Metabolic consequences of methotrexate therapy in tumour-bearing rats

The metabolic response of the tumour-bearing host to methotrexate (MTX) therapy was investigated with particular attention to effects resulting from MTX-induced anorexia. Biochemical changes in female Dark Agouti rats bearing mammary adenocarcinomas and treated with MTX (0.5 mg/kg, 2 i.m. injections, 24 h apart) were compared with untreated (CON) tumour-bearing rats, and tumour-bearing rats pair-fed (PF) to the MTX group. MTX treatment halted progression of the tumour (tumour 6% of bodyweight) while the tumour burden doubled in the CON and PF groups. A number of biochemical and haematological changes were specific to MTX treatment and did not result from decreased food intake. MTX treatment was associated with significantly decreased plasma calcium, bilirubin, alkaline phosphatase, aspartate aminotransferase and the total white cell count. Decreases in plasma albumin and total protein concentrations were observed in both MTX and PF rats. Other parameters commonly used to assess renal and liver function were not significantly affected by MTX. MTX reversed the hypoglycaemia, hyperketonaemia and hypertriglyceridaemia induced by tumour-bearing. In contrast, PF rats had an even more pronounced hypoglycaemia and hyperketonaemia than the CON rats. Measurement of glucose uptake in vivo with 2-deoxy[U-14C]-glucose showed that MTX treatment halved the glucose requirement of the tumour (8.2% of bodyweight compared to 12.2% in the control). It is concluded that the potentially adverse effects of MTX treatment on host metabolism are outweighed by the beneficial effects of a reduced metabolic demand resulting from inhibition of tumour progression.