S 12363 is a new Vinca
alkaloid derivative, characterized by the grafting of an alpha-aminophosphonate, onto the Vinca nucleus, facilitating
drug penetration and increasing intracellular
drug retention. As a high cytotoxic activity had been demonstrated in in vitro and in vivo models recommended by the National Cancer Institute, a phase I trial was initiated in
cancer patients. In order to quantify
S 12363 systemic levels in humans, two
monoclonal antibody-based immunoassays, RIA (radio-) and EIA (
enzyme immunoassay) were developed. The gamma-emitting probe used in the RIA, 125I-(deacetyl-O4-vinblastine)-tyramine, bound very tightly to the
monoclonal antibody (dissociation constant, Kd = 2.5 x 10(-11) M), demonstrating a high affinity mainly directed toward the catharantine nucleus (
vindesine,
vincristine,
vinblastine, 100% cross-reactivity;
vinorelbine, 0.3% cross-reactivity). In the EIA, a deacetyl O4-
vinblastine/ovalbumine conjugate was used as the competing
antigen. Its binding to the
monoclonal antibody was revealed by an anti-mouse
immunoglobulin G conjugated to
biotin which interacts with
streptavidin labeled with
alkaline phosphatase. This method permitted obtaining nearly the same sensitivity and reproducibility with EIA as with RIA, their respective minimum quantitation limits being 0.100 and 0.040 ng/ml (106 and 42 pM) of
S 12363 in plasma. These assays allowed the study of
S 12363 systemic pharmacokinetics in
cancer patients during a phase I trial up to 72 h after dosing. As determined by RIA, the
S 12363 plasma profile was triphasic with a terminal half-life; t1/2 gamma = 49 +/- 16 h, a plasma clearance, CL = 0.14 +/- 0.04 liter/h/kg, and a volume of distribution at steady state, Vdss = 5.0 +/- 2.8 liter/kg. The pharmacokinetics of
S 12363 is linearly related to dose when increased from 0.08 up to 0.84 mg/m2 in humans. Its plasma profile and pharmacokinetic parameters are close to those of other
Vinca alkaloids with clearance and terminal half-life being intermediate between those of
vinblastine and
vincristine. Therapeutic doses are 4 to 10 times lower and should be a direct consequence of the higher uptake and retention by the cells of this new aminophosphonate Vinca
alkaloid derivative.