4-Methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208), a newly synthesized dithiocarbamate derivative, exhibits antitumor effect in vivo with low toxicity. However, the antitumor effect of TM208 in combination with drugs in clinical use for cytotoxic chemotherapy has not been identified. In our study, the antitumor effects and toxicities of TM208 in combination with cisplatin (DDP), cyclophosphamide (CTX) and 5-fluorouracil (5-Fu), respectively, were evaluated in vivo using a transplanted solid-type hepatocarcinoma H22 mice model. The results suggested that 5-Fu (5 mg/kg/2d) potentiated the antitumor effect of TM208 (100 mg/kg/d) with significantly higher tumor inhibition rates (P<0.01) and a slight elevation of toxicity; however, DDP and CTX in combination with TM208 did not exhibit similar enhanced antitumor effect. For further investigation, we found that the TM208 and 5-Fu combination therapy led to G2/M cell cycle arrest of tumor cells in vivo by downregulating the protein expression of cyclin B1, cdc2, cdk7, and upregulating the expression of p21 and p53. The protein expression levels of cyclin D1 and cyclin E were also downregulated in tumor cells treated with TM208 and 5-Fu, while those of cdk4 and cdk2 remained unchanged. The change of mRNA expression level of cdc2 was consistent with that of its protein in each group, while the mRNA expression of cyclin B1 remained unchanged among each group. These results demonstrated the dosage regimen of TM208 for combination therapy and could serve as evidence for clinical use of TM208 as an antineoplastic drug.
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