Role of Lysine in catalysing Ester Hydrolysis
RECENTLY, Gero and Withrow1 have cited the catalysis of alkaline triglyceride hydrolysis by lysine as a chemical model of a biological reaction. They postulated a bifunctional2 attack by lysine upon the carbonyl O and C of the ester linkage as the mechanism of this hydrolysis.
Chemical Model of a Biological Reaction
WE were searching for a model of an enzymatic reaction in the hope that the relatively simple chemistry of the model reaction might throw some light on the enzyme reaction itself. In particular, we were interested in finding a model which would duplicate some of the properties of lipases, notably their ability to catalyse the hydrolysis of lipids and the characteristic pH dependence of lipolytic activity which reaches a maximum near pH 8.5 with most lipases, and one just below pH 7 with some. Lipases being proteins, the model would have to be restricted to the functional groups available in proteins. The high potency of lipases, despite this restriction, together with the well-known chemical mechanism of ester hydrolysis, made us suspect that bifunctional catalysis1 might play a decisive part.
Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors.
(2''R)-4'-O-Tetrahydropyranyladriamycin (THP) is a new derivative of doxorubicin (adriamycin, ADM). The concentrations of THP and ADM required to inhibit by 50% the growth of a cultured L1210 cells was 0.003 microgram/ml and 0.016 microgram/ml, respectively. Various therapeutic designs of combinations of THP with other antitumor agents were investigated in vivo using the L1210 murine leukemia. The combination of THP with cytosine arabinoside (Ara-C), cyclocytidine hydrochloride (Cyclo-C), 6-mercaptopurine (6-MP) and cyclophosphamide (EX) showed a great effectiveness following daily intraperitoneal treatment from days 1 to 10. High therapeutic effects were also obtained with the combinations of THP with Ara-C, Cyclo-C, vincristine (VCR) and EX following intravenous combination therapy one day following implantation of L1210 leukemia. Schedule dependency and its therapeutic efficacy of THP were examined. THP showed almost the same antitumor activity on the solid-type sarcoma-180 or solid-type Ehrlich carcinoma as ADM by intraperitoneal or intravenous treatment. THP showed some superior activity to ADM in the advanced stage of L1210 leukemia. High antitumor activity of THP on murine leukemia L1210 has been reported by Tsuruo et al. (Cancer Res. 42: 1462-1467, 1982) and was also confirmed. THP gave many mice cures, especially in the intravenous treatment.