Effects of varying the interval between courses of methotrexate on its myelotoxic and anti-leukaemic activities.

The toxicity produced by two courses of methotrexate separated by different intervals has been studied in matched groups of rats. The maximum degree of neutropenia reached when courses were separated by 8 days or more was no greater than that seen after a single course of methotrexate. However, when courses of neutropenia following the second course of methotrexate was directly related to the level of depression of bone marrow cell numbers at the time of the second course. Conversely the anti-leukaemic effects of 2 courses of methotrexate, in terms of time of onset of leukaemia and time of death in rats transplanted with a syngeneic T-cell leukaemia, are shown to be similar when courses of methotrexate are separated by between 2 and 12 days. Thus in this system, chemotherapeutic schedules using methotrexate may be designed on the basis of minimal host toxicity without prejudicing anti-leukaemic effects. These results are discussed in relation to toxicity and anti-leukaemic effects observed during UKALL trials of treatment in acute lymphoblastic leukaemia.