J. Howle, G. Gale, A. Smith
May 15, 1972
Citations
0
Influential Citations
41
Citations
Quality indicators
Journal
Biochemical pharmacology
Abstract
Abstract The neutral, square-planar platinum complex cis -dichloro(dipyridine)platinum (II) ( cis -PPC), which is a structural analog of cis -dichlorodiammineplatinum(II) ( cis -PtII) and possesses similar antitumor and antimitotic properties, was synthesized using [G- 3 H]pyridine and used to determine certain characteristics of its interactions with selected living and non-living systems. Cis -dichloro([G- 3 H]dipyridine)platinum(II) ( cis -PPC- 3 H) associates with intact Ehrlich ascites tumor cells in vitro at 2° and 37° and resists dissociation by washing with saline or trichloroacetic acid (TCA) as well as solubilization in alkali followed by reprecipitation with TCA. Dialysis experiments showed that cis -PPC- 3 H associates avidly with calf thymus DNA, high molecular weight yeast RNA, and bacterial and yeast transfer RNA, but not with bovine serum albumin, dextran, or purified erythrocyte membranes. Dialysis of the platinum-nucleic acid complexes in distilled water or NaCl results in loss of a portion of the original radioactivity. The platinum-DNA bond is also resistant to dissociation by solubilization in alkali followed by TCA precipitation. The homopolymers, polyadenylate and polycytidylate, bind cis -PPC- 3 H to the same extent as RNA on a weight basis; polyguanylate and polyuridylate bind the platinum complex to a greater extent than does RNA. Similar to nitrogen mustard (HN 2 ), bonding of cis -PPC- 3 H to DNA in vitro is inhibited by NaCl; however, prior alkylation of the DNA with HN 2 does not influence its subsequent bonding with cis -PPC- 3 H. It was proposed that the antitumor and antimitotic action of the square-planar platinum complex depends upon the dissociation of one or both chlorine atoms from the platinum atom. The resulting cationic, aquated species subsequently forms a bond with nucleic acid, and does so with a possibly greater affinity for guanylate and uridylate. The site of establishment of this bond(s) is probably dissimilar to that of the HN 2 -nucleic acid bond.