Ambiguous effect of chlorpromazine on doxorubicin activity against P388D1 tumours in mice

Chlorpromazine (CPZ) can decrease the toxicity of doxorubicin (DOX). We wanted to determine whether this CPZ pretreatment could affect the response of tumours to therapeutic doses of DOX. Six groups of eight female CDF1 mice received 1 million leukaemia P388D1 cells i.p. For 5 days, they received DOX i.p. (total dose 0, 6 or 12 mg/kg), preceded by saline or 5 mg/kg CPZ s.c. CPZ in the absence of DOX had no effect on survival [median survival time (MST) of 19 days vs. 20]. In mice receiving DOX only, MST was greater than 60 days. Mice receiving DOX + CPZ were similar to DOX till day 25, but subsequently died earlier (MST of 27 and 34 days, for DOX 6 and 12 mg/kg). At death or day 60, 31% (5/16) of DOX mice and 88% (14/16) of DOX + CPZ had macroscopic tumours (P less than 0.005, both DOX dose groups combined). However, only 19% (3/16) of DOX and 6% (1/16) of DOX + CPZ had tumours in the abdominal cavity, the others being in the abdominal wall close to the site of injection. The results suggests that while CPZ did not affect the killing of cancer cells in the abdominal cavity, it did block the effect of DOX on cells in the abdominal wall and skin. This block may be caused by decreased local delivery of DOX, due to the hypothermia produced by CPZ.