The selectivity of action of alkylating agents and drug resistance. I. Biochemical changes occurring in sensitive and resistant strains of the Yoshida ascites sarcoma following chemotherapy.

The Absorption, Distribution and Excretion of 3H-Chlorambucil in Rats Bearing the Yoshida Ascites Sarcoma

“…The progressive rapid loss of label from the liver after initial uptake, was similar to data presented by Connors and Melzack (Harrap and Hill, 1970;Hill, Jarman and Harrap, 1971). However, after the in vivo treatment described above, the initial uptake of the drug by the cells was similar (i.e.…”

“…Only after this period of time was the difference between the 2 cell strains apparent. These results might be explained by reference to the different metabolism of the drug by these cells in vitro, namely that the resistant cells have a greater ability to hydrolyse and metabolize the drug (Harrap and Hill, 1970 (Hill, Jarman and Harrap, 1971). Furthermore, it is only after, or coincident with this period that peak binding to cell macromolecules in both cell strains is noted, which would support the hypothesis that there can be slow release from this lipophylic association followed by subsequent binding to protein and nucleic acids.…”

An autoradiographic study of the binding of 3H‐chlorambucil to cells of a drug‐sensitive and drug‐resistant strain of the Yoshida ascites sarcoma

“…These events were paralleled by increases in cell volume and levels of DNA, RNA and protein (Hill, unpublished observations, 1972), which had also been previously noted after treatment of tumour-bearing animals as characteristic of the 'unbalanced growth' condition (Harrap & Hill, 1969). Similar effects were not, however, seen in drug-resistant cells after treatment in vitro with an LD,, dose of chlorambucil.…”

“…Using biochemical methods differences in the extent of drug uptake and subsequent metabolism by the two tumour cell lines have been reported previously (Harrap & Hill, 1969;Hill & Riches, 1971;Hill, 1972). These differences were shown to be dependent on both the cell concentration and drug concentration employed for in vitro incubation .…”

“…Earlier experiments (Harrap & Hill, 1969) have shown that under some conditions there is a difference in the uptake of the drug chlorambucil in sensitive and resistant Yoshida sarcoma cells. This difference, an increased level of the drug in the sensitive strain, was later demonstrated (Hill & Riches, 1971) using a tritiumlabelled drug; however, the increased binding (two-fold) was much less than the difference in drug sensitivity.…”