Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1986 Oct;54(4):607–613. doi: 10.1038/bjc.1986.216

In vitro cytotoxicity patterns of standard and investigational agents on human bone marrow granulocyte-macrophage progenitor cells.

J A Ajani, G Spitzer, B Tomasovic, B Drewinko, V M Hug, K Dicke
PMCID: PMC2001502  PMID: 3778805

Abstract

Inhibitory concentrations (ICs) against human bone marrow granulocyte-macrophage colony forming cells (GM-CFC) were established for 26 cancer chemotherapy agents, including seven investigational agents by ten day exposure. Each drug was tested at four or more concentrations to generate reliable survival curves. The analysis of the survival curves produced three patterns according to which drugs were classified: class A drugs had a shouldered curve with terminal exponential kill of GM-CFC, class B drugs produced initial exponential component followed by a plateau, and class C drugs produced linear curves. These categories provide the relationship between drug concentration and cytotoxicity, e.g., the cytotoxicity of class B drugs, after initial kill, did not increase in spite of serial doubling of concentrations whereas the class C drugs had proportional killing with two-fold concentration increment. A number of drugs were active at in vitro concentrations of less than or equal to 0.01 microgram ml-1 and caused log reduction of GM-CFC with an approximate concentration of 0.0001 microgram ml-1. Drugs known to require in vivo bioactivation, namely dacarbazine, procarbazine, and ifosfamide were active at high concentrations (greater than 10.0 micrograms ml-1). We propose that for myelosuppressive agents the GM-CFC provides a useful biologic reference to determine in vitro cut off concentrations to be utilized for drug screening. For nonmyelosuppressive agents, however, it may be suboptimal.

Full text

PDF
607

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ajani J. A., Blaauw A. A., Spitzer G., Baker F. L., Tomasovic B., Umbach G., Thielvoldt D., Zander A. R., Dicke K. A. Differential cytotoxic activity of chemotherapy agents on colony-forming cells from human tumors and normal bone marrow in vitro. Exp Hematol. 1985;13 (Suppl 16):95–100. [PubMed] [Google Scholar]
  2. Alberts D. S., Salmon S. E., Chen H. S., Moon T. E., Young L., Surwit E. A. Pharmacologic studies of anticancer drugs with the human tumor stem cell assay. Cancer Chemother Pharmacol. 1981;6(3):253–264. doi: 10.1007/BF00256978. [DOI] [PubMed] [Google Scholar]
  3. Baker F. L., Spitzer G., Ajani J. A., Brock W. A., Lukeman J., Pathak S., Tomasovic B., Thielvoldt D., Williams M., Vines C. Drug and radiation sensitivity measurements of successful primary monolayer culturing of human tumor cells using cell-adhesive matrix and supplemented medium. Cancer Res. 1986 Mar;46(3):1263–1274. [PubMed] [Google Scholar]
  4. Findley H. W., Jr, Steuber C. P., Ruymann F. B., Culbert S., Ragab A. H. Effect of retinoic acid on the clonal growth of childhood myeloid and lymphoid leukemias: a pediatric oncology group study. Exp Hematol. 1984 Nov;12(10):768–773. [PubMed] [Google Scholar]
  5. Hug V., Thames H., Blumenschein G. R., Spitzer G., Drewinko B. Normalization of in vitro sensitivity testing of human tumor clonogenic cells. Cancer Res. 1984 Mar;44(3):923–928. [PubMed] [Google Scholar]
  6. Jiang T. L., Liu R. H., Salmon S. E. Antitumor activity of didemnin B in the human tumor stem cell assay. Cancer Chemother Pharmacol. 1983;11(1):1–4. doi: 10.1007/BF00257406. [DOI] [PubMed] [Google Scholar]
  7. Jiang T. L., Salmon S. E., Liu R. M. Activity of camptothecin, harringtonin, cantharidin and curcumae in the human tumor stem cell assay. Eur J Cancer Clin Oncol. 1983 Feb;19(2):263–270. doi: 10.1016/0277-5379(83)90425-x. [DOI] [PubMed] [Google Scholar]
  8. Ludwig R., Alberts D. S., Miller T. P., Salmon S. E. Evaluation of anticancer drug schedule dependency using an in vitro human tumor clonogenic assay. Cancer Chemother Pharmacol. 1984;12(3):135–141. doi: 10.1007/BF00256533. [DOI] [PubMed] [Google Scholar]
  9. Rozencweig M., Sanders C., Rombaut W., Crespeigne N., Decoster G., Kenis Y., Klastersky J. Phase II study of carminomycin in a human tumor cloning assay. Invest New Drugs. 1984;2(3):267–270. doi: 10.1007/BF00175375. [DOI] [PubMed] [Google Scholar]
  10. Rozencweig M., Sanders C., Rombaut W., Crespeigne N., Kenis Y., Klastersky J. Phase II study of ametantrone in a human tumor cloning assay. Eur J Cancer Clin Oncol. 1985 Feb;21(2):195–198. doi: 10.1016/0277-5379(85)90173-7. [DOI] [PubMed] [Google Scholar]
  11. Salmon S. E., Liu R. M., Casazza A. M. Evaluation of new anthracycline analogs with the human tumor stem cell assay. Cancer Chemother Pharmacol. 1981;6(2):103–109. doi: 10.1007/BF00262325. [DOI] [PubMed] [Google Scholar]
  12. Salmon S. E., Meyskens F. L., Jr, Alberts D. S., Soehnlen B., Young L. New drugs in ovarian cancer and malignant melanoma: in vitro phase II screening with the human tumor stem cell assay. Cancer Treat Rep. 1981 Jan-Feb;65(1-2):1–12. [PubMed] [Google Scholar]
  13. Salmon S. E., Young L., Soehnlen B., Liu R. Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin. J Clin Oncol. 1984 Apr;2(4):282–286. doi: 10.1200/JCO.1984.2.4.282. [DOI] [PubMed] [Google Scholar]
  14. Shoemaker R. H., Wolpert-DeFilippes M. K., Kern D. H., Lieber M. M., Makuch R. W., Melnick N. R., Miller W. T., Salmon S. E., Simon R. M., Venditti J. M. Application of a human tumor colony-forming assay to new drug screening. Cancer Res. 1985 May;45(5):2145–2153. [PubMed] [Google Scholar]
  15. Shoemaker R. H., Wolpert-DeFilippes M. K., Venditti J. M. Potentials and drawbacks of the human tumor stem cell assay. Behring Inst Mitt. 1984 May;(74):262–272. [PubMed] [Google Scholar]
  16. Umbach G. E., Hug V., Spitzer G., Thames H., Drewinko B. Responses of human bone marrow progenitor cells to fluoro-ara-AMP, homoharringtonine, and elliptinium. Invest New Drugs. 1984;2(3):263–265. doi: 10.1007/BF00175374. [DOI] [PubMed] [Google Scholar]
  17. Umbach G. E., Hug V., Spitzer G., Tomasovic B., Thames H., Ajani J. A., Drewinko B. Survival of human bone marrow cells after in vitro treatment with 12 anticancer drugs and implications for tumor drug sensitivity assays. J Cancer Res Clin Oncol. 1985;109(2):130–134. doi: 10.1007/BF00391887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Umbach G. E., Singletary S. E., Tomasovic B., Spitzer G., Hug V., Drewinko B. Dose-survival curves of cis-platinum, melphalan, and velban in human granulocyte/macrophage progenitor cells. Int J Cell Cloning. 1984 Nov;2(6):335–340. doi: 10.1002/stem.5530020601. [DOI] [PubMed] [Google Scholar]
  19. Verma D. S., Spitzer G., Beran M., Zander A. R., McCredie K. B., Dicke K. A. Colony stimulating factor augmentation in human placental conditioned medium. Exp Hematol. 1980 Aug;8(7):917–923. [PubMed] [Google Scholar]
  20. Von Hoff D. D., Casper J., Bradley E., Sandbach J., Jones D., Makuch R. Association between human tumor colony-forming assay results and response of an individual patient's tumor to chemotherapy. Am J Med. 1981 May;70(5):1027–1041. doi: 10.1016/0002-9343(81)90859-7. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES