RGD Reference Report - 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.

General

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.
Authors:	Toshimitsu, H Yoshimoto, Y Augustine, CK Padussis, JC Yoo, JS Angelica Selim, M Pruitt, SK Friedman, HS Ali-Osman, F Tyler, DS
Citation:	Toshimitsu H, etal., Ann Surg Oncol. 2010 Feb 24.
RGD ID:	2316960
Pubmed:	PMID:20182810 (View Abstract at PubMed)
DOI:	DOI:10.1245/s10434-010-0971-x (Journal Full-text)
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 O(6)-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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
melanoma		ISO	Mgmt (Rattus norvegicus)	2316960; 2316960	protein:increased activity:skin tumor (rat)	RGD
melanoma		IEP		2316960	protein:increased activity:skin tumor (rat)	RGD

Objects Annotated

Genes (Rattus norvegicus)

Mgmt (O-6-methylguanine-DNA methyltransferase)

Genes (Mus musculus)

Mgmt (O-6-methylguanine-DNA methyltransferase)

Genes (Homo sapiens)

MGMT (O-6-methylguanine-DNA methyltransferase)

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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.