During the last 30 years, camptothecins have emerged as an important new class of anti-tumor drugs. Two water soluble camptothecin derivatives, topotecan and irinotecan, have been approved by the FDA. Karenitecin (also known as BNP1350) is a highly lipophilic camptothecin derivative undergoing clinical development. It is characterized by substantial lactone stability and long plasma half-life. In vitro studies conducted on a panel of over 20 human cancer cell lines indicate that Karenitecin is significantly more potent than either topotecan or SN-38, the active metabolite of irinotecan. Equilibrium dialysis studies with human plasma revealed that Karenitecin is 98 to 99% protein-bound. We have also reported that α1-acid glycoprotein can effectively protect Karenitecin lactone from hydrolysis. To begin to correlate the effect of plasma protein binding on potency for this class of drugs, we have conducted cytotoxicity studies using media that contain 40 mg/ml human serum albumin and 1 mg/ml α1-acid glycoprotein, approximating certain aspects of the protein fraction of human plasma. Karenitecin is found to be more potent in the presence of plasma proteins than other camptothecins with much larger free drug fractions. The data suggest that the activity of Karenitecin in the presence of plasma proteins is not limited to the free fraction as measured by equilibrium dialysis. The preferential affinity of camptothecins for either human serum albumin or α1-acid glycoprotein and the lactone protective effect may better explain the observed cytotoxic activity of camptothecins.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]