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O6-benzylguanine-mediated enhancement of chemotherapy.

Publication ,  Journal Article
Friedman, HS; Keir, S; Pegg, AE; Houghton, PJ; Colvin, OM; Moschel, RC; Bigner, DD; Dolan, ME
Published in: Mol Cancer Ther
September 2002

We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990) that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and cyclophosphamide activity in malignant glioma xenografts growing in athymic nude mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the combination of temozolomide plus irinotecan (CPT-11) displays a schedule-dependent enhancement of antitumor activity secondary to trapping of topoisomerase I by O6-methylguanine residues in DNA. These studies suggested that there might be favorable therapeutic interactions between O6-BG and combinations of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus cyclophosphamide or temozolomide plus CPT-11, respectively. Our present results indicate that the combination of cyclophosphamide plus BCNU plus O6-BG produces growth delays modestly-to-markedly-superior to combinations of cyclophosphamide with BCNU. Although the combination of temozolomide and CPT-11 reveals a marked increase in activity compared with either agent used alone, the addition of O6-BG to this combination dramatically increased the growth delay of the O6-alkylguanine-DNA alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest that a Phase I trial of CPT-11 plus temozolomide plus O6-BG in AGT-positive tumors may be an important intervention to maximize the therapeutic benefits of the combination of CPT-11 and temozolomide.

Duke Scholars

Published In

Mol Cancer Ther

ISSN

1535-7163

Publication Date

September 2002

Volume

1

Issue

11

Start / End Page

943 / 948

Location

United States

Related Subject Headings

  • Temozolomide
  • Protein Synthesis Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Irinotecan
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Friedman, H. S., Keir, S., Pegg, A. E., Houghton, P. J., Colvin, O. M., Moschel, R. C., … Dolan, M. E. (2002). O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther, 1(11), 943–948.
Friedman, Henry S., Stephen Keir, Anthony E. Pegg, Peter J. Houghton, O Michael Colvin, Robert C. Moschel, Darell D. Bigner, and M Eileen Dolan. “O6-benzylguanine-mediated enhancement of chemotherapy.Mol Cancer Ther 1, no. 11 (September 2002): 943–48.
Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC, et al. O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther. 2002 Sep;1(11):943–8.
Friedman, Henry S., et al. “O6-benzylguanine-mediated enhancement of chemotherapy.Mol Cancer Ther, vol. 1, no. 11, Sept. 2002, pp. 943–48.
Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC, Bigner DD, Dolan ME. O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther. 2002 Sep;1(11):943–948.

Published In

Mol Cancer Ther

ISSN

1535-7163

Publication Date

September 2002

Volume

1

Issue

11

Start / End Page

943 / 948

Location

United States

Related Subject Headings

  • Temozolomide
  • Protein Synthesis Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Irinotecan
  • Humans