APPLICATION OF A HUMAN-TUMOR COLONY-FORMING ASSAY TO NEW DRUG SCREENING

Authors:
  • RSRH SHOEMAKER
    RH SHOEMAKER
  • MWMK WOLPERTDEFILIPPES
    MK WOLPERTDEFILIPPES
  • DKDH KERN
    DH KERN
  • MLMM LIEBER
    MM LIEBER
  • RMRW MAKUCH
    RW MAKUCH
  • NMNR MELNICK
    NR MELNICK
  • WMWT MILLER
    WT MILLER
  • SSSE SALMON
    SE SALMON
  • RSRM SIMON
    RM SIMON
  • JVJM VENDITTI
    JM VENDITTI
  • DVDD VONHOFF
    DD VONHOFF
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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (5) , 2145-2153
    • PMID:3986767
Abstract
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 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 0.05-0.11% for the 6 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. It also identified 3 assay limitations: compounds requiring systemic metabolic activation were 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 were 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. 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.

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