[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Tumor Biology 2: Animal Models of Human Cancers 1: Hematopoietic, Metastasis, etc.
Tasidotin HCl (ILX651): In vivo antitumor effects after intravenous or oral administration
Larry Arthaud and
Genzyme Corporation, San Antonio, TX
Tasidotin HCl is a third-generation synthetic pentapeptide analog of dolastatin with a unique mechanism of action that potentially differs from that of microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids). Tasidotin HCl has been chemically modified to provide improved pharmacological properties. It is orally bioavailable with a potentially enhanced therapeutic window over previous generations of dolastatins. The following studies were initiated in order to evaluate the antitumor activity of Tasidotin HCl as compared to several approved anticancer agents. Tasidotin HCl was tested in four xenograft models: PANC-1 and MiaPaCa-2 pancreatic ca, PC-3 prostate ca, and H460 non-small cell lung carcinoma. Tasidotin HCl was administered intravenously in the pancreatic models and orally for the remaining two studies. In the PANC-1 model, Tasidotin HCl resulted in an increase in life span (T/C) of 1.7x - 1.9x compared with vehicle treated control animals and similar to docetaxel, paclitaxel, vinblastine, and vincristine (1.6x - 2.1x) and superior to gemcitabine (1.4x). Similar results were seen in the MiaPaCa-2 model. Tasidotin HCl resulted in an increase in life span greater than 3.2x compared with vehicle treated control animals and similar to the taxanes and vincas (2.1->3.2x) and superior to gemcitabine (1.6x). In the PC-3 study, Tasidotin HCl was compared with Abraxane, docetaxel, and paclitaxel. On Day 38 (21 days after tumor implantation), all therapies were highly effective against this model. Tasidotin HCl treatment inhibited tumor growth by 95% (T/C of 4.9-5.3%), while the other agents suppressed tumor growth by 91-94% (T/C values of 6.1-9.4%). Treatment of animals bearing H460 NSCLC xenografts with Tasidotin HCl was not effective resulting in an increase-in-lifespan of 1.2x compared with the untreated control animals. Treatment with taxanes and vincas resulted in increase-in-lifespans of 1.7-2.0x. Tasidotin HCl was well tolerated in all of the studies resulting in a maximum weight loss of 13%. These data indicate that Tasidotin HCl is as effective in these preclinical mouse models as standard anticancer agents. The data also suggest that Tasidotin HCl differentiates from taxanes and vincas and it warrants further clinical evaluation. Phase 2 trials are ongoing in melanoma, non-small cell lung, and prostate cancers.
Copyright © 2006 by the American Association for Cancer Research.