New Epothilone KOS-1803 Optimizes Tumor Penetration

LOS ANGELES—The third-generation epothilone KOS-1803 may optimize tumor penetration while limiting exposure to other tissues, researchers reported at the 2007 American Association for Cancer Research annual meeting (abstract 1438). KOS-1803 is a potent microtubule stabilizer. Compared with other epothilones, investigators maintain that it has higher drug accumulation in the tumor and a larger volume of distribution, including large tumor-to-brain ratio and long elimination half-life.

Ziyang Zhong, PhD, and colleagues at Kosan Biosciences, Hayward, California, conducted the research in collaboration with Memorial Sloan-Kettering Cancer Center investigators.

Dr. Zhong reported significant tumor regression with KOS-1083 in multiple mouse xenograft models, including breast, ovarian, lung, prostate, colorectal, and neuroblastoma. In a taxane-insensitive breast xenograft model, KOS-1803 in low doses suppressed tumor growth by nearly 100%. In ovarian carcinoma-bearing mice, KOS-1803, given at 15 mg/kg every 6 days for five doses, achieved a total cure of the cancer without relapse in all mice.

Excellent antitumor activity was also shown in a neuroblastoma mouse model, in which 50% of mice treated with the compound were cured. In various other tumor models, KOS-1803 demonstrated clear anti-tumor activity at low dosing intensity and infrequent dosing (every 6 to 7 days or every 12 days), Dr. Zhong said. Tolerability was good, with GI disturbance the most common toxicity and no evidence of neurotoxicity.