TY - JOUR
T1 - Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice
AU - Uitendaal, Martin P.
AU - Schornagel, Jan H.
AU - Leyva, Albert
AU - Pinedo, Herbert M.
PY - 1984
Y1 - 1984
N2 - 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 μg/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 (≤86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound alone and in a synergistic manner. From P388 tumor-bearing mice 27% survived methotrexate and eventually died of tumor. Co-infusion of thymidine or inosine decreased the percentage of toxic deaths and caused an increase in life span of more than 50% as compared to untreated tumor-bearing mice. However, the diminishing effect on survival with thymidine and inosine doses above 0.5 mg/hr indicated loss of the antitumor effect of methotrexate. This was also observed with combinations of the nucleosides. The influence of thymidine on the antitumor effect of methotrexate was compared in L1210- and P388-bearing mice (both in ascites) with 13 μg/hr methotrexate for 48 hr and 4 mg/hr thymidine for 96 hr. The increase in life span for L1210-bearing mice (8.6 days, 96%) was significantly longer than that with P388-bearing mice (6.1 days, 56%), probably due to biochemical differences between these tumors. It is concluded that co-administration of inosine and/or thymidine allows the use of methotrexate doses otherwise not tolerated, though with loss of anti-tumor effect. The choice of the tumor model may greatly influence the outcome of in-vivo studies on the modulation of methotrexate action by nucleosides.
AB - 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 μg/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 (≤86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound alone and in a synergistic manner. From P388 tumor-bearing mice 27% survived methotrexate and eventually died of tumor. Co-infusion of thymidine or inosine decreased the percentage of toxic deaths and caused an increase in life span of more than 50% as compared to untreated tumor-bearing mice. However, the diminishing effect on survival with thymidine and inosine doses above 0.5 mg/hr indicated loss of the antitumor effect of methotrexate. This was also observed with combinations of the nucleosides. The influence of thymidine on the antitumor effect of methotrexate was compared in L1210- and P388-bearing mice (both in ascites) with 13 μg/hr methotrexate for 48 hr and 4 mg/hr thymidine for 96 hr. The increase in life span for L1210-bearing mice (8.6 days, 96%) was significantly longer than that with P388-bearing mice (6.1 days, 56%), probably due to biochemical differences between these tumors. It is concluded that co-administration of inosine and/or thymidine allows the use of methotrexate doses otherwise not tolerated, though with loss of anti-tumor effect. The choice of the tumor model may greatly influence the outcome of in-vivo studies on the modulation of methotrexate action by nucleosides.
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U2 - 10.1016/0277-5379(84)90146-9
DO - 10.1016/0277-5379(84)90146-9
M3 - Article
C2 - 6542016
AN - SCOPUS:0021678568
SN - 0277-5379
VL - 20
SP - 1527
EP - 1532
JO - European Journal of Cancer and Clinical Oncology
JF - European Journal of Cancer and Clinical Oncology
IS - 12
ER -