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In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication

Ciccarelli, Richard B. and Solomon, Mark J. and Varshavsky, Alexander and Lippard, Stephen J. (1985) In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication. Biochemistry, 24 (26). pp. 7533-7540. ISSN 0006-2960. doi:10.1021/bi00347a005. https://resolver.caltech.edu/CaltechAUTHORS:20210122-162658489

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Abstract

The mechanism of action of the antitumor drug cis-diamminedichloroplatinum(II), cis-DDP, was investigated by using the ~5200 base pair (bp) chromosome of simian virus 40 (SV40) as an in vivo chromatin model. Comparative studies were also carried out with the clinically ineffective isomer trans-DDP. Although 14 times more trans- than cis-DDP in the culture medium is required to inhibit SV40 DNA replication in SV40-infected green monkey CV-1 cells, the two isomers are equally effective at inhibiting replication when equimolar amounts are bound to SV40 DNA in vivo. Since both isomers are transported into CV-1 cells at similar rates, differential uptake cannot account for the greater ability of cis-DDP to inhibit SV40 DNA replication. Rather, this result is explained by the finding that cis-DDP-DNA adducts accumulate continuously over the incubation period, whereas trans-DDP binding to DNA reaches a maximum at 6 h and thereafter decreases dramatically. We suggest that the different accumulation behavior of cis-DDP and trans-DDP on DNA is due to their differential repair in CV-1 cells. A variety of non-histone proteins, including SV40 capsid proteins but virtually no histones, are cross-linked to SV40 DNA in vivo by either cis- or trans-DDP. More DNA-protein cross-links are formed by trans-DDP than by cis-DDP at equivalent amounts of DNA-bound platinum. Since the cis-DDP analogue dichloro(ethylenediamine)platinum(II) inhibits SV40 DNA replication as efficiently as cis- and /trans-DDP but does not form DNA-protein cross-links, platinum-mediated DNA-protein cross-linking is not directly responsible for the inhibition of DNA replication. We discuss these findings in relation to the known cytotoxic and antitumor properties of cis-DDP.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/bi00347a005DOIArticle
ORCID:
AuthorORCID
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 1985 American Chemical Society. Received June 25, 1985. This work was supported by U.S. Public Health Service Grants CA 34992 (to S.J.L.) and CA 30367 (to A.V.). R.B.C. was a Damon Runyon-Walter Winchell Cancer Fund Postdoctoral Fellow (DRG-716) and M.J.S. a National Science Foundation Predoctoral Fellow. We thank Engelhard Corp. for generously providing K₂PtCl₄ from which all platinum complexes were synthesized.
Funders:
Funding AgencyGrant Number
NIHCA34992
NIHCA30367
Damon Runyon-Walter Winchell Cancer FundDRG-716
NSF Graduate Research FellowshipUNSPECIFIED
Issue or Number:26
DOI:10.1021/bi00347a005
Record Number:CaltechAUTHORS:20210122-162658489
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210122-162658489
Official Citation:In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication Richard B. Ciccarelli, Mark J. Solomon, Alexander Varshavsky, and Stephen J. Lippard Biochemistry 1985 24 (26), 7533-7540 DOI: 10.1021/bi00347a005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107686
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:25 Jan 2021 15:15
Last Modified:16 Nov 2021 19:05

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