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
Annals of Surgical Oncology, ISSN: 1068-9265, Vol: 17, Issue: 8, Page: 2247-2254
2010
- 18Citations
- 19Captures
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Metrics Details
- Citations18
- Citation Indexes18
- 18
- CrossRef16
- Captures19
- Readers19
- 19
Article Description
Background: 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. Materials and Methods: 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. Results: 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 O6-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. Conclusion: 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. © Society of Surgical Oncology 2010.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77954951941&origin=inward; http://dx.doi.org/10.1245/s10434-010-0971-x; http://www.ncbi.nlm.nih.gov/pubmed/20182810; http://link.springer.com/10.1245/s10434-010-0971-x; https://link.springer.com/article/10.1245%2Fs10434-010-0971-x; http://www.springerlink.com/index/10.1245/s10434-010-0971-x; https://dx.doi.org/10.1245/s10434-010-0971-x; https://link.springer.com/article/10.1245/s10434-010-0971-x; http://www.springerlink.com/index/pdf/10.1245/s10434-010-0971-x
Springer Science and Business Media LLC
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