Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma.

Published

Journal Article

Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma.PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days.In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P < .04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment.The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

Full Text

Duke Authors

Cited Authors

  • Toshimitsu, H; Yoshimoto, Y; Augustine, CK; Padussis, JC; Yoo, JS; Angelica Selim, M; Pruitt, SK; Friedman, HS; Ali-Osman, F; Tyler, DS

Published Date

  • August 2010

Published In

Volume / Issue

  • 17 / 8

Start / End Page

  • 2247 - 2254

PubMed ID

  • 20182810

Pubmed Central ID

  • 20182810

Electronic International Standard Serial Number (EISSN)

  • 1534-4681

International Standard Serial Number (ISSN)

  • 1068-9265

Digital Object Identifier (DOI)

  • 10.1245/s10434-010-0971-x

Language

  • eng