Summary
The scope of the present study was to examine whether the cytokinetic phenomena occurring in human tumors under the influence of cisplatin correlate with the response of the tumors to therapy with the drug. Therefore, three strains of heterotransplanted human head and neck carcinomas showing different degrees of sensitivity to cisplatin were investigated by flow cytometry at various intervals after a single administration of cisplatin at four different dose levels (3, 6, 9 or 12 mg/kg). Three types of cell-cycle alterations were observed that depended on the dose of cisplatin and the degree of drug sensitivity shown by the tumors investigated. The obviously weakest kind of tumor reaction was a delay in the G2 cell phase. This phenomenon also occurred in the case of non-responsiveness to therapy, whereby the growth, histological structure and mitotic activity of the tumors remained nearly unaltered after cisplatin treatment. Wich increasing cytotoxicity, additional accumulations of cells in the S phase and, finally, long-lasting blocks at the G1/S boundary were found. The latter phenomenon, which manifested at high dose levels used in sensitive tumors, was obviously irreversible, as it did not completely disappear until the tumor cells had died and been removed by immigrating macrophages. It was always accompanied by severe histological destruction, tumor cell necrotization, and marked depression of the mitotic index. Thus, the hindrance of cell traversal through the S phase obviously represents the main and significant cytokinetic event, which indicates a potent antitumor effect for cisplatin that leads to pronounced tumor regression. This finding supports the hypothesis that inhibition of DNA synthesis is the mechanism underlying the cytotoxicity of cisplatin.
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References
Barlogie B, Drewinko B (1977) Cell cycle-related induction of cell progression delay. In: M. D. Anderson Hospital and Tumor Clinic (eds) Growth kinetics and biochemical regulation of normal and malignant cells. Williams and Wilkins, Baltimore, pp 315–327
Bergerat J-P, Barlogie B, Göhde W, Johnston DA, Drewinko B (1979) In vitro cytokinetic response of human colon cancer cells tocis-dichlorodiammineplatinum(II). Cancer Res 39: 4356–4363
Braakhuis BJM, Schoevers EJ, Heinermann G, Sneeuwloper G, Snow GB (1983) Chemotherapy of human head and neck cancer xenografts with three clinically active drugs: cis-platinum, bleomycin and methotrexate. Br J Cancer 48: 711–716
Eastman A, Schule N (1988) Enhanced DNA repair as a mechanism of resistance tocis-diamminedichloroplatinum(II). Biochemistry 27: 4730–4734
Göhde W, Schumann J, Büchner T, Barlogie B (1975) Influence of irradiation and cytostatic drugs on proliferation patterns of tumor cells. Pulse Cytophotometry 2: 138–152
Harder HC, Rosenberg B (1970) Inhibitory effects of antitumor platinum compounds on DNA, RNA and protein syntheses in mamalian cells in vitro. Int J Cancer 6: 207–216
Harder SC, Smith RG, Leroy RF (1976) Template primer inactivation bycis-andtrans-dichlorodiammineplatinum for human DNA polymerase α, β, and Rauscher murine leukemia virus reverse transciptase, as a mechanism of cytotoxicity. Cancer Res 36: 3821–3829
Hartog JHJ, Altona C, Boom JH van, Marcelis ATM, Marel GA van der, Rinkel LJ, Wille-Hazeleger G, Reedijk J (1983) Cis-platinum induced distortions in DNA. Eur J Biochem 134: 485–495
Heyden HW von, Schröder M, Achterrath W (1980) Chemotherapie von Tumoren im Kopf-Halsbereich mit Cisplatin. In: Seeber S, Schmidt CG, Nagel G, Achterrath W (eds) Cisplatin — derzeitiger Stand und neue Entwicklungen in der Chemotherapie maligner Neoplasien. Karger, Basel, pp 127–130
Heyden HW von, Schröder M, Lindermaier G, Beyer H-J, Klee M, Kehl A, Nagel GA (1980) Stand der zytostatischen Therapie der Plattenepithelkarzinome im Bereich des Kopfes und Halses. In: Seeber S, Schmidt CG, Nagel G, Achterrath W (eds) Cisplatin — derzeitiger Stand und neue Entwicklungen in der Chemotherapie maligner Neoplasien. Karger, Basel, pp 116–126
Howle JA, Gale GR (1970)cis-Dichlorodiammineplatinum(II): persistent and selective inhibition of deoxyribonucleic acid synthesis in vivo. Biochem Pharmacol 19: 2757–2762
Jacobs C, Bertino JR, Goffinet DR, Fee WE, Goode RI (1978) 24-hour infusion of cis-platinum in head and neck cancers. Cancer 42: 2135–2140
Kerrison JS, Sadler PJ (1977) Solvolysis ofcis-[Pt(NH3)2Cl2] in dimethyl sulphoxide and reactions of glycine with [PtCl3(Me2SO)] as probed by195Pt nuclear magnetic resonance shifts and195Pt−15N coupling constants. J Chem Soc [D]:861–863
Köpf-Maier P, Köpf H (1986) Cytostatische Platin-Komplexe: eine unerwartete Entdeckung mit weitreichenden Konsequenzen. Naturwissenchaften 73: 239–247
Köpf-Maier P, Wagner W, Liss E (1983) Induction of cell arrest at G1/S and in G2 after treatment of Ehrlich ascites tumor cells with metallocence dichlorides and cis-platinum in vitro. J Cancer Res Clin Oncol 106: 44–52
Loehrer PJ, Einhorn LH (1984) Cisplatin. Ann Intern Med 100: 704–713
Pascoe JP, Roberts JJ (1974) Interactions between mammalian cell DNA and inorganic platinum compounds: I. DNA interstrand crosslinking and cytotoxic properties of platinum(II) compounds. Biochem Pharmacol 23: 1345–1357
Pinto AL, Lippard SJ (1985) Binding of the antitumor drugcis-diamminedichloroplatinum(II) (cisplatin) to DNA. Biochim Biophys Acta 780: 167–180
Pinto AL, Lippard SJ (1985) Sequence-dependent termination of in vitro DNA synthesis bycis- andtrans-diamminedichloroplatinum(II). Proc Natl Acad Sci USA 82: 4616–4619
Randolph VL, Vallejo A, Spiro RH, Shah J, Strong EW, Huvos AG, Wittes RE (1978) Combination therapy of advanced head and neck cancer. Cancer 41: 460–467
Rao PN (1980) The molecular basis of drug-induced G2 arrest in mammalian cells. Mol Cell Biochem 29: 47–57
Reedijk J, Lohmann PHM (1985) Cisplatin: synthesis, antitumor activity and mechanism of action. Pharm Weekbl [Sci] 7: 173–180
Rosenberg B, Van Camp L, Krigas T (1965) Inhibition of cell division inEscherichia coli by electrolysis products from a platinum electrode. Nature 205: 698–699
Sorenson CM, Eastman A (1988) Influence ofcis-diamminedichloroplatinum(II) on DNA synthesis and cell cycle progression in excision repair proficient and deficient Chinese hamster ovary cells. Cancer Res 48: 6703–6707
Sorenson CM, Eastman A (1988) Mechanism ofcis-diamminedichloroplatinum(II)-induced cytotoxicity; role of G2 arrest and DNA double-strand breaks. Cancer Res 48: 4484–4488
Taylor SG (1979) Head and neck cancer. In: Pinedo HM (ed) Cancer chemotherapy. Excerpta Medica, Amsterdam, pp 237–256
Warenius HM (1980) Identification and separation of mouse and human components of heterotransplanted human tumors. In: Sparrow A (ed) Immunodeficient animals for cancer research. MacMillan, London, pp 207–220
Wennerberg J, Alm P, Biörklund A, Killander D, Langström E, Tropè C (1984) Cell cycle perturbations in heterotransplanted squamous-cell carcinoma of the head and neck after mitomycin C and cisplatin treatment. Int J Cancer 33: 213–222
Zwelling LA, Kohn KW (1979) Mechanism of action ofcis-dichlorodiammineplatinum(II). Cancer Treat Rep 63: 1439–1444
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Jäckel, M., Köpf-Maier, P. Influence of cisplatin on cell-cycle progression in xenografted human head and neck carcinomas. Cancer Chemother. Pharmacol. 27, 464–471 (1991). https://doi.org/10.1007/BF00685161
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DOI: https://doi.org/10.1007/BF00685161