Biologic Studies on the Development of DON Resistance in a Mast-Cell Neoplasm of the Mouse

Abstract

The ascitic form of the mast-cell neoplasm P815 and the glutamine antagonist DON (6-diazo-5-oxo-l-norleucine), a growth inhibitor of P815, were used as a biologic system for studying the development of DON resistance. Titration studies were performed in which varying doses of ascitic tumor cells (10² to 10⁷) were inoculated into untreated and DON-treated mice. Mice inoculated with 10⁵ or more cells and treated with DON developed growing populations while under treatment, but consistently outlived the untreated control mice by more than 100 percent of the average survival time of controls. Some DON-treated mice inoculated with 10² or 10³ cells did, however, survive indefinitely. A number of isolations of tumor cells were made from treated mice inoculated with the various cell doses. Characterizing these isolations for sensitivity or resistance revealed the following: Some cell populations were resistant and remained so; others, while showing resistance, lost this characteristic during serial transfer in untreated mice, and some were near-sensitive. Reconstruction studies were done by mixing various numbers of sensitive and known-resistant cells. Through this technique it was possible to detect, on the basis of survival time, as few as 10 to 20 resistant cells. From these experiments it was concluded: (1) Some cells sensitive to DON may be destroyed during DON treatment, but others persist as sensitive cells. (2 Resistance to DON may develop in these cells and hence during contact with DON. (3) Some resistant populations that are not stable are mixed populations (sensitive and resistant) in which sensitive cells apparently have a selective advantage over resistant cells during transfer through untreated mice.