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

C. Lynn Cheng, Stewart P. Johnson, Stephen T. Keir, Jennifer A. Quinn, Francis Ali-Osman, Csaba Szabo, Hongshan Li, Andrew L. Salzman, M. Eileen Dolan, Paul Modrich, Darell D. Bigner, Henry S. Friedman

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

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 LD10). 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.

Original languageEnglish (US)
Pages (from-to)1364-1368
Number of pages5
JournalMolecular Cancer Therapeutics
Volume4
Issue number9
DOIs
StatePublished - Sep 2005
Externally publishedYes

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temozolomide
DNA Mismatch Repair
Heterografts
Glioma
Growth
Poly(ADP-ribose) Polymerases
Neoplasms
Poly (ADP-Ribose) Polymerase-1
Therapeutics
Nude Mice

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair- deficient malignant glioma xenograft. / Cheng, C. Lynn; Johnson, Stewart P.; Keir, Stephen T.; Quinn, Jennifer A.; Ali-Osman, Francis; Szabo, Csaba; Li, Hongshan; Salzman, Andrew L.; Dolan, M. Eileen; Modrich, Paul; Bigner, Darell D.; Friedman, Henry S.

In: Molecular Cancer Therapeutics, Vol. 4, No. 9, 09.2005, p. 1364-1368.

Research output: Contribution to journalArticle

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 2005, 'Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair- deficient malignant glioma xenograft', Molecular Cancer Therapeutics, vol. 4, no. 9, pp. 1364-1368. https://doi.org/10.1158/1535-7163.MCT-05-0128
Cheng, C. Lynn ; Johnson, Stewart P. ; Keir, Stephen T. ; Quinn, Jennifer A. ; Ali-Osman, Francis ; Szabo, Csaba ; Li, Hongshan ; Salzman, Andrew L. ; Dolan, M. Eileen ; Modrich, Paul ; Bigner, Darell D. ; Friedman, Henry S. / Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair- deficient malignant glioma xenograft. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 9. pp. 1364-1368.
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abstract = "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 LD10). 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.",
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AU - Quinn, Jennifer A.

AU - Ali-Osman, Francis

AU - Szabo, Csaba

AU - Li, Hongshan

AU - Salzman, Andrew L.

AU - Dolan, M. Eileen

AU - Modrich, Paul

AU - Bigner, Darell D.

AU - Friedman, Henry S.

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