Summary
The biological behavior of HeLa cells exposed to 1-methyl-1-nitrosourea was examined by determining the survival fraction in asynchronous and synchronous cultures. Asynchronous cell population exposed to 1-methyl-1-nitrosourea for 1 h exhibited a shoulder type survival curve, indicating that damage must be accumulated before the lethal effect occurs. A fraction of 25% of cells survives the concentration of 100 μg/ml. The duration of treatment with the drug did not have a significant effect on the cell survival. The experiments with synchronized cells showed that MNU exhibits the killing in all phases of the cell age, but the most sensitive are these in S phase. However, they are still six times more resistant at the same concentration than the culture in plateau phase. At the concentration of 100 μg/ml nondividing plateau cells are about 35 times more sensitive than exponentially growing cells. We can conclude that MNU acts as the most active killing agents on the cells which are in nondividing plateau phase.
Similar content being viewed by others
References
Ban, J., Han, A., Korbelik, M.: An improves method for cell cycle analysis of synchronized mammalian cells (HeLa-FA 3). Iug. Phys. Pharm. Acta 10, 173–181 (1974)
Ban, J., Brdar, B.: 1-Methyl-1-nitrosourea: I. Effects on the synthesis of nucleic acids and protein in cultured cells and some RNA-viruses. Period. Biol. 80, 41–47 (1978)
Barranco, S.C., Humphrey, R.M.: The effects of 1,3-Bis(2-chloroethyl)-1-nitrosourea on survival and cell progression in Chinese hamster cells. Cancer Res. 31, 191–195 (1971a)
Barranco, S.C., Humphrey, R.M.: The effect of Bleomycin on survival and cell progression in Chinese hamster cells in vitro. Cancer Res. 31, 1218–1223 (1971b)
Barranco, S.C., Novak, J.K., Humphrey, R.M.: Response of mammalian cells following treatment with bleomycin and 1,3-Bis(2-chloroethyl)-1-nitrosourea during plateau phase. Cancer Res. 33, 691–694 (1973)
Barranco, S.C., Novak, J.K., Humphrey, R.M.: Studies on recovery from chemically induced damage in mammalian cells. Cancer Res. 35, 1194–1204 (1975)
Barranco, S.C., Haenelt, B.R., Bolton, W.E.: Cell cycle time determinations based on liquid scintillation counting of 3H-TdR labeled mitotic cells. Cell Tissue Kinet. 10, 335–340 (1977)
Bhuyan, B.K., Scheidt, L.G., Fraser, T.J.: Cell cycle phase specificity of antitumor agents. Cancer Res. 32, 398–407 (1972)
Bhuyan, B.K., Fraser, T.J., Day, K.J.: Cell proliferation kinetics and drug sensitivity of exponential and stationary populations of cultured L 1210 cells. Cancer Res. 37, 1057–1063 (1977)
Brdar, B., Ban, J.: Inhibition of viral RNA synthesis by 1-methyl-1-nitrosourea. Eur. J. Canc. (sub. for publ.)
Carter, S.K., Schabel, F.M., Broder, L.E., Johnston, T.P.: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) and other nitrosoureas in cancer treatment: A review. In: G. Klein and S. Weinhouse (eds.), Advances in cancer research, Vol. 16, pp. 273–332. New York: Academic Press 1972)
Cox, R., Irving, C.C.: Effect of N-methyl-N-nitrosourea on the DNA of rat bladder epithelium. Cancer Res. 36, 4114–4118 (1976)
Drewinko, B., Loo, T.L., Gottlieb, J.A.: A comparison of the lethal effects of three nitrosourea derivatives on cultured human lymphoma cells. Cancer Res. 36, 511–515 (1976)
Elkind, M.M., Whitemore, G.F.: The radiobiology of cultured mammalian cells. New York: Gordon and Beach 1967
Emanuel, N.M., Vermel, E.M., Ostrovskaya, L.A., Korman, N.P.: Experimental and clinical studies of the antitumor activity of 1-methyl-1-nitrosourea (NSC-23909). Cancer Chem. Rep. 58, 135–148 (1974)
Frei, J.V.: Toxicity tissue changes, and tumor induction in inbred Swiss mice by methylnitrosoamine and-anide compounds. Cancer Res. 30, 11–17 (1970)
Hahn, G.M., Gordon, L.F., Kurkjian, S.D.: Response of cycling and noncycling cells to 1,3-Bis(2-chloroethyl)-1-nitrosourea and to bleomycin. Cancer Res. 34, 2373–2377 (1974)
Han, A., Korbelik, M., Ban, J.: DNA-to-protein cross-linking in synchronized HeLa cells exposed to ultra-violet light. Int. J. Radiat. Biol. 27, 63–74 (1975)
Han, A., Sinclair, W.K., Kimler, B.F.: The effect of N-ethylmaleimide on the response to X-rays of synchronized HeLa cells. Radiat. Res. 65, 337–350 (1976)
Howard, A., Pelc, S.R.: Synthesis of DNA in normal and irradiated cells and its relation to chromosome breakage. Heredity 6, 261–265 (1953)
Kann, H.E., Kohn, K.W., Lyles, J.M.: Inhibition of DNA repair by the 1,3-bis(2-chloroethyl)-1-nitrosourea breakdown product, 2-chloroethyl isocyanate. Cancer Res. 34, 398–402 (1974)
Kirtikar, D.M., Goldthwait, D.A.: The enzymatic release of 6D-methylguanine and 3-methyladenine from DNA reacted with the carcinogen N-methyl-N-nitrosourea. Proc. Natl. Acad. Sci. U.S. 71, 2022–2026 (1974)
Kleihues, P.: Blockierung der DNS-Synthese durch N-methyl-N-nitroso-Harnstoff in vivo. Arzneim. Forsch. 19, 1041–1043 (1969)
Kleilhues, P., Margison, G.P.: Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA. Nature 259, 153–155 (1976)
Kolarić, K.: Combination chemotherapy with 1-methyl-1-nitrosourea (MNU) and cyclophosphamide in solid tumors. Z. Krebsforsch. 89, 311–319 (1977)
Lawley, P.D., Shah, S.A.: Methylation of DNA by 3H-14C-methyl-labelled N-methyl-N-nitrosourea. Evidence for transfer of the intact methyl group. Chem. Biol. Interactions 7, 115–120 (1973)
Plant, J.E., Roberts, J.J.: Novel mechanism for the inhibition of DNA synthesis following methylation. Effect of N-methyl-N-nitrosourea on HeLa cells. Chem. Biol. Interactions 3, 337–324 (1971)
Plant, J.E., Roberts, J.J.: Extension of the pre-DNA synthetic phase of the cell cycle as a consequence of DNA alkylation in Chinese hamster cells. Possible mechanism of DNA repair. Chem. Biol. Interactions 3, 343–351 (1971)
Roberts, J.J., Pascoe, J.M., Plant, J.E., Sturrock, J.E., Crathorn, A.R.: Quantitative aspects of the repair of alkylated DNA in cultured mammaian cells, I. Effect on HeLa and Chinese hamster cell survival of alkylation of cellular macromolecules. Chem. Biol. Interactions 3, 29–47 (1971)
Schabel, F.M. Jr., Johnston, T.P., McCabel, G.S.: Experimental evaluation of potential anticancer agents. VIII. Effects of certain nitrosoureas on intracerebral L 1210 leukemia. Cancer Res. 23, 725–733 (1963)
Serebryanyi, A.M., Smotraeva, M.A., Kruglyakova, K.A., Kostyanovskii, R.G.: Carbamoylation of DNA in N-nitroso-N-methylurea. Dokl. Akad. Nauk SSSR 185, 817–819 (1969)
Skinner, W.A., Gram, H.F., Green, M.O.: Potential anticancer agents. XXXI. The relationship of chemical structure to antileukemic activity with analogs of 1-methyl-3-nitro-1-nitrosoguanidine (NCS-9369). J. Med. Chem. 2, 299–333 (1960)
Terasima, T., Tolmach, L.: Growth and nucleic acids synthesis in synchronously dividing populations of HeLa cells. Exp. Cell Res. 30, 344–362 (1963)
Tobey, R.A., Crissman, H.A.: Comparative effects of three nitrosourea derivatives on mammalian cell cycle progression. Cancer Res. 35, 460–470 (1975)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ban, J., Brdar, B. & Sorić, J. The effects of 1-methyl-1-nitrosourea on the survival pattern of cycling and noncycling HeLa cells. J Cancer Res Clin Oncol 94, 265–275 (1979). https://doi.org/10.1007/BF00419286
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00419286