Is better drug availability in secondary neoplasms responsible for better response to chemotherapy?

Abstract

The response of intramuscular Lewis Lung carcinoma (3LL) and its pulmonary metastases to graded doses of adriamycin (AM) was investigated in C57B1/6 mice given the drug i.v. 11 days after tumor implantation and the effect was quantitated by recording tumor or metastases weight at various intervals after treatment. In the same experimental tumor model the distribution of AM in primary and secondary neoplasms was studied by a fluorimetric procedure. The results indicate that, compared to the primary 3LL implant, AM has a much more pronounced effect on a percentage basis on the lung nodules, where the drug reaches 3–5 times the levels in the intramuscular tumor. In order to clarify the role of this better drug availability in determining the higher response at the metastic site, the experimental correlation law between AM amount (peak level or area under the concentration versus time curve, AUC) and the drug effect (the smallest ratio of mean tumor or metastases weights in treated to untreated animals) was investigated for both primary and secondary tumors, and the concentration-response curves thus constructed were compared with the dose-response curves. If the effect is related to drug concentration, there is definitely less difference between the response of intramuscular 3LL and its metastases to AM and it even disappears at certain concentrations. The ed₅₀ for the primary tumor is 10 times higher than for the lung nodules if derived from the dose-response curve, and only 2–3 times higher if derived from the concentration-response curve. Moreover, the lack of linear relationship and the biexponential correlation between the variables of effect and dose or peak concentration or AUC, either for the intramuscular or pulmonary 3LL, indicates that the effect does not increase proportionally to the drug amounts, suggesting that other factors beside AM concentration may contribute to the better drug response at the metastatic site.