Combination Effects Following Addition of the Tumour-Vascular Disrupting Agent ASA404 (Vadimezan) to Taxane-Containing Regimens of Trastuzumab and Bevacizumab in Human Breast Cancer Xenograft Models.
Authors: Evans D. , Cozens R. 
Published: December 2010

The tumour vasculature is essential for maintaining tumour growth and regulating the tumour microenvironment through the supply of nutrients and oxygen. ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid, DMXAA) is a flavonoid, non tubulin-binding Tumour-Vascular Disrupting Agent (Tumour-VDA) that induces breakdown of the established tumour vasculature resulting in the inhibition of tumour blood supply leading to tumour ischemia and extensive necrosis of the tumour core. Unlike anti-angiogenics, ASA404 has limited effects on angiogenesis at the tumour periphery and as a consequence the remaining peripheral tumour rim represents a source for regrowth of the tumour upon cessation of ASA404 treatment. Preclinical and clinical studies have highlighted the effectiveness of combining chemotherapies, especially taxanes, with ASA404 for marked tumour inhibition. In the present studies, the influence of adding ASA404 to taxane-containing regimens of trastuzumab and bevacizumab was examined in breast cancer xenograft models. The effects of the combination of trastuzumab plus paclitaxel +/- ASA404 was examined using the BT-474 breast cancer model in C.B-17 SCID mice. Adminstration schedules were as follows: ASA404 (15 and 20 mg/kg iv, once daily on days 1, 5 and 9), paclitaxel (P) (10 and 15 mg/kg iv, qod x5) and trastuzumab (T) (10 mg/kg ip, biwk x4). Efficacy was assessed on day 27 as the % T/C (growth inhibition) or % mean reduction from the mean tumour volume at day 1 (T/To; regression of tumour volume). ASA404 alone showed no anti-tumour effects. Dual combination of P+T at 15 and 10 mg/kg respectively produced significant tumour inhibition with 21% T/C. Combination of ASA404 at 15 or 20 mg/kg with P (15 mg/kg) and T (10 mg/kg) resulted in significant tumour inhibition (11% T/C) and regression (45% T/To) being observed respectively. The 20 mg/kg ASA404-containing triple combination therapy significantly improved the efficacy compared to the corresponding ASA404 monotherapy or P+T dual therapy and yielded partial regressions in 3 of 11 mice by day 27. The effects of the combination of bevacizumab plus docetaxel +/- ASA404 was examined using the MCF-7 breast cancer model in nu/nu nude mice. Adminstration schedules were as follows: ASA404 (20 mg/kg iv, once daily on days 1, 5 and 9), docetaxel (D) (4 and 6 mg/kg iv, qwk x3) and bevacizumab (B) (10 mg/kg ip, biwk x4). Efficacy was assessed on day 17. ASA404 alone had a modest, non-significant anti-tumour effect (64% T/C). Dual combination of B with D at 4 or 6 mg/kg resulted in 28% and 13 % T/C respectively. The triple combination of ASA404 with B+D (4 or 6 mg/kg) resulted in tumour regressions (8% and 5% T/To respectively), although this observed improvement of the triple therapy over the B+D combination or ASA404 alone was not statistically signifcant. These data indicate the potential value for the combination of ASA404 (vadimezan) to the taxane-containing regimens of trastuzumab and bevacizumab in these preclinical breast cancer models.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3142.