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Activation of the trans Geometry in Platinum Antitumor Complexes: A Survey of the Cytotoxicity of trans Complexes Containing Planar Ligands in Murine L1210 and Human Tumor Panels and Studies on Their Mechanism of Action¹

Departments of Chemistry [N. F., M. V. B.] and Medicine [J. D. R.], The University of Vermont and Vermont Cancer Center, Burlington, Vermont 05405, and Drug Development Section, The Institute of Cancer Research, Belmont, Sutton, Surrey, SM2 5NG, UK [L. R. K.]

The cytotoxicity of transplatinum complexes of structural formula trans-[PtCl₂(L)(L')] [L = L' = pyridine or thiazole, or L = quinoline (R' = methyl; R'' = methyl, phenyl, or CH₂phenyl) and L' = R'R''SO] has been studied in murine L1210 and human tumor cell lines. The results confirm previous observations that use of a sterically hindered planar ligand greatly enhances cytotoxicity, in comparison to trans-[PtCl₂(NH₃)₂], such that in some cases cytotoxicity equivalent to that of the clinically used agent cisplatin [cis-[PtCl₂(NH₃)₂]] is obtained. Results from both the panel of human ovarian carcinoma cell lines and the National Cancer Institute screening panel confirm a different pattern of cytotoxicity, with respect to cisplatin. The new trans-platinum complexes are also non-cross-resistant with cisplatin in both murine and human (human ovarian carcinma panel) tumor cell lines. Preliminary mechanistic studies using both cis- and trans-[PtCl₂(pyridine)₂] in L1210 cells have been carried out, to delineate the reasons for both the dramatically enhanced cytotoxicity and the lack of cross-resistance with the clinically used agents. Intracellular uptake is enhanced for pyridine relative to ammine (NH₃) complexes. The pyridine complexes also inhibit DNA synthesis, implying a role for DNA binding in their mechanism of action. Binding of the pyridine complexes to calf thymus DNA is, however, signficantly less than for the analogous ammine complexes. The presence of trans-pyridine ligands results in steric hindrance, which retards the rate of reaction of trans-[PtCl₂(pyridine)₂], relative to trans-[PtCl₂(NH₃)₂], with other important biomolecules such as glutathione. The results point to a potential new class of platinum antitumor complexes acting by a new mechanism and with activity complementary to agents such as cisplatin.

¹ This publication was supported in part by Grant P30 CA22435 from the National Cancer Institute. Its contents are solely the reponsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. The work was also supported by award of the J. Walter Juckett Fellowship for 1991/1992 from The Lake Champlain Cancer Research Organization to N. F.

² To whom requests for reprints should be addressed.

Received 4/ 9/92. Accepted 7/ 1/92.

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