Enzyme-Driven Chemo-and Radiation-Therapy with 12 Pyrimidine Nucleoside Analogs Not Yet in the Clinic

Author(s): Sheldon Greer, Tieran Han, Cristina Dieguez, Nicola McLean, Rafael Saer, Isildinha Reis, Joe Levi, Victor E. Marquez.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , Issue 2 , 2017

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Abstract:

Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemotherapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U). Among patients with colon (19) and pancreatic tumors (40), 53 and 68 %, respectively, displayed T/N values >4 for CD suggesting chemotherapy with 5-FdC, 4-N-methylamino-5-FdC, 5-trifluoromethyldeoxycytidine and radiosensitization with 5- CldC, 4-N-methylamino-5-CldC, 5-iododeoxycytidine and 5-bromodeoxycytidine. The percent of patients with tumors with a T/N value >4 for U/CK in lung (72), colon (23) and breast (28) was 47, 61 and 68, respectively, suggesting zebularine (plus thymidine) treatment for tumors involving gene silencing.

Evidence is presented that the 4-N-alkylamino-dC substituted nucleosides and those with large 5-substitutions are activated only via CD to thymidine kinase (TK) using end–points of cytotoxicity and/or radiosensitization: H4U, the inhibitor of CD is an antagonist, cells with low CD or no TK are resistant to the analogs, the end points are indifferent to the dCK status of cells, they are poor substrates for dCK and good substrates for CD, whereas 5-FdC and 5-CldC are good substrates for both enzymes. The analogs present opportunities for Collateral Sensitivity for 5-azacytidine and gemcitabine resistant tumors.

Keywords: Chemotherapy, radiosensitization, activation of prodrugs, dCkinase, cytidine deaminase, dCMPdeaminase, uridine/cytidine kinase, pyrimidine nucleoside analogs.

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Article Details

VOLUME: 17
ISSUE: 2
Year: 2017
Page: [250 - 264]
Pages: 15
DOI: 10.2174/1871520616666161013145853
Price: $58

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