In vivo therapy of neoplastic meningitis with methotrexate and 5-[I-125]iodo-2 '-deoxyuridine

We examined whether the administration of methotrexate (MTX) prior to the i njection of 5-[I-125]iodo-2'-deoxyuridine ((125)IUdR) in rats with intrathe cal (i.t.) TE-671 human rhabdomyosarcoma would enhance (125)IUdR uptake by tumor cells and augment the therapeutic efficacy of this Auger-electron-emi tting radiopharmaceutical. TE-671 cells were exposed in vitro to medium +/- MTX, and the percentage of cells in various phases of the cell cycle and t he uptake of (125)IUdR assessed. In addition, nude rats were injected i.t. with TE-671 cells and later infused i.t. with saline or MTX for 24 h prior to (125)IUdR injection, and the radioactivity associated with their spinal cords was determined. Exposure of tumor cells in vitro to MTX leads to an i ncrease in the uptake of (125)IUdR as a consequence of both a rise in the a bsolute uptake per cell and an increase in the percentage of S-phase cells. A corresponding increase of radioactivity within the spinal cords of tumor -bearing rats also occurs in the presence of MTX. Tumor-bearing animals wer e infused/injected with MTX and/or (125)IUdR, and the onset of paralysis wa s determined as a function of time. We find that: (i) MTX infusion leads to a slight increase in time to onset of paralysis (median [M] = 24 vs. 22 da ys, p = 0.79); (ii) (125)IUdR injection results in a statistically signific ant delay Cp < 0.01) in the onset of paralysis (M = 39 days); (iii) MTX adm inistration prior to (125)IUdR injection further increases the therapeutic efficacy (M = 45 days).