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

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.

The effect of new antepartum weight gain guidelines and prepregnancy body mass index on the development of pregnancy-related hypertension.

We evaluated the impact of adherence to the new Institute of Medicine weight gain guidelines within each prepregnancy body mass index (PPBMI) category on the development of pregnancy-related hypertension (PRH). Patients with singleton term deliveries (≥37 weeks) with documented PPBMI and pregnancy weight gain information were identified from a database of women enrolled for outpatient nursing services. Included were women without history of cardiovascular disease, PRH, or diabetes at initiation of services (N = 7676). Data were stratified by PPBMI (underweight = < 18.5 kg/m(2); normal weight = 18.5 to 24.9 kg/m(2); overweight = 25.0 to 29.9 kg/m(2); obese = ≥ 30.0 kg/m(2)). PRH rates were compared overall and within each PPBMI group for those women gaining less than recommendations, within recommendations, and above recommendations using Pearson's chi-square and Kruskal-Wallis H test statistics. Overall, PRH rates were 5.0%, 5.4%, and 10.8% for less than, within, and above recommendation groups, respectively (P < 0.001). Above recommendation weight gain resulted in higher PRH incidence in each PPBMI category (underweight 7.6%, normal weight 6.2%, overweight 12.4%, and obese 17.0%), reaching statistical significance in all but the underweight PPBMI group. Excessive weight gain above established guidelines was associated with increased rates of PRH. Regardless of PPBMI, women should be counseled to avoid excessive weight gain during pregnancy.