Factors affecting growth and drug sensitivity of mouse mammary tumor lines in collagen gel cultures.

A series of mouse mammary tumor subpopulation lines were compared for growth properties and sensitivity to chemotherapeutic drugs when grown as boluses in a collagen gel matrix versus in monolayer culture. Although the cell lines exhibited characteristic rates of bolus expansion in collagen, this growth was not paralleled by an exponential increase in cell number with time. Cell boluses contained a higher proportion of cells in G0-G1 phases of the cell cycle than did the same cell lines in monolayer cultures. Histological examination revealed areas of necrosis in boluses. Thus cells growing in collagen cultures resembled cells growing as solid tumors and cells from other three-dimensional culture systems. The growth of cell boluses in collagen gel cultures was reduced nonexponentially by melphalan, methotrexate, and 5-fluorouracil in contrast to the exponential decrease in growth measured in cloning assays. The lowest concentration to which cells first responded to drug was in general similar for collagen gel assays and for cloning assays. The rank order of sensitivity of different cell lines in the two assays was identical for methotrexate (four cell lines), similar for melphalan (four of five lines), but quite different for 5-fluorouracil. In contrast to cloning assays cell boluses continued to grow, albeit at a reduced rate, in the presence of high drug concentrations. This was not due to either diminished drug availability in collagen gel or drug penetration into the bolus.