- 20060526
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 5
IP  - 3
DP  - 2006 Mar
TI  - 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.
PG  - 732-8
AB  - 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.
FAU - Ueno, Tomio
AU  - Ueno T
AD  - Department of Surgery, Duke University Medical Center, Box 3118, Durham, NC 
      27710, USA.
FAU - Ko, Sae Hee
AU  - Ko SH
FAU - Grubbs, Elizabeth
AU  - Grubbs E
FAU - Yoshimoto, Yasunori
AU  - Yoshimoto Y
FAU - Augustine, Christi
AU  - Augustine C
FAU - Abdel-Wahab, Zeinab
AU  - Abdel-Wahab Z
FAU - Cheng, Tsung-Yen
AU  - Cheng TY
FAU - Abdel-Wahab, Omar I
AU  - Abdel-Wahab OI
FAU - Pruitt, Scott K
AU  - Pruitt SK
FAU - Friedman, Henry S
AU  - Friedman HS
FAU - Tyler, Douglas S
AU  - Tyler DS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 129732-90-7 (O(6)-benzyl-2'-deoxyguanosine)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - G9481N71RO (Deoxyguanosine)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/*administration & dosage/toxicity
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Chemotherapy, Cancer, Regional Perfusion
MH  - Dacarbazine/administration & dosage/*analogs & derivatives/toxicity
MH  - Deoxyguanosine/administration & dosage/*analogs & derivatives/toxicity
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Humans
MH  - Injections, Intra-Arterial
MH  - Melanoma/*drug therapy
MH  - O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Skin Neoplasms/*drug therapy
MH  - Temozolomide
MH  - Xenograft Model Antitumor Assays
EDAT- 2006/03/21 09:00
MHDA- 2006/05/27 09:00
CRDT- 2006/03/21 09:00
PHST- 2006/03/21 09:00 [pubmed]
PHST- 2006/05/27 09:00 [medline]
PHST- 2006/03/21 09:00 [entrez]
AID - 5/3/732 [pii]
AID - 10.1158/1535-7163.MCT-05-0098 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2006 Mar;5(3):732-8. doi: 10.1158/1535-7163.MCT-05-0098.