Abstract 1779: Antitumor effect and tumor distribution of PM01183 in human pancreatic and breast xenograft mouse models
Authors: Bishop Alan , Pernice Tiziana , Aviles Pablo M. , Cataluña Oscar , Palomares Mandy , Lopez Raquel , Nuñez Praxedes , Cuevas Carmen , Guillén M José 
Published: August 2012

Abstract
Background: PM01183 is a new alkaloid that binds to the minor groove of DNA and causes cell cycle perturbations, mainly consisting in a delayed progression of S phase and cycle arrest in G2/M. T Currently, PM01183 clinical development includes Phase II single agent trials (pancreas, breast and platinum-resistant/refractory ovarian) as well as Phase I trials in combination (with doxorubicin and gemcitabine) and in advanced acute leukemia. The antitumor in vivo activity, as well as plasma and tumor pharmacokinetics in breast and pancreatic tumor xenografted models are presented here. Material and Methods: Athymic female nu/nu mice were subcutaneously implanted with SW1990 (pancreas) or MDA-MB-231 (breast) cells. When tumors reached ca. 300 mm3, tumor bearing animals were randomly allocated into experimental groups (efficacy, placebo and pharmacokinetics -PK-). The animals belonging to the efficacy study received three doses in a weekly (q7dx3) schedule of PM01183 at 0.18 mg/kg or placebo. The antitumor activity was followed by the change in tumor volume for treated and placebo groups. The PK group received a single dose of PM01183 at 0.18 mg/kg. Then, plasma and tumor samples (N=3-4/sampling time) were collected at different times and up to 24 h post-administration. Tumor samples were diluted 1:4 w/v with water and homogenized using Precellys®24 bead beating technology. Once homogenized the samples were processed as per plasma. PM01183 was detected in plasma and tumor extracts by electrospray ionization/tandem mass spectrometry after extraction by supported liquid extraction (SLE). The lower limit of quantitation (LLOQ) for plasma samples was 0.1 ng/mL. The LLOQ for breast and pancreas tumors were 0.5 and 1 ng/g tumor, respectively. Results: PM01183 induced statistically significant antitumor activity in both SW 1990 (P&lt;0.01) and MDA-MB-231 (P&lt;0.05) tumor models. The plasma PK in mice bearing either SW 1990 or MDA-MB-231 tumors were similar, yielding AUCs (0-24h) of 60.3 and 65.3 ng*hr/mL, respectively; Clearance of 2919.2 and 2680.5 mL/hr/kg, respectively; volume of distribution of 8808 and 7892.1 mL/kg, respectively; and, terminal half lifes of 5.6 and 7.1 h, respectively. PM01183 was detected in both xenografted tumors up to 24 h post-dosing. The area under curve (AUCs 0-24h) for PM01183 in pancreas and breast tumors were 34.36 ng*hr/g and 70.89 ng*hr/g, with terminal half-life of 14.05 h and 15.48 h, respectively. Conclusion: PM01183 demonstrated in vivo antitumor activity in pancreatic and breast xenograft models, similar plasma pharmacokinetics parameters and tumor distribution until 24 h after a single iv administration.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1779. doi:1538-7445.AM2012-1779