Skip to main content
SpringerLink
Log in

In vitro cellular characteristics and survival responses of human astrocytoma clones to chloroethyl-nitrosoureas and dianhydrogalactitol

  • Preclinical
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Three permanent clones were derived from a single astrocytoma cell line and were characterized for in vitro cell kinetics, chromosomal properties and for their responses to the anticancer drugs: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU); 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU); 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea) (PCNU); and 1,2:5,6-dianhydrogalactitol (GAL); all of which have been shown to cross the blood brain barrier. The clones showed different population doubling times, saturation densities, plating efficiencies, chromosome counts, ploidy, cell cycle phase distributions and DNA indices. The only positive correlation among these parameters was between the population doubling times and the modal chromosome numbers; the lower the chromosome number, the shorter the doubling time. No correlation was observable between any of the cellular properties and responses to the four drugs. The clones showed a differential sensitivity to the nitrosoureas, seen maximally as a 600-fold difference in survival between two of the clones treated with the same dose of BCNU. In contrast, the clones exhibited almost identical and uniform sensitivities to galactitol, suggesting that this agent exerted its cytotoxic effects by similar mechanisms in each of the clones. By comparison BCNU (at the tested doses and duration of drug exposure used in this study) was found to be the most effective of the agents tested.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Edwards MS, Levin VA, Wilson CB: Brain tumor chemotherapy: an evaluation of agents in current use for Phase I and II trials. Cancer Treat Rep 64:1179–1205, 1980

    Google Scholar 

  2. Tsuruo T, Fidler IJ: Differences in drug sensitivity among tumor cells from parent tumors, selected variants, and spontaneous metastases. Cancer Res 41:3058–3064, 1981

    Google Scholar 

  3. Barranco SC, Haenelt BR, Gee EL: Differential sensitivities of five rat hepatoma cell lines to anticancer drugs. Cancer Res 38:656–660, 1978

    Google Scholar 

  4. Romsdahl MM, Hsu TC: Establishment and biologic properties of human malignant melanoma cell lines grown in vitro. Surg Forum 18:78–79, 1967

    Google Scholar 

  5. Zante J, Schumann J, Barlogie B, Göhde W, Büchner T: New preparation and staining procedures for specific and rapid analysis of DNA distribution. In: Göhde W, Schumann J, Büchner T (eds): Pulse-Cytophotometry. European Press, Ghent, Belgium, 1976, pp. 97–106

    Google Scholar 

  6. Guseman LF, Bryant J: Mathematic modeling and analysis of flow microfluorometry DNA distributions. In: Lutz D (ed): Pulse Cytophotometry. European Press, Ghent, Belgium, 1978, pp. 79–92

    Google Scholar 

  7. Barlogie B, Göhde W, Johnston DA, Smallwood L, Schumann J, Drewinko B, Freireich EJ: Determination of ploidy and proliferative characteristics of human solid tumors by pulse cytophotometry. Cancer Res 38:3333–3339, 1978

    Google Scholar 

  8. Levin VA, Wilson CB: Chemotherapy: the agents in current use. Seminars in Oncology 2:63–72, 1975

    Google Scholar 

  9. Walker MD: Chemotherapy adjuvant to surgery and radiation therapy. Semin Oncol 2:69–72, 1975

    Google Scholar 

  10. Hoshino T, Nomura K, Wilson CB, Knebel KD, Gray JW: The distribution of nuclear DNA from human brain-tumor cells. J Neurosurg 49:13–21, 1978

    Google Scholar 

  11. Lehmann J, Krug H: Flow-through fluorocytophotometry of different brain tumors. Acta Neuropathol (Berl) 49:123–132, 1980

    Google Scholar 

  12. Borchers H, Beck H-P: Flow cytometric malignancy grading of brain tumors. Basic Appl Histochem 24:364, 1980

    Google Scholar 

  13. Mørk SJ, Laerum OD: Modal DNA content of human intracranial neoplasms studied by flow cytometry. J Neurosurg 53:198–204, 1980

    Google Scholar 

  14. Mark J: Chromosome patterns in benign and malignant tumors in the human nervous system. In German J (ed) Chromosomes and Cancer, Wiley, New York, 1974, pp. 481–495

    Google Scholar 

  15. Mark J, Westermark B, Ponten J, Hugosson R: Banding patterns in human glioma cell lines. Hereditas 87:243–260, 1977

    Google Scholar 

  16. Barranco SC, Novak JK, Humphrey RM: Studies on recovery from chemically induced damage in mammalian cells. Cancer Res 35:1194–1204, 1975

    Google Scholar 

  17. Bertrant M, Deen DF, Hoshino T, Knebel K: Recovery from potentially lethal damage induced by spirohydantoin mustard on 9L cells in vitro. Cancer Treat Rep 64:889–895, 1980

    Google Scholar 

  18. Hahn GM, Ray GR, Gordon LF, Kallman RF: Response of solid tumor cells exposed to chemotherapeutic agents in vivo: cell survival after 2 and 24 hour exposure. J Natl Cancer Inst 50:529–533, 1973

    Google Scholar 

  19. Barranco SC, Drewinko B, Humphrey RM: Differential response by human melanoma cells to 1,3-Bis(2-chloroethyl)-1-nitrosourea and bleomycin. Mutat Res 19:277–280, 1973

    Google Scholar 

  20. Barranco SC, Humphrey RM: The effects of β-2′ Deoxythioguanosine on survival and progression in mammalian cells. Cancer Res 31:583–586, 1971

    Google Scholar 

  21. Biedler JL, Riehm H, Peterson RHF, Spengler BA: Membrane-mediated drug resistance and phenotypic reversion to normal growth behavior of Chinese hamster cells. J Natl Cancer Inst 55:671–680, 1975

    Google Scholar 

  22. Danø K: Development of resistance to daunomycin in Ehrlich ascites tumor. Cancer Chemother Rep 55:133–141, 1971

    Google Scholar 

  23. Harris M: Phenotypic expression of drug resistance in hybrid cells. J Natl Cancer Inst 50:423–429, 1973

    Google Scholar 

  24. Barranco SC, Ho DHW, Drewinko B, Romsdahl MM, Humphrey RM: Differential sensitivities of human melanoma cells grown in vitro to arabinosylcytosine. Cancer Res 32:2733–2736, 1972

    Google Scholar 

  25. Schimke RT, Alt FW, Kellems RE, Kaufman RJ, Bertino JR: Amplification of dihydrofolate reductase genes in methotrexate-resistant cultured mouse cells. Cold Spring Harbor Symposium Quant Biol 42:649–657, 1978

    Google Scholar 

  26. LePage GA, Junga IG, Bowman B: Biochemical and carcinostatic effects of 2′-deoxythioguanosine. Cancer Res 24:835–840, 1964

    Google Scholar 

  27. Yung W-KA, Shapiro JR, Shapiro WR: Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res 42:992–998, 1982

    Google Scholar 

  28. Drewinko B, Loo TL, Gottlieb JA: A comparison of the lethal effects of three nitrosourea derivatives on cultured human lymphoma cells. Cancer Res 36:511–515, 1976

    Google Scholar 

  29. Barranco SC, Townsend, Jr CM, Quraishi MA, Burger NL, Nevill HC, Howell KH, Boerwinkle WR: Heterogeneous responses of an in vitro model of human stomach cancer to anticancer drugs. Invest N Drugs, 1:103–113, 1983

    Google Scholar 

  30. Tropé C, Aspergren K, Kullander S, Astedt B: Heterogeneous response of disseminated human ovarian cancers to cytostatistics in vitro. Acta Obstet Gynecol Scnad 58:543–546, 1979

    Google Scholar 

  31. Tropé C, Hakansson L, Dencker H: Heterogeneity of human adenocarcinomas of the colon and the stomach as regards sensitivity to cytostatic drugs. Neoplasma 22:423–430, 1975

    Google Scholar 

  32. Hakansson L, Tropé C: On the presence within tumours of clones that differ in sensitivity to cytostatic drugs. Acta Path Microbiol Scand Sec A 82:35–40, 1974

    Google Scholar 

  33. Heppner GH, Dexter DL, DeNucci T, Miller FR, Calabresi P: Heterogeneity in drug sensitivity among tumor cell sub-populations of a single mammary tumor. Cancer Res 38:3758–3763, 1978

    Google Scholar 

  34. Levin VA, Edwards MS: Chemotherapy of primary malignant gliomas. In Thomas DGT, Graham DI (eds): Brain Tumours. Butterworths, London, 1980, pp. 344–358

    Google Scholar 

  35. Geran RI, Congleton GF, Dudeck LE, Abbott BJ, Gargus JL: A mouse ependymoblastoma as an experimental model for screening potential antineoplastic drugs. Cancer Chemother Rep 4:53–87, 1974

    Google Scholar 

  36. Levin VA, Freeman-Dove MA, Maroten CE: Dianhydrogalactitol (NSC-132313) pharmaco-kinetics in normal and tumor bearing rat brain and antitumor activity against three intracerebral rodent tumors. J Natl Cancer Inst 56:535–539, 1976

    Google Scholar 

  37. Espana P, Wiernik PH, Walker MD: Phase II study of dianhydrogalactitol in malignant glioma. Cancer Chemother Rep 62:1199–1200, 1978

    Google Scholar 

  38. Egan RT, Childs DS, Layton DD, Laws, Jr ER, Bisel HF, Holbrook MA, Fleming TR: Dianhydrogalactitol and Radiation Therapy. JAMA 241:2046–2050, 1979

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Therapy, University of Texas Medical Branch, Rm. 551 Basic Science Bldg, 77550, Galveston, TX, U.S.A.

    Norma H. Rubin

  2. Department of Medicine, University of Texas Medical Branch, 77550, Galveston, TX, U.S.A.

    B. Gail Macik, W. R. Boerwinkle &  S. C. Barranco

  3. Department of Genetics, School of Medicine, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    Cacilda Casartelli

Authors
  1. Norma H. Rubin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cacilda Casartelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Gail Macik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. R. Boerwinkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. C. Barranco
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rubin, N.H., Casartelli, C., Macik, B.G. et al. In vitro cellular characteristics and survival responses of human astrocytoma clones to chloroethyl-nitrosoureas and dianhydrogalactitol. Invest New Drugs 1, 129–137 (1983). https://doi.org/10.1007/BF00172071

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00172071

Key words

Search

Navigation