Effect of scheduling of combinations of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on the Harding-Passey and Cloudman S91 mouse melanomas.

Harding-Passey mouse melanoma (HP) cells (10(6)) were administered i.p. to female BALB/c x DBA/2 F1 (hereafter called CD2F1) mice on Day 0. We showed earlier (H. Z. Hill, et al., Arch Surg., 114: 135-138, 1979) that a single dose of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) administered on Day 0 or on subsequent days was equally effective regardless of the day of administration. We now show that a single dose of 10 mg of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU) per kg was most effective in prolonging survival of HP-bearing CD2F1 mice when administered on Day 0. There was then a decline in effectiveness to Day 10, at which time the increase in survival of the drug-treated animals was no longer significant. The effect of sequential scheduling of DTIC and MeCCNU on HP was studied. The first drug was given on Day 0 or on Day 10. The second drug followed on the same day or on subsequent days. The greatest enhancement of survival was seen when DTIC was administered on Day 0 and MeCCNU on Day 1. Nine of 10 mice on this schedule were cured. When treatment of HP was started on Day 10, the most enhancement was again seen for DTIC on Day 10 and MeCCNU on the next day. Reversal of the order of the two drugs produced less prolongation of survival and fewer cures. The effect of scheduling two doses of DTIC was also studied using the HP model. The first dose was given on Day 0 or on Day 10. The second dose produced the greatest enhancement of survival when administered 3 to 4 days after the first dose, but the enhancement was less than that seen when DTIC was followed by MeCCNU. For comparison, the two drugs were also studied in female DBA/2 mice carrying the Cloudman S91 melanoma. In combination, on Day 0, in only one of three experiments was survival prolonged beyond the controls. Other schedules were ineffective. The enhancement seen when HP-bearing CD2F1 mice are treated with the best combination of the two drugs is clearly not seen with S91. The results imply that dosage scheduling in the treatment of murine melanomas must be individualized. Extrapolation to the human situation suggests the same conclusion.