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[Nucleoside kinases and new types of antitumor nucleosides]
1Faculty of Pharmaceutical Sciences, Hokkaido University.
Abstract:
The nucleoside kinases phosphorylate nucleosides to corresponding nucleoside 5'-monophosphates. Their activities are essential for activation of chemotherapeutically important nucleoside analogues. Since, among them, deoxycytidine kinase has high activity in a wide variety of tumor tissues, a relatively low substrate specificity, and is not cell-cycle regulated, 2'-substituted-2'-deoxycytidine analogues should be suitable for antitumor antimetabolites. Gemcitabine, DMDC, and CNDAC have been developed for such analogues. These nucleosides showed potent antitumor activity against various solid tumors. They inhibited mainly DNA synthesis of tumor cells and, to some extent, inhibited RNA synthesis. To inhibit RNA synthesis of tumor cells would be important to kill solid tumor cells, which are heterogenous. ECyd was designed as an inhibitor of both DNA and RNA syntheses and showed potent antitumor activity against a variety of human tumor cells in xenografts.
Insights
Novel deoxycytidine analogues, including gemcitabine and ECyd, show potent antitumor activity by inhibiting DNA and RNA synthesis in tumor cells. These findings highlight their potential as effective antimetabolites for cancer treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Nucleoside kinases phosphorylate nucleosides, activating crucial chemotherapeutic agents.
- Deoxycytidine kinase is a key enzyme in tumor tissues, exhibiting broad substrate specificity and lack of cell-cycle regulation.
- 2'-substituted-2'-deoxycytidine analogues are promising antitumor antimetabolites due to deoxycytidine kinase's properties.
Purpose of the Study:
- To evaluate the antitumor potential of novel 2'-substituted-2'-deoxycytidine analogues.
- To investigate the mechanism of action, focusing on DNA and RNA synthesis inhibition.
- To assess the efficacy of these analogues against various human tumor cells in preclinical models.
Main Methods:
- Development and synthesis of novel 2'-substituted-2'-deoxycytidine analogues (e.g., Gemcitabine, DMDC, CNDAC, ECyd).
- Assessment of antitumor activity against various solid tumors and human tumor cell lines.
- Evaluation of effects on DNA and RNA synthesis in tumor cells.
- Testing in human tumor xenograft models.
Main Results:
- Gemcitabine, DMDC, and CNDAC demonstrated potent antitumor activity against diverse solid tumors.
- These nucleosides primarily inhibited DNA synthesis and, to a lesser extent, RNA synthesis in tumor cells.
- ECyd was specifically designed to inhibit both DNA and RNA synthesis, showing significant antitumor efficacy in human tumor xenografts.
Conclusions:
- 2'-substituted-2'-deoxycytidine analogues are effective antitumor antimetabolites.
- Inhibition of both DNA and RNA synthesis is a viable strategy for targeting heterogeneous solid tumors.
- ECyd represents a promising therapeutic agent with dual-action inhibition for enhanced anticancer effects.