ABT-751 is an orally active
antimitotic agent that is currently in Phase II clinical trials. This agent binds to the
colchicine site on ss-
tubulin and inhibits polymerization of microtubules. This disruption of microtubule dynamics leads to a block in the cell cycle at the G2/M phase, and promotes apoptosis.
ABT-751, as a single agent, has antitumor activity against a series of xenograft models including
non-small cell lung cancer (NSCLC) and
colon cancer. The current studies were conducted to determine whether
ABT-751 enhances antitumor activity of standard cytotoxic
therapies currently in clinical use.
METHODS: Efficacy of
ABT-751, in combination with
cisplatin,
5-FU, and radiation, was evaluated in the Calu-6 NSCLC, HT-29 colon, and HCT-116 colon
carcinoma xenograft models, respectively.
Tumor-bearing athymic mice were treated with
ABT-751 orally once a day at 75 or 100 mg/kg/day on a 5-days-on, 5-days-off schedule for two cycles.
RESULTS: Efficacy of
ABT-751 at 100 mg/kg/day was tested in combination with
cisplatin at its maximum tolerable dose (MTD) (10 mg/kg/day, i.p. x1) in Calu-6
tumor-bearing athymic mice. The percent treated/control (%T/C)
tumor volume ratios on day 38 were 35, 37, and 6, and the percent
tumor growth delay (%TGD) values were 71, 65, and 188 for
cisplatin,
ABT-751 and the combination groups, respectively. HT-29 colon
tumors were used to test
ABT-751 in combination with an MTD of
5-FU, 30 mg/kg/day, i.p., q.d. x5. The %T/C ratios on day 38 were 22, 28, and 5 and the %TGD values were 75, 75, and 150 for
5-FU,
ABT-751, and the combination groups, respectively. Treatment of HCT-116 colon
carcinoma tumors with
ABT-751, concurrent with the
radiation treatment, was able to both enhance radiation-induced
tumor regression, and delay the time to recurrence and progression. Growth curves allowed calculation of enhancement of radiation-induced growth delay (defined as the additional time required for a treated
tumor to reach four times its original size) of 2, 9, and 12 days, for
ABT-751 alone, radiation alone, and the combination, respectively.
CONCLUSION: Collectively, these studies demonstrate that
ABT-751 enhanced efficacy of standard cytotoxic
therapies in a variety of
tumor xenograft models, and that enhancement was at least additive in all systems.