Augmentation of antitumor activity of 5'-deoxy-5-fluorouridine by thymosin fraction 5 in mouse bladder cancer cells in vitro and in vivo.
5'-Deoxy-5-fluorouridine (5'-dFUrd) is a prodrug of 5-fluorouracil (5-FUra) activated by pyrimidine nucleoside phosphorylase (PyN Pase), mainly by uridine phosphorylase (Urd Pase) in rodents and by thymidine phosphorylase (TdR Pase) in humans, which is preferentially located in tumor tissues compared to normal tissues. It has been reported that PyN Pase is induced by cytokines such as tumor necrosis factor (TNF), interleukin-1alpha (IL-1alpha) and interferon (IFN). Thymosin is a glycoprotein extract obtained from the calf thymus and is a potent immunopotentiating preparation. In this study, the antiproliferative activity of 5'-dFUrd used in combination with thymosin fraction 5 (TF5) was investigated in mouse bladder cancer cell line MBT-2 in vitro and in vivo. In vitro TF5 enhanced the activity of 5'-dFUrd by up to 4.11-fold, whereas the activity of other cytostatics such as 5-FUra, mitomycin C, adriamycin, cis-platinum, etoposide, vinblastine and methotrexate was not changed. In vivo when the effects of combination therapy with 5'-dFUrd and TF5 in C3H/HeN mice implanted with MBT2 were studied, tumor growth was not suppressed by TF5 alone while tumor growth was suppressed to some degree by 5'-dFUrd alone. However, tumor growth suppression was enhanced when 5'-dFUrd was used in combination with TF5. In order to investigate this mechanism, Urd Pase in MB2 was measured, and it was found that TF5 increased enzyme activity by up to 1.8-fold in MBT2. This increased susceptibility might be a result of the induction of Urd Pase, which is the essential enzyme for the conversion of 5'-dFUrd to 5-FUra. These results suggested that the therapeutic benefit of 5'-dFUrd would be improved by its use in combination with TF5 and the modulation of converting enzymes for antitumor prodrugs could be a novel therapeutic strategy for treating human cancers.
Ikemoto
S
S
Department of Urology, Osaka City University Medical School, Japan.
Sugimura
K
K
Wada
S
S
Yasumoto
R
R
Yamamoto
K
K
Kishimoto
T
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005467:Floxuridine / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011355:Prodrugs / Q000627:therapeutic use*; D013947:Thymosin / Q000008:administration & dosage / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D007166:Immunosuppressive Agents; D011355:Prodrugs; C033782:thymosin fraction 5; D005467:Floxuridine; D013947:Thymosin; C025034:doxifluridine