Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-19
2003-09-16
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S073000, C514S050000, C514S105000, C514S249000
Reexamination Certificate
active
06620816
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the administration to a warm blooded animal including humans of the combination of tegafur, uracil, and folinic acid and its administration with cyclophosphamide for the treatment of tumors.
BACKGROUND OF THE INVENTION
5—Fluorouracil (5—FU) is a known anti-tumor agent. The combination of 5-fluorouracil and folinic acid is a known treatment for cancer including adenocarcinoma of the female breast. Tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) is a prodrug of 5-fluorouracil. In vivo, 5-fluorouracil is rapidly inactivated by the enzyme dihydropyridine dehydrogenase (DPD). Uracil competitively inhibits DPD metabolism of 5—FU generated from tegafur. Thus, coadministration of uracil with tegafur results in higher exposures of active 5—FU as compared to tegafur alone. It is also known that 5-fluorouracil cannot be administered orally.
U.S. Pat. No. 4,328,229 discloses an anti-cancer composition containing 1-(2-tetrahydrofuryl)-5-fluorouracil (“tegafur”) and uracil. The composition is used for delivery of 5-fluorouracil to a tumor sensitive to 5-fluorouracil in a warm-blooded animal. It is disclosed that the composition can be co-administered in a variety of dosage forms including an oral dosage form.
U.S. Pat. No. 5,534,513 discloses an anti-tumor composition containing tegafur and uracil in a molar ratio of 1:4. This anti-tumor composition is stated to be further potentiated by the administration of folinic acid or a pharmaceutically acceptable salt thereof. It is disclosed in the '513 patent that the combination can be administered in a variety of dosage forms including an oral dosage form.
Cyclophosphamide has been shown useful for the treatment of certain malignancies. For decades, cyclophosphamide has remained one of the most commonly used chemotherapeutic agents for the treatment of breast cancer. Cyclophosphamide acts primarily by alkylation, however it also inhibits DNA synthesis. It is known that cyclophosphamide may be administered orally or intravenously. The primary side effects of oral administration are myelosuppression and nausea.
It has been observed by Applicants that 5-fluorouracil can enhance the activity of cyclophosphamide. However, because 5-fluorouracil cannot be administered orally, the mode of administration for this combination therapy treatment requires a more invasive form of administration such as by intravenous injection, and therefore typically requires administration by trained medical personnel.
It would be an advance in the art of treating tumors, especially breast cancer tumors, if a therapy could be developed employing the administration of cyclophosphamide and 5-fluorouracil, especially where 5-fluorouracil may be administered in a convenient oral dosage form.
SUMMARY OF THE INVENTION
The present invention is generally directed to the administration of tegafur, uracil, folinic acid or a pharmaceutically acceptable salt thereof, and cyclophosphamide in suitable dosage forms to warm-blooded animals, including humans, for the treatment of tumors, especially breast cancer tumors. In a particular aspect of the invention, tegafur, uracil, folinic acid or a pharmaceutically acceptable salt thereof, and cyclophosphamide are administered in oral dosage form(s) to a warm-blooded animal, including humans, having a tumor. In a preferred form of the invention, tegafur and uracil are present in respective amounts sufficient for tegafur to effectively and efficiently convert to 5-fluorouracil. In a particularly preferred embodiment of the invention, tegafur and uracil are present in a molar ratio of about 1:4 (hereinafter referred to as “UFT”).
There is also disclosed a method of treating cancer by orally administering an anti-tumor effective amount of the combination of tegafur and uracil, preferably as UFT, and folinic acid or a pharmaceutically acceptable salt thereof to a warm-blooded animal, including humans, having a tumor who is undergoing cyclophosphamide therapy treatment.
REFERENCES:
patent: 4328229 (1982-05-01), Fujii et al.
patent: 5534513 (1996-07-01), Junji et al.
patent: 5688773 (1997-11-01), Chiocca et al.
Haga, S. et al “Antitumor Efficacy of Combination Chemotherapy with UFT and Cyclophosphamide against Human Breast Cancer Xenografts in Nude Mice”, Anticancer Research, 1999, vol. 19 (3A), 1791-1796.*
Fukuda, M. et al “Combination Therapy for Advanced Breast Cancer: Cyclophosphamide, Doxorubicin, UFT, and Tamoxifen” Oncology, 1999, vol. 13, No. 7 (suppl. 3), 77-81.*
Smith, I.E. “Epirubicin, Cyclophosphamide and UFT Plus Oral Calcium Folinate in Advanced Breast Cancer”, Oncology, 1999, vol. 13, No. 7 (suppl. 3), 82-85.*
Y. Tanaka, et al.; Int. J. Cancer 1999, vol. 83, pp. 127-134.
Bunnell Craig A.
Dugan Terry S.
Ressler-Tatro Jody
Winer Eric P.
Bristol--Myers Squibb Company
Gibbons Maureen S.
Krishnan Ganapathy
Wilson James O.
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