ABI-007, nanoparticle albumin-bound paclitaxel, enhances tumor radioresponse.
Authors: Kathy A. Mason, Nicole Wiedenmann, David Valdecanas, Thomas Buchholz, Luka Milas
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5439 

ABI-007 is an albumin stabilized, Cremophor-free, nanoparticle formulation of paclitaxel designed to overcome insolubility of paclitaxel. The ABI-007 formulation eliminates the need for the toxic solvent Cremophor that limits the dose of paclitaxel that can be safely administered and consequently, overall drug efficacy. The aim of this study was to determine if ABI-007 showed anti-tumor efficacy against a mouse ovarian carcinoma (OCa-1) and whether it could augment the effect of radiotherapy when given in a combined chemo-radiotherapy regimen. A single cell suspension of OCa-1 tumor cells was injected intramuscularly into the hind legs of C3H mice. When tumors grew to a mean diameter of 7mm, treatment with single dose radiation of 10 Gy to the tumor-bearing leg, ABI-007 90mg/kg iv, or both were initiated. The maximum tolerable dose of paclitaxel was previously established to be 60mg/kg in this strain of mice and the dose of ABI-007 was chosen to be 1.5 times the MTD of the parent drug. ABI-007 was given prior to radiation at times ranging from 5 days to 9 h or 24 h following radiation exposure. Treatment endpoint was absolute tumor growth delay (AGD) defined as the difference in days to grow from 7-12mm in diameter between treated and untreated tumors. For groups treated with the combination of ABI-007 and radiation an enhancement factor (EF) was calculated as the ratio of the difference in days to grow from 7 to 12mm in diameter between the combination treated tumors and those treated with ABI-007 alone to the AGD of tumors treated with radiation only. Treatment groups consisted of 8-10 mice each. No drug related animal toxicity was observed at a dose of 90mg/kg iv. ABI-007 as a single agent significantly prolonged the growth delay of the OCa-1 tumor by about 2 weeks, with the untreated tumors growing to 12 mm diameter in 16 days and those treated with ABI-007 in 31 days. ABI-007 was slightly more effective as a single agent than a single dose of 10 Gy radiation. The data clearly show that ABI-007 when given at any time up to 5 days before radiation produced a supra-additive anti-tumor effect. At short inter-treatment intervals of 9-24 h the EF was about 1.3, increased to a maximum EF of 2.5 at inter-treatment intervals of 2-3 days, and then decreased to an EF of 1.8 at 4 days, and 1.5 at 5 days. When ABI-007 was given after radiation, the combined anti-tumor treatment effect was less than additive. Thus, ABI-007 possesses single agent anti-tumor activity against this ovarian tumor and greatly augments the effect of radiotherapy in a time dependent manner. As we have previously demonstrated for paclitaxel and docetaxel, enhanced treatment effects of the two agents are likely the result of multiple mechanisms with a cell cycle related mechanism (G2/M arrest) controlling the short inter-treatment intervals and tumor re-oxygenation being the dominate mechanism when the treatments are separated by several days (Semin Radiat Oncol 9 (Supp 1): 2-26,1999).