Potentiation of the antitumor activity of tegafur in Sarcoma 180-bearing mice by chlordiazepoxide, diazepam and oxazepam.

The effects of chlordiazepoxide, diazepam and oxazepam administration on the antitumor activity, acute toxicity and metabolism of tegafur were investigated in mice and compared with those in the case of 5-fluorouracil (5-FU). Tegafur was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg kg-1·d-1 for 3d, i.p.). The pretreatment with these drugs increased the antitumor activity of tegafur against the solid form of Sarcoma 180 and the acute toxicity. In chlordiazepoxide-, diazepam- or oxazepam-treated mice, after the administration of tegafur, the level of tegafur in the plasma was lower than that in untreated mice and a large amount of 5-FU was released. A low level of 5-FU in the plasma after the administration of 5-FU was also observed in chlordiazepoxide-, diazepam- or oxazepam-treated mice. In the liver and kidneys of chlordiazepoxide-, diazepam-, or oxazepam-treated mice, the level of 5-FU after the administration of tegafur was higher. On the other hand, chlordiazepoxide, diazepam or oxazepam significantly enhanced the activities of hepatic drug-metabolizing enzymes. It can therefore be presumed that the antitumor activity of tegafur was enhanced by chlordiazepoxide, diazepam or oxazepam as a result of promotion of the conversion of tegafur to 5-FU, mainly via the induction of hepatic drug-metabolizing activities.