Application of a human tumor colony-forming assay to new drug screening.

The applicability of a human tumor colony-forming assay to drug screening was investigated in terms of feasibility, validity, and potential for discovering new antitumor drugs. Feasibility was addressed in a pilot study during which basic methods, appropriate assay quality controls, and a standardized protocol for screening were developed. Considerable variability was noted in the availability and colony growth of different tumor types. The majority of the evaluable experiments utilized breast, colorectal, kidney, lung, melanoma, or ovarian tumors. For many tumor types, little evidence of growth was observed, or only rare specimens formed colonies. Colony-forming efficiencies ranged from 0.05 to 0.11% for the six most useful tumors listed above. A set of quality control measures was developed to address technical problems inherent in the assay. Testing of standard agents in the pilot study established that most of these agents could be detected as active. However, it also identified three assay limitations: compounds requiring systemic metabolic activation are inactive; medium constituents may block the activity of certain antimetabolites; and compounds without therapeutic efficacy may be positive in the assay. The assay categorized nontoxic clinically ineffective agents as true negatives with 97% accuracy. Of 79 compounds which were negative in the current National Cancer Institute prescreen (leukemia P388), 14 were active in the assay. Several demonstrated outstanding in vitro activity and are structurally unrelated to compounds already in development or in clinical trials. A subset of these active compounds were found to lack activity in a P388 in vitro colony-forming assay. This indication of differential cytotoxicity to human tumor cells makes this subset of compounds particularly interesting as antitumor drug leads. The demonstrated sensitivity to most standard agents, discrimination of nontoxic compounds, reproducibility of survival values within assays and between laboratories, and evidence of ability to identify active compounds which were negative in the in vivo prescreen suggest that the human tumor colony-forming assay may be a valuable tool for antitumor drug screening. However, because of technical limitations inherent in the current assay methodology, this must be confined to selected tumor types and limited to screening on a moderate scale.

[1]  L. Muhlbaier,et al.  In vitro versus in vivo correlations of chemosensitivity of human medulloblastoma. , 1984, Cancer research.

[2]  R. Shoemaker,et al.  Potentials and drawbacks of the human tumor stem cell assay. , 1984, Behring Institute Mitteilungen.

[3]  V. Sondak,et al.  Chemosensitivity testing of human solid tumors. A review of 1582 assays with 258 clinical correlations , 1984, Cancer.

[4]  W. T. Beck Vinca alkaloid-resistant phenotype in cultured human leukemic lymphoblasts. , 1983, Cancer treatment reports.

[5]  Curt Ga,et al.  Evidence for multidrug-resistant cells in human tumor cell populations. , 1983 .

[6]  J. Riordan,et al.  Multidrug-resistance phenotype in Chinese hamster ovary cells. , 1983, Cancer treatment reports.

[7]  Biedler Jl,et al.  Drug resistance in Chinese hamster lung and mouse tumor cells. , 1983 .

[8]  Venditti Jm The National Cancer Institute antitumor drug discovery program, current and future perspectives: a commentary. , 1983 .

[9]  D. V. Von Hoff,et al.  Prospective clinical trial of a human tumor cloning system. , 1983, Cancer research.

[10]  I. Tannock,et al.  A critical appraisal of the "human tumor stem-cell assay". , 1983, The New England journal of medicine.

[11]  A. Cochran,et al.  Cloning of human solid tumors in soft agar , 1982, International journal of cancer.

[12]  S. Salmon,et al.  In vitro chemosensitivities of human tumor stem cells to the Phase II drug 4'-(9-acridinylamino)methanesulfon-m-anisidide and prospective in vivo correlations. , 1982, Cancer research.

[13]  R. Makuch INTERPRETING CLONOGENIC ASSAY RESULTS , 1982, The Lancet.

[14]  E. Frei The National Cancer Chemotherapy Program. , 1982, Science.

[15]  Lieber Mm,et al.  Soft agar colony formation assay for chemotherapy sensitivity testing of human solid tumors. , 1982 .

[16]  K. Tveit,et al.  Colony growth and chemosensitivity in vitro of human melanoma biopsies. relationship to clinical parameters , 1982, International journal of cancer.

[17]  J. Venditti Preclinical drug development: rationale and methods. , 1981, Seminars in oncology.

[18]  R. Makuch,et al.  Association between human tumor colony-forming assay results and response of an individual patient's tumor to chemotherapy. , 1981, The American journal of medicine.

[19]  C. Coltman,et al.  Activity of mitoxantrone in a human tumor cloning system. , 1981, Cancer research.

[20]  J. Willson,et al.  Inhibition of human ovarian cancer colony formation by adriamycin and its major metabolites. , 1980, Cancer research.

[21]  Y. Rustum,et al.  Colony growth in soft agar of human melanoma, sarcoma, and lung carcinoma cells disaggregated by mechanical and enzymatic methods. , 1980, Cancer research.

[22]  V. Courtenay,et al.  Growth of human tumour cell colonies from biopsies using two soft-agar techniques. , 1978, British Journal of Cancer.

[23]  D. Alberts,et al.  Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. , 1978, The New England journal of medicine.

[24]  A. Rossier Letter to the Editor , 1986, Paraplegia.

[25]  R. Shoemaker,et al.  In vitro chemosensitivity assay based on the concept of total tumor cell kill. , 1984, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[26]  B. Spengler,et al.  Drug resistance in Chinese hamster lung and mouse tumor cells. , 1983, Cancer treatment reports.

[27]  R. Shoemaker,et al.  Evidence for multidrug-resistant cells in human tumor cell populations. , 1983, Cancer treatment reports.

[28]  D. Alberts,et al.  New drugs in ovarian cancer and malignant melanoma: in vitro phase II screening with the human tumor stem cell assay. , 1981, Cancer treatment reports.

[29]  D. V. Von Hoff,et al.  Use of an image analysis system to count colonies in stem cell assays of human tumors. , 1980, Progress in clinical and biological research.

[30]  A. Hamburger,et al.  Primary bioassay of human tumor stem cells. , 1977, Science.