Platinum-amine compounds: importance of the labile and inert ligands for their pharmacological activities toward L1210 leukemia cells.

A series of Pt-amine compounds was assayed for their ability to inhibit the growth of cultured L1210 leukemia cells [median inhibitory dose (lD50)], their toxicity in mice [highest nonlethal dose in healthy mice (LD0)], their antitumor activity against leukemia L1210 cells grafted intraperitoneally into mice [mean survival of treated leukemic mice:mean survival of untreated leukemic mice (T/C)], and the ability to hydrolyze their labile ligands in vitro [hydrolysis half-time (t1/2)]. All Pt compounds exhibiting antitumor activity had a pair of labile ligands in the cis geometry with different charges, and the leaving groups had a wide range of hydrolysis rates. Among the compounds that showed antitumor activity, ID50 depended more on the inert ligands than on the labile ligands and was correlated with T/C. A relationship between LD0 and t1/2 was verified in the series of cis-Pt(II) compounds with the exception of the oxalate derivatives. Pt(II) and Pt(IV) compounds exhibited similar ID50, LD0, and T/C.

Does the antitumoral activity of platinum (IV) derivatives result from their in vivo reduction?

The antitumoral activity of some octahedral platinum(IV) and square-planar platinum(II) derivatives against Yoshida ascites tumor in the rat is reported. It is shown that only those octahedral platinum(IV) complexes which give active reduction products are active. These results support the hypothesis that the antitumor activity of octahedral complexes involves activation by in vivo reduction. Anticancer drugs functioning by this mechanism may be preferentially toxic to or may localize in hypoxic areas of tumors.