Antagonism between inhibitors of DNA synthesis

To improve therapeutic efficiency, cytotoxic agents are often used in combination. In selecting agents for combination therapy, those with similar modes of action have generally been avoided but recently agents which inhibit DNA synthesis have been used clinically in combination. Thus methotrexate, a folic acid analogue, and cytosine arabinoside, a pyrimidine analogue, are sometimes used together in the treatment of acute leukaemia (Mathe et al., 1971). In addition to being effective drugs when used alone, or in combination with certain other drugs, these 2 agents share the inmportant property of being suitable for intrathecal administration, and this may seem a compelling reason for using them together in the prophylaxis or treatment of meningeal leukaemia. We have been unable to find any documented evidence for the effectiveness of methotrexate and cytosine arabinoside in combination and we have therefore investigated their action in rats and mice, using body weight and survival as indices of activity. Inbred male Wistar rats, aged 4-6 months and weighing 350-450 g, were housed 3 per cage. The dosages of the drugs, calculated individually for each rat, were 1-0 or 2-0 mg/kg body weight of methotrexate and 25 or 50 mg/kg of cytosine arabinoside in 0-2 ml saline, given 3 times daily intraperitoneally on 2 consecutive days. Controls received saline injections on a similar schedule. Inbred female CBA mice, weighing Accepted 28 July 1972