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• W2324650167 abstract "Abstract PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. PM01183 displays significant antitumor activity in several murine models of human cancer. PM01183 is currently in phase I/II clinical development for cancer treatment. Nonclinical combination studies are increasingly relevant during the development of any anticancer compound. As such, PM01183 was assayed in combination (two-drugs) with representatives of alkylating agents (dacarbazine, temozolomide and cisplatin), antimetabolites (5-FU and gemcitabine), DNA-topoisomerase inhibitors (irinotecan and doxorubicin) and tubulin binding agents (paclitaxel and vinorelbine). Different models were used depending on the combination explored: STS (HT1080) for dacarbazine; glioma (U-87 MG) for temozolomide; gastric (HGC-27) for cisplatin and 5-FU; pancreas (SW1990) for gemcitabine; colon (HT-29) and NSCLC (H460) for irinotecan; and ovarian (A2780) for doxorubicin, paclitaxel and vinorelbine. Athymic nu/nu mice bearing tumors (ca. 150 mm3) were randomly allocated to 13 treatment groups: i) placebo; ii) PM01183 at 4 different dose levels, namely MTD (0.180 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; iii) Compound to be combined, at 4 different dose levels MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, iv) PM01183 plus the combined compound, administered with the combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of MTD ratios. The antitumor activity was followed by T/C, (change in tumor volume for each treated -T- and placebo -C- groups during placebo-treated survival period). Then, the fraction affected (Fa) by the treatment was calculated (1-T/C) and, the combination index (CI) by the CI-isobol method determined. Synergism (CI ≤ 1 at Fa &gt; 0.8) was recorded when PM01183 was combined with dacarbazine (HT1080), cisplatin (HGC-27), 5-fluororacil (HGC-27), gemcitabine (SW1990), irinotecan (H460), doxorubicin (A2780), paclitaxel (A2780) and vinorelbine (A2780). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2011-3538" @default.
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• W2324650167 date "2011-04-01" @default.
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• W2324650167 title "Abstract 3538: In vivo combination studies of PM01183 with alkylating, antimetabolites, DNA-topoisomerase inhibitors and tubulin binding agents" @default.
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