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Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.

Publication ,  Journal Article
Cheng, CL; Johnson, SP; Keir, ST; Quinn, JA; Ali-Osman, F; Szabo, C; Li, H; Salzman, AL; Dolan, ME; Modrich, P; Bigner, DD; Friedman, HS
Published in: Mol Cancer Ther
September 2005

Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair-proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD(10)). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair-proficient xenografts. In these experiments, mice were treated with a lower amount of temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair.

Duke Scholars

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

September 2005

Volume

4

Issue

9

Start / End Page

1364 / 1368

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Temozolomide
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly (ADP-Ribose) Polymerase-1
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Medulloblastoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Cheng, C. L., Johnson, S. P., Keir, S. T., Quinn, J. A., Ali-Osman, F., Szabo, C., … Friedman, H. S. (2005). Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Mol Cancer Ther, 4(9), 1364–1368. https://doi.org/10.1158/1535-7163.MCT-05-0128
Cheng, C Lynn, Stewart P. Johnson, Stephen T. Keir, Jennifer A. Quinn, Francis Ali-Osman, Csaba Szabo, Hongshan Li, et al. “Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.Mol Cancer Ther 4, no. 9 (September 2005): 1364–68. https://doi.org/10.1158/1535-7163.MCT-05-0128.
Cheng CL, Johnson SP, Keir ST, Quinn JA, Ali-Osman F, Szabo C, et al. Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Mol Cancer Ther. 2005 Sep;4(9):1364–8.
Cheng, C. Lynn, et al. “Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.Mol Cancer Ther, vol. 4, no. 9, Sept. 2005, pp. 1364–68. Pubmed, doi:10.1158/1535-7163.MCT-05-0128.
Cheng CL, Johnson SP, Keir ST, Quinn JA, Ali-Osman F, Szabo C, Li H, Salzman AL, Dolan ME, Modrich P, Bigner DD, Friedman HS. Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Mol Cancer Ther. 2005 Sep;4(9):1364–1368.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

September 2005

Volume

4

Issue

9

Start / End Page

1364 / 1368

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transplantation, Heterologous
  • Temozolomide
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly (ADP-Ribose) Polymerase-1
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Medulloblastoma