Prodrugs of thiolamines as radioprotective agents;
he radiotherapy of tumor tissue is highly effective but can be limited by the damage caused to normal tissue during exposure to the solid tumor to radiation. Sulfydryl-containing compounds have long been known to possess radio-protective properties. Of all the compounds that have been studies as potential radio-protective agents over the past 50 years, cysteamine and L-cysteine are still considered among the most efficacious. Unfortunately, their therapeutic usefulness has been limited by their toxicity at radio-protective doses. The classical prodrug approach to drug design may provide a way to solve these toxicity-related problems. Four prodrugs were synthesized, tow of cysteamine and two of L-cysteine, by a chemical condensation between the thiolamine and the carbonyl group of either D-ribose or D-glucose (RibCyst, BlcCyst, and GlcCys, respectively).. These thiazolidine compounds undergo nonenzymatic ring opening and subsequent hydrolysis to release the free drug. The dissociation process produces a relatively constant supply of the thiolamine, which may eliminate toxicity due to the presence of a high concentration of the compound at any time. Extensive toxicity studies utilizing both 3-day growth curve and clonogenic toxicity assays were performed on exponentially growing V79 cells. The results indicate that the inherent toxicity of cysteamine is greatly reduced when given as a prodrug, thus confirming from a toxicity standpoint the usefulness of constructing proddrugs of cysteamine. L-Cysteine exhibited limited toxicity in the assays used, but when toxicity was seen, it was eliminated when the amino acid was provided as RibCys or a slightly reduced when given as GlyCys. The ability of the parent compounds and their respective prodrugs to alter the normal response of V79 cells to ionizing radiation was also studied using a clonogenic assay. The results indicate that the radioprotective ability of both cysteamine and L-cysteine is reduced when given as prodrugs under the conditions studied. This may be due to differing hydrolysis rate of the prodrugs or the kinetics of cell uptake. The capacity of these compounds to protect against radiation-inducted DNA single strand breaks was determined using the alkaline elution technique. Protection against DNA damage was seen with the cysteamine series. In fact, the cysteamine prodrugs were more protective than cysteamine itself. The behavior of L-cysteine and its prodrugs was the opposite of the cysteamine series. L-Cysteine was able to protect against DNA damage as efficiently as cysteamine, whereas the L-cysteine prodrugs showed limited ability to protect under the conditions testsed.
Digital reproduction of “Prodrugs of thiolamines as radioprotective agents.” Spencer S. Eccles Health Sciences Library. Print version of “Prodrugs of thiolamines as radioprotective agents.” available at J. Willard Marriott Library Special Collection. RM31.5 1994 .K63.