Table 3

Milestone Publications Relating to DISC and MTT Cell Death (Apoptotic) Assays

1936: Methods description of dye exclusion assay to measure cell death in normal and tumor cells (Schrek,R. Am J Cancer 28:389-92,'36)

1954: Methods description of tetrazolium reduction to measure cell death in human tumors, with first clinical correlations between assay results and treatment outcome (Black, M.M. and Speer,F.D. J Natl Cancer Inst 14:1147-58,'54)

1962: Correlation between clinical outcome and radiation-induced apoptosis in CLL (Schrek,R. et al. Blood 20:432-42,'62)

1979: Correlation between dye exclusion (apoptotic) endpoint and clinical outcome in leukemia/lymphoma (Durkin,W.J. et al. Cancer Res 39:402-7,'79)

1983: Methods description of DISC assay and clinical correlations in hematologic and solid tumors (Weisenthal,L.M. et al. Cancer Res 43:749-57,'83)

1984,86: Laboratory detection of acquired drug resistance in hematologic neoplasms with DISC assay (Weisenthal,L.M. et al Recent Results Cancer Res 94:161-73,'84; Weisenthal,L.M. et al Cancer Treat Rep 70:1283-95,'86)

1985,1991: Critical analysis of hypothesis that clonogenic assays provide the only valid method for determining in vitro drug effects (Weisenthal,L.M. and Lippman,M.E. Cancer Treat Rep 69:615-32,85; Weisenthal, L.M. Developments in Oncology. Kluwer Academic Publishers,Dordrecht. 64:103-50,91).

1987 - 94: Demonstration of equivalency between DISC, tetrazolium (MTT), ATP, and FDA endpoints in cultures containing a high percentage of tumor cells (See Table 1)

1989 - 99: Demonstration of correlations between assay results and patient survival with DISC and MTT assays (refs. 4 - 14,21,22)

1983 - 1999: Many publications showing strong and consistent correlations between assay results and clinical outcomes (Table 2, Figs. 2,3,5, and 6)

1997: Demonstration that MTT assay results provide the single most powerful predictor of therapeutic outcome in childhood leukemia (Kaspers,G.J. et al. Blood 90:2723-9,'97)

1999: Demonstration that CLL patients with fludarabine resistance die much more quickly when treated with fludarabine than when treated with drugs other than fludarabine (Bosanquet,A. Br J Haematol 106:71-7,'99)

1999: Clinical correlation analysis indicating cost-effectiveness of DISC-assay directed chemotherapy (Mason,J.M., et al. Int J Technol Assess Health Care 15:173-84,'99)

1999: Demonstration that MTT assay-directed treatment of gastric and colon cancer results in superior survival compared to empiric therapy (Hoffman,R. et al. Submitted for publication)