Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-01-31
2004-06-01
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S045000, C514S049000, C514S050000
Reexamination Certificate
active
06743782
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to acyl derivatives of deoxyribonucleosides and to the use of those derivatives to enhance the delivery of exogenous deoxyribonucleosides to animal tissue. More specifically, this invention relates to the acyl derivatives of 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxycytidine and 2′-deoxythymidine and the use of those novel derivatives to increase the bioavailability of the deoxyribonucleosides to animal tissue and thereby to support cellular metabolic functions. Even more specifically, this invention relates to the use of the novel acyl derivatives to treat or prevent a variety of physiological and pathological conditions in cell tissue, including damage by radiation, sunlight, mutagens, wounds, and other conditions.
BACKGROUND OF THE INVENTION
There are many physiological and pathological conditions of animal tissue where the supply of exogenous deoxyribonucleosides may have useful therapeutic applications. In the treatment of wounds, repair of liver tissue, promotion of repair and survival after radiation, and numerous other conditions, the supply of DNA and/or deoxyribonucleosides at a high and sustained level may substantially improve the natural DNA and tissue repair processes of the affected cells.
In promoting wound healing, liver regeneration, recovery from radiation damage, and in other pathological and physiological conditions, it is likely that exogenously supplied DNA serves merely as a storage depot for deoxyribonucleosides. That depot gradually releases deoxyribonucleotides and deoxyribonucleosides during enzymatic degradation. Thus the administration of deoxyribonucleosides or derivatives disclosed herein may have value as a method for delivering those deoxyribonucleosides to tissues, which method is preferable to the administration of foreign DNA insofar as wound healing, tissue regeneration, recovery from irradiation, and the like, is concerned.
A number of investigators have attempted to use DNA and/or deoxyribonucleosides to treat a variety of conditions in experimental animals and to enhance or augment cellular repair processes, including DNA repair. It has been demonstrated that administration of exogenous DNA to experimental animals after exposure to ionizing radiation can result in dramatically increased survival and functional recovery. Studies on cell cultures in vitro demonstrate that the actual restorative agents are probably deoxyribonucleosides, the enzymatic degradation products of DNA. These compounds enhance the actual repair of damaged DNA in vitro. However, depolymerized DNA or deoxyribonucleosides administered to animals were ineffective in promoting survival or recovery after irradiation. Kanazir et al.,
Bull. Inst. Nuc. Sci “Boris, Kidrinch
” 9:145-153 (1959). There is reason to believe that this apparent contradiction is due to the rapid catabolism of deoxyribonucleosides in vivo by the liver and other organs. Thus, after administration of deoxyribonucleosides, tissues were only exposed to effective concentrations for a matter of minutes. Beltz, et al.,
Bioch. Biophys. Acta
297:258-267 (1973). In cell cultures, optimum survival after irradiation was found when deoxyribonucleosides were present in the incubation medium for at least 3 hours. When DNA is administered by intraperitoneal injection, it is gradually depolymerized to give a sustained release of free deoxyribonucleosides into the circulation. DNA is not, however, a suitable pharmaceutical agent to administer to humans, either orally or parenterally.
Hunting, D. J., et al.,
Carcinogenesis
6:1525-1528 (1985), disclose that deoxyribonucleotide synthesis is rate limiting for excision repair of UV-induced DNA damage. The authors found that there was an increase in repair ligation in cells made permeable to added deoxyribonucleotide triphosphates.
Golba, S., et al.,
Int. J. Rad. Biol
. 13:261-268 (1967), disclose that after whole-body irradiation, administration of heterologous DNA improved survival and accelerated the rate of recovery of body weight and of red blood cells, granulocytes and lymphocyte counts in the peripheral blood. No secondary disease or change in the blood count was observed in the next 12 months. Goh, K.,
Proc. Soc. Exp. Biol. Med
. 145:938-943 (1974), discloses addition of exogenous deoxyribonucleotides resulted in prevention or healing of “pulverized” chromosomes found in cultures of leukocytes taken from a human subjected to accidental exposure to fast neutron and gamma irradiation. Horikawa, M., et al.,
Exp. Cell Res
. 34:198-200 (1964), disclose the effect of the addition of various cell extracts and compounds to an incubation medium containing mouse L cells in culture which were irradiated in culture with X-irradiation (2000 R). Homogenates of L cells, L cell nuclei, or purified DNA from either L cells or salmon sperm all strongly enhanced the survival of the irradiated cells. RNA from either yeast or L cells was found to be ineffective. The authors suggest that the DNA hydrolysates (e.g., deoxynucleotides) are the actual reactivating agents, since heterologous DNA is as effective as homologous DNA.
Pantic, V., et al.,
Nature
193:993-994 (1962), disclose administration of DNA to X-irradiated rats given lethal doses of radiation. The authors found that while DNA treatment did not totally prevent cellular damage in the intestine and liver after irradiation, tissue structure and function were much closer to normal in DNA-treated animals examined 4 or 9 days after irradiation than in untreated irradiated controls.
Paoletti, C., et al.,
Rev. Francais. Etudes Clin. et Bio
. 9:950-955 (1964), disclose a study on the effect of administration of DNA and 2-aminoethyl-isothiouronium (AET) to rats. Mice were given a mixture of AET and thiogel orally, then irradiated (700 rad) and subsequently given i.p. injections of 1 mg calf thymus DNA. The mice receiving the DNA injections recovered their weight and initial leukocyte counts more rapidly than mice similarly treated but not receiving the DNA injections.
Petrovic, D., et al.,
Int. J. Radiat. Biol
. 18:243-258 (1970), disclose evidence concerning the molecular basis of the restorative effect of DNA in cultured mammalian cells. The authors found that the survival of irradiated cells in culture was enhanced by the addition of either DNA or equimolar amounts of deoxyribonucleosides. DNA was effective only if serum containing active deoxyribonuclease was present in the incubation medium. Thus, the authors concluded that the deoxyribonucleosides were probably the actual reactivating factors responsible for repair of radiation-induced damage. In another study, Petrovic disclosed that maximal restoration is attained when deoxyribnucleosides are in the incubation medium for at least 3 hours after irradiation. The best restoration was achieved with either a mixture of all four major deoxyribonucleosides, or a combination of deoxyguanosine with either deoxyadenosine or deoxycytidine. Petrovic, D., et al.,
Studia Biophysica
43:13-18 (1974). Petrovic et al. also report that in irradiated HeLa cells, treatment with a mixture of the four major deoxyribonucleosides increased survival. Petrovic et al.,
Int. J. Radiat. Res
. 11:609-611 (1967).
Savkovic, N.,
Nature
203:1297-1298 (1964), discloses that 8 or 17 day old rats subjected to X-radiation (600 rem), and immediately treated with homologous testes DNA, had a much higher fertility rate than did untreated irradiated controls. Histological studies demonstrated that DNA treatment after irradiation markedly protected the structural integrity of the testes and the function of the spermatogenic processes. Savkovic also reported that heterologous DNA extracted from various organs of adult rats was effective in enhancing the survival of mice subjected to irradiation. The DNA reduced the effects of radiation by a factor of 9 to 13. Savkovic, N., et al.,
Nature
211:1179-1180 (1966). Savkovic, N., et al.,
Int. J. Rad. Biol
. 9:361-368 (1965) also disclose that treatment of irradiated rats with
Bamat Michael K.
Von Borstel Reid W.
Nixon & Vanderhye
Wellstat Therapeutics Corporation
Wilson James O.
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