Alterations in serum levels, anti-tumor activity and toxicity of methotrexate in rats after a short period of nutritional depletion.

The alterations in serum levels, anti-tumor activity and host toxicity of methotrexate (MTX) were tested in tumor bearing rats following a period of dietary manipulation. A protein deprived (PD) diet or a diet containing a normal protein content (NP) was administered for 5 days and MTX injected intra-peritoneally (i.p.) at the end of the 5 day period. The MTX serum levels were significantly elevated in rats which received the PD diet, as compared to NP dietary rats. This elevation correlated with an enhanced tumor response to MTX administration. In addition, bone marrow toxicity and intestinal tract toxicity, measured with flow cytometry (FCM) of the bone marrow and morphometry of the jejunal mucosa respectively was increased in rats receiving the PD diet. These results indicate that the serum clearance of MTX is delayed in animals suffering from malnutrition, leading to both enhanced tumor response and increased host toxicity.