Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice.

  title={Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice.},
  author={Martin P. Uitendaal and Jan H. Schornagel and Alberto Leyva and Herbert Michael Pinedo},
  journal={European journal of cancer \& clinical oncology},
  volume={20 12},
Combinations of thymidine and inosine (ranging from 0 to 7.5 mg/hr) were co-administered during a 72-hr continuous i.v. infusion of 3 micrograms/hr methotrexate in normal and P388 solid tumor-bearing DBA/2 mice. Methotrexate alone was lethal to all normal mice. Inosine at 1.0-7.5 mg/hr could reverse toxicity up to 100% while thymidine at 0.5-7.5 mg/hr was less effective (less than or equal to 86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound… Expand
Effect of hyperthermia and X-irradiation on survival and occurrence of metastases in mice bearing P388 tumor.
  • L. Perlaky, A. Fónagy, E. Unger, E. Hidvégi
  • Medicine
  • International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
  • 1989
Significant fewer metastases were observed in liver and spleen after hyperthermia and 5-10% metastasis occurred after transplantation of ascites tumor cells treated at 43.5 degrees C, and the possible alterations of P388 tumor cell membrane and surface proteins induced by in vitro hyperthermic treatment are discussed. Expand
Antitumor Effect of Nocardà ¬ arubra Cell Wall Skeleton on Syngeneically Transplanted P 388 Tumors
The antitumor activity of the immunomodulator, Nocardìarubra cell wall skeleton (N-CWS), was investigated using syngeneically trans planted P388 leukemia cells in a solid form. The s.c. growth ofExpand
Antitumor effect of Nocardia rubra cell wall skeleton on syngeneically transplanted P388 tumors.
Findings indicate that macrophages are the main effector cells playing a critical role in the suppression of P388 tumor growth in DBA/2 mice, and that tumor necrosis factor produced by these cells may be involved in the macrophage-mediated cytostatic effect induced by N-CWS. Expand


Potentiation of the antitumor activity of methotrexate by concurrent infusion of thymidine.
The results indicate that the increase in therapeutic selectivity achieved with the simultaneous infusion of methotrexate and thymidine may result from a complex modulation of cellular metabolism rather than simple end product reversal by the provision of thymidylate. Expand
Methotrexate with thymidine, inosine, and allopurinol rescue: a phase I clinical study.
A phase I clinical study of a combination of thymidine (TdR), inosine (IR), and allopurinol used as rescue from 24-hour infusions of methotrexate (MTX) was undertaken following animal studies thatExpand
The prevention of methotrexate toxicity by thymidine infusions in humans.
TdR offers significant protection against MTX toxicity and deserves further clinical study, as determined by labeling indices and cytofluorographic analyses. Expand
Synergism between purines and thymidine (TDR) in reversal of methotrexate (MTX) toxicity in mice using continuous infusions.
The role of purine is investigated in the reversal by TdR of MTX toxicity and its role in the de novo synthesis of purines and thymidylate is investigated. Expand
Thymidine rescue of high-dose methotrexate in humans.
Thymidine is an effective rescue agent for high-dose methotrexate in humans and recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Expand
Reversal of methotrexate inhibition of colony growth of L1210 leukemia cells in semisolid medium.
The use of a high-purine-low-thymidine combination has advantages over the use of leucovorin in controlling toxicity over a wide range of MTX concentrations and in providing some degree of selective protection to normal proliferating cells. Expand
The mechanism of action of methotrexate in cultured L5178Y leukemia cells.
MTX may inhibit dihydrofolate reductase enzyme, rapidly deplete S-phase L5178Y of reduced folates, and thus produce a purineless and thymineless state, and as treatment continues, MTX intensifies the thyminless state, possibly by direct inhibition of thymidylate synthetase enzyme. Expand
Modulation versus Rescue of Antimetabolite Toxicity by Salvage Metabolites Administered by Continuous Infusion1
A comparison of leucovorin rescue versus the utilization of thymidine plus preformed purine indicated that these salvage metabolites were as effective in reducing the toxicity of high-dose MTX while retaining antitumor activity. Expand
The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides.
While leucovorin reversed the MTX toxicity to CFU-C competitively, rescue by nucleosides was noncompetitive, the significance and possible usefulness of these findings for chemotherapeutic protocols are discussed. Expand
Thymidine requirements for the rescue of patients treated with high-dose methotrexate.
This study demonstrates that the minimum dose of thymidine required for rescue is in the range of 1 g/sq m/day, demonstrating that the 8-fold larger doses used in previous studies of dThd rescue may have obscured potential selectivity based on differential utilization of d Thd by normal and malignant cells. Expand