1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU), a lipophilic substance, is therapeutically effective against many murine tumors, especially Lewis lung carcinoma (LL), but is surprisingly ineffective against Ridgway osteogenic sarcoma (ROS). Most alkylating agents and doxorubicin (DX) are active against ROS but have relatively little therapeutic activity against LL; most are water soluble. We have analyzed these differences further by measuring blood and tumor concentrations of MeCCNU and DX in LL- and ROS-bearing mice (C57BL/6J × DBA/2 F1 and AKR/J × DBA/2J F1, respectively) after i.p. injection of the maximum tolerated doses (MeCCNU, 40, and DX, 15 mg/kg). MeCCNU blood levels were similar in the two tumor-bearing strains, falling rapidly from 12- to 1.8-µg equivalents/ml between 1 and 6 hr and to zero by 24 hr. DX plasma levels were also similar in the two mouse strains. Presumably, differences in drug concentrations and half-life in the circulation are not the cause of the differential sensitivity. Tumor levels were more illuminating. MeCCNU concentrations were 3-fold higher in LL than in ROS. At 1, 3, 6, and 24 hr, the levels in µg equivalents/g were, respectively, 20, 13, 5, and 1.5 in LL and 5, 3, 2, and 1.7 in ROS. Conversely, ROS had approximately 50% higher concentrations of DX than did LL at each time interval. It was noted in MeCCNU assays that LL contained significantly more ether-extractable lipids than did ROS (3.1 ± 0.4 versus 0.67 ± 0.2 mg/g). The above results suggest that LL and ROS differ in sensitivity to the two drugs because of differences in uptake that may be related to differences in lipophilicity of the drugs and lipid content of the tumors.
Supported by National Cancer Institute Grants CA-18856 and CA-08748 and by the Elsa U. Pardee Foundation.