The membrane-bound high affinity folate receptor (FR) is expressed at high levels on a wide range of primary and metastatic human cancers, such as those originating from ovary, lung, breast, endometrium, kidney and brain tissue. Since folate-linked conjugates are known to be efficiently bound and internalized by FR-expressing cells, similar to the free vitamin, we have explored the possibility of using folate to target a small molecule chemotherapeutic drug to FR-enriched cells and tumors. Herein we report on the in vitro and in vivo evaluation of EC145, a novel folate conjugate of the potent microtubule inhibiting agent, desacetylvinblastinehydrazide. When tested on cells in culture, EC145 inhibited the growth of FR-positive KB cells in a dose-responsive fashion, and this activity could be completely blocked in the presence of excess free folate. In addition, EC145 displayed no activity on FR-negative cells, thereby demonstrating this compound’s specificity. EC145’s activity was next evaluated against FR-positive tumors in mice. In two different models (Balb/c mice bearing subcutaneous M109 tumors, and in nude mice bearing aggressive KB xenografts) and among repeated experiments, intravenous EC145 therapy was found to shrink established tumors to un-measurable levels in 80 to 100% of the animals. Furthermore, the activity occurred in the apparent absence of weight loss or major organ tissue degeneration. Taken together, these results indicate that a very potent anti-proliferative agent can be specifically delivered to FR-positive tumors to provide therapeutic benefit without causing unwanted toxicity.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]