This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sorenson, C. M. Articles by Eastman, A. Search for Related Content PubMed PubMed Citation Articles by Sorenson, C. M. Articles by Eastman, A.

Influence of cis-Diamminedichloroplatinum(II) on DNA Synthesis and Cell Cycle Progression in Excision Repair Proficient and Deficient Chinese Hamster Ovary Cells¹

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105

DNA has been implicated as the critical intracellular target for cis-diamminedichloroplatinum(II) (cis-DDP) action. Inhibition of DNA synthesis is a consequence of platination and has become accepted as the critical step in cis-DDP-induced toxicity. We have previously demonstrated that, following incubation with cis-DDP, murine leukemia L1210 cells progress through synthesis only to arrest in the G₂ phase of the cell cycle. The G₂ arrest was transient at low drug concentrations and was persistent at higher concentrations with a concomitant loss of viability. Chinese hamster ovary cell lines both proficient and deficient for DNA excision repair have been used to analyze the relationship between inhibition of DNA synthesis and toxicity and to determine whether DNA repair is necessary for cell cycle progression. Two repair-deficient cell lines were hypersensitive to cis-DDP and demonstrated a marked arrest in the G₂ phase. The arrest was transient over only a small range of concentrations. At higher concentrations, the arrest was persistent and the cells subsequently died. Incorporation of [³H]thymidine into macromolecules demonstrated no inhibition of DNA synthesis while these cells progressed through the S phase. In contrast, at higher, but nontoxic, concentrations of cis-DDP, the repair-proficient cells exhibited inhibition of DNA synthesis while in S. At toxic concentrations, these cells also arrested in G₂. Therefore, direct inhibition of DNA synthesis correlated only with the concentration of drug and not with the different sensitivities of the cell lines. Arrest of cells in G₂ did correlate with toxicity. In every cell line, the appearance of G₂-arrested cells preceded cell disintegration. It is proposed that the G₂-arrested cells preceded cell disintegration. It is proposed that the G₂ arrest results from the inability of the cells to transcribe genes required for passage into mitosis. Cells proficient in DNA repair can circumvent this arrest by repairing the damaged DNA and permitting transcription to proceed. These results support the hypothesis that inhibition of DNA synthesis is not the critical step in cis-DDP-induced cytotoxicity.

¹ This work was supported by National Cancer Institute Research Grants CA36039 and CA00906, and by Cancer Center Support Grants CA36727 and ACS SIG-16.

² To whom requests for reprints should be addressed, at Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, NE 68105-1065.

Received 6/20/88. Revised 8/29/88. Accepted 9/ 2/88.

This article has been cited by other articles:

				F. Yu, J. Megyesi, and P. M. Price Cytoplasmic initiation of cisplatin cytotoxicity Am J Physiol Renal Physiol, July 1, 2008; 295(1): F44 - F52. [Abstract] [Full Text] [PDF]

				Z. Yang, L. M. Schumaker, M. J. Egorin, E. G. Zuhowski, Z. Guo, and K. J. Cullen Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin. Cancer Res., October 1, 2006; 12(19): 5817 - 5825. [Abstract] [Full Text] [PDF]

				C. Voland, A. Bord, A. Peleraux, G. Penarier, D. Carriere, S. Galiegue, E. Cvitkovic, O. Jbilo, and P. Casellas Repression of cell cycle-related proteins by oxaliplatin but not cisplatin in human colon cancer cells. Mol. Cancer Ther., September 1, 2006; 5(9): 2149 - 2157. [Abstract] [Full Text] [PDF]

				P. R. Andreassen, G. P.H. Ho, and A. D. D'Andrea DNA damage responses and their many interactions with the replication fork Carcinogenesis, May 1, 2006; 27(5): 883 - 892. [Abstract] [Full Text] [PDF]

				D. Wang and S. J. Lippard Cisplatin-induced Post-translational Modification of Histones H3 and H4 J. Biol. Chem., May 14, 2004; 279(20): 20622 - 20625. [Abstract] [Full Text] [PDF]

				A. Biroccio, C. Gabellini, S. Amodei, B. Benassi, D. Del Bufalo, R. Elli, A. Antonelli, M. D'Incalci, and G. Zupi Telomere Dysfunction Increases Cisplatin and Ecteinascidin-743 Sensitivity of Melanoma Cells Mol. Pharmacol., March 1, 2003; 63(3): 632 - 638. [Abstract] [Full Text] [PDF]

				T. Petit, D. J. Bearss, D. A. Troyer, R. M. Munoz, and J. J. Windle p53-independent Response to Cisplatin and Oxaliplatin in MMTV-ras Mouse Salivary Tumors Mol. Cancer Ther., February 1, 2003; 2(2): 165 - 171. [Abstract] [Full Text] [PDF]

				E. A. Kohn, N. D. Ruth, M. K. Brown, M. Livingstone, and A. Eastman Abrogation of the S Phase DNA Damage Checkpoint Results in S Phase Progression or Premature Mitosis Depending on the Concentration of 7-Hydroxystaurosporine and the Kinetics of Cdc25C Activation J. Biol. Chem., July 12, 2002; 277(29): 26553 - 26564. [Abstract] [Full Text] [PDF]

				V. M. Gonzalez, M. A. Fuertes, C. Alonso, and J. M. Perez Is Cisplatin-Induced Cell Death Always Produced by Apoptosis? Mol. Pharmacol., April 1, 2001; 59(4): 657 - 663. [Full Text]

				K. M. Henkels and J. J. Turchi Cisplatin-induced Apoptosis Proceeds by Caspase-3-dependent and -independent Pathways in Cisplatin-resistant and -sensitive Human Ovarian Cancer Cell Lines Cancer Res., July 1, 1999; 59(13): 3077 - 3083. [Abstract] [Full Text] [PDF]

				J. Zlatanova, J. Yaneva, and S. H. Leuba Proteins that specifically recognize cisplatin-damaged DNA: a clue to anticancer activity of cisplatin FASEB J, July 1, 1998; 12(10): 791 - 799. [Abstract] [Full Text]

				D. B. Zamble, T. Jacks, and S. J. Lippard p53-dependent and -independent responses to cisplatin in mouse testicular teratocarcinoma cells PNAS, May 26, 1998; 95(11): 6163 - 6168. [Abstract] [Full Text] [PDF]

				C. J. Barnes, A. F. Wahl, B. Shen, M. S. Park, and R. A. Bambara Mechanism of Tracking and Cleavage of Adduct-damaged DNA Substrates by the Mammalian 5'- to 3'-Exonuclease/Endonuclease RAD2 Homologue 1or Flap Endonuclease 1 J. Biol. Chem., November 22, 1996; 271(47): 29624 - 29631. [Abstract] [Full Text] [PDF]