METALLOTHIONEIN AND ZINC HOMEOSTASIS DURING TUMOR PROGRESSION - EFFECT OF METHOTREXATE TREATMENT

Zinc homeostasis was studied during the induction, growth, and methotr exate (MTX) treatment of Dark Agouti rat mammary adenocarcinomas (DAMA ). A progressive fall in plasma Zn concentration (pZn), significant at a tumor burden of less than 1% body weight (bw), was sustained during tumor enlargement to give a 54% reduction in pZn at 16.3% bw (n = 6/g roup). The hypozincemia was attributed to the increasing Zn demand for tumor growth. Zn content of the 16.3% bw tumors equaled that of muscl e (normally 60% of total body Zn). Tumor metallothionein (tMT) was suf ficient to bind <3% of total tumor Zn, and hepatic MT (hMT) remained a t basal concentrations during early tumor growth, doubling only in the presence of significant necrosis in large tumors. Methotrexate (MTX, 0.5 mg/Kg im x 2 d) at respective tumor burdens of 5 and 10% bw (n = 9 , 10/group) gave 2 therapeutic effects, dependent on tumor size: 1.5% bw tumors in 7 rats remained close to their original size until experi ment end when pZn, hMT, and tMT were typical of 5% bw untreated tumors . 2. Tumors in 5 rats given MTX at 10% bw had marked subcapsular necro sis and regression to a size similar to those in group 1; pZn returned toward normal, whereas hMT was 6 times its 5% bw counterpart. Host we ight loss was significantly reduced, as were tumor-associated changes in plasma glucose and calcium. In summary, neither tMT nor hMT appears to play a role in the hypozincemia that follows DAMA Zn sequestration and growth. Critically timed MTX can result in tumor regression and r eturn of plasma Zn, Ca, and glucose toward normal. This is associated with an increase in hMT and reduction in host weight loss, suggesting a flow of Zn from the resorbing tumor to the host, enabling the synthe sis of hMT and retention of host structural proteins.