Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1985-06-24
1990-01-16
Lilling, Herbert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 50, 536231, A61B 1900, C07H 1700, A61K 3170
Patent
active
048943649
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention pertains to combination radiotherapy of tumors and more specifically to pharmaceutical compositions and methods of treatment and therapy designed to sensitize tumors in animals, notably humans, and render them more sensitive to radiation, thus significantly reducing the amount of radiation required to kill neoplastic cells while at the same time making the radiation far more tissue specific to the tumor site.
More conventional radiation sensitizers are hypoxic cell sensitizers such as the antifilarial agent, misonidazole, which causes the complexities of neurotoxicity when it is utilized in humans. The 5-halogenated pyrimidine analogs are very distinct agents from the hypoxic cell sensitizers, for they have a completely different mode of action. We have found that cultured mammalian cells, when exposed to bromo-2'-deoxyuridine (BrdU) or other halogenated analogs of thymidine incorporate the compound into DNA resulting in sensitization of these cells to X-irradiation. Rapid catabolism or degradation of BrdU has limited its clinical effectiveness for the sensitization of rapidly growing neoplasias.
We have determined that 5-chloro-2'-deoxycytidine (CldC), which is not readily degraded due to the 4-amino group that protects the compound from catabolism by nucleoside phosphorylases, is anabolized by a different set of enzymes than the corresponding dU analog. In addition CldC is less cytotoxic than CldU. An object of the present invention is to define a class of stable, selective cell sensitizers that are not easily catabolized against tumors, both rapidly and moderately growing and malignant, and that will allow the X-ray therapist to focus the X-ray beam (or other source of radiation) on the tumor tissue site using significantly less, say one-fourth, of the dose of radiation otherwise required to achieve the same extent of tumor kill without damage to the underlying tissue. Expressed in another way, the radiotherapist is able to more aggressively kill neoplastic tissue while causing no more damage to normal tissue using the procedures and materials of the present invention than with conventional modalities of irradiation.
Thus an object of the present invention is to provide therapeutic materials and procedures for treating skin lesions using, for instance, ultraviolet light, near visible light (313 nm), and for solid tumors: X- or gamma ray, beta, neutron and other radiation entities.
Another object of the invention is to sensitize possible sites of metastic invasion to radiation, particularly X-ray, using the disclosed materials and procedures.
Should the patient develop toxcicity from the mildly aggressive therapy employed, particularly with the pretreatment with FdU and PALA either before or with the sensitizing composition, thymidine or deoxycytidine, two non-toxic metabolites, may be provided the patient at the conclusion of radiation therapy. These serve to mitigate the untoward effects, if any, of the drug therapy by antagonizing or reversing any toxic effects of the chemotherapeutic agents employed.
The method of the present invention may be used primarily with x-ray or gamma (derived from cobalt, for example) radiation. We also consider the procedure to be effective with the use of ultraviolet light, near visible light (313 nm) for skin lesions and for beta, neutron and other radiation entities. The molecular basis of sensitization has been clearly established for ultraviolet light (260 nm) and near visible light (313 nm) (both nonpenetrating) and for X- or gamma-radiation.
SUMMARY OF THE INVENTION
According to one aspect, patients having tumors requiring radiation therapy are administered, preferably on a slow release basis, 5-chloro-2-deoxycytidine and/or 5-chloro 2'-halo-2'-deoxycytidine, wherein halo is fluoro, chloro, bromo or iodo, preferably chloro. The deoxycytidine compound is preferably administered with a deamination inhibitor, preferably tetrahydrouridine (H.sub.4 U) and/or 2'-deoxytetrahydrouridine (dH.sub.4 U) for a period of time
REFERENCES:
patent: 3870700 (1975-03-01), Kotic et al.
patent: 4210638 (1980-07-01), Greer
patent: 4434788 (1984-03-01), Nakotsugawa
Mitchell et al., Int. J. Radiation Oncology Biol. Phys. 12, pp. 1513-1518, (1986).
Santos et al., Chemical Modifiers of Cancer Treatment Conference, in Paris, France, Mar. 21-25, 1988.
Martinez et al., Int. J. Radiation Oncology Biol. Phys. 11, pp. 123-128, (1985).
Jackson et al., Am. J. Clin. Oncol., 10(5), pp. 437-443, (1987).
Russo et al., Cancer Research 44, pp. 1702-1705, (1984).
Kinsella et al., Int. J. Radiation Oncology Biol. Phys. 10, No. 1, pp. 69-76, (1984); 10, No. 8, pp. 1399-1406, (1984); 13, No. 5, pp. 733-739, (1987).
Giusti et al., Enzym. Biol. Clin. 11, pp. 375-383, (1970).
Phuphanich et al., Int. J. Radiation Oncology Biol. Phy., vol. 10, pp. 1769-1772, (1984).
Kinsella et al., Cancer, Mar. 1, pp. 908-915, (1987).
Szybaski et al., Cancer Chemotherapy Report, Part 1, vol. 58, No. 4, pp. 539-557, (1974).
Brown et al., Chemical Abstracts, vol. 75, 1971, 95151k.
Altman et al., Chemical Abstracts, vol. 66, 1967, 72969h.
Chang et al., Chemical Abstracts, vol. 98, 1983, 191297h.
Tsuneo et al., Chemical Abstracts, vol. 74, 1971, 28490m.
Yoshida et al., Chemical Abstracts, vol. 96, 1982, 210557n.
Kreis et al., Helv. Chem. Acta, 61, (1978), pp. 1011-1016.
Mekras et al., Chemical Abstracts, vol. 101, 1984, 65639p.
Perez et al., Chemical Abstracts, vol. 101, 1984, 225942n.
Perez et al., "Marked Radiosensitization of Cells in Culture to X Ray by 5-Chlorodeoxycytidine Coadministered with Tetrahydrouridine, and Inhibitors of Pyrimidine Biosynthesis", Int. J. Radiation Oncology Bio. Phys. vol. 1, pp. 1453-1458.
Perez et al., "Sensitization to X Ray by 5-Chloro-2'-deoxycytidine Co--administered with Tetrahydrouridine in Several Mammalian Cell Lines and Studies of 2'-Chloro Derivatives", Int. J. Radiation Oncology Biol. Phys., vol. 12, pp. 1523, 1527.
Russell et al., "In Vitro and in Vivo Radiation Sensitization by the Halogenated . . . ", Cancer Research, vol. 46, pp. 2883-2887, Jun. 1986.
Mekras et al., "Use of 5-Fluorodeoxycytidine and Tetrahydrouridine to Exploit High Levels of Deoxycytidylate Deaminase in Tumors to Achieve DNA--and . . . , Cancer Research", vol. 44, pp. 2551-2560, Jun. 1984.
Santos et al., "Radiation, Pool Size and Incorporation Studies with the Potential Selective Radiosensitizer, 5-Chloro-2'-Deoxycytidine in Mice," University of Miami, School of Medicine, Miami, Fla. 33101 USA.
Ellims et al., "Deoxycytidylate Deaminase Activity in Lymphoproliferative Disorders", Monash University Department of Medicine, Alfred Hospital, Prahran, 3181, Victoria, Australia and Division of Anatomical Patholyg, Prince Henry's Hospital, St. Kilda Rd., Melbourne, 3004, Victoria Australia, Feb. 2, 1983.
LandOfFree
Method and materials for sensitizing neoplastic tissue to radiat does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method and materials for sensitizing neoplastic tissue to radiat, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method and materials for sensitizing neoplastic tissue to radiat will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1334929