Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-17
2001-11-27
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06323205
ABSTRACT:
BACKGROUND OF THE INVENTION
This application relates to a composition comprising 10-propargyl-10-deazaaminopterin and a taxol, and to methods of using this composition in the treatment of tumors.
10-Propargyl-10-deazaaminopterin (“10-propargyl-10dAM”) is a member of a large class of compounds which have been tested and in some cases found useful in the treatment of tumors. This compound, which has the structure shown in
FIG. 1
, was disclosed by DeGraw et al., “Synthesis and Antitumor Activity of 10-Propargyl-deazaaminopterin,”
J Medical Chem.
36: 2228-2231(1993) and shown to act as an inhibitor of growth in the murine L1210 cell line and to a lesser extent of the enzyme dihydrofolate reductase (“DHFR”). In addition, some results were presented for the antitumor properties of the compound using the E0771 murine mammary tumor model. This data was equivocal because of the small number of mice used in the test (3 per dosage), the absence of any standard deviation information which would quantify the reliability of the data, and the fact that the highest dose used was in fact toxic to the mice. Nevertheless, assuming this data has some predictive value for the efficacy of a drug in treating human tumors, it would at best predict a drug which, at equivalent levels of tolerance had properties comparable to or perhaps slightly better than methotrexate.
The parent application, which was published as PCT Publication No. W098/02163, discloses the surprising observation that more highly purified 10-propargyl-10dAM compositions when tested in a xenograft model for their efficacy against human tumors have now been shown to be far superior to methotrexate (“MTX”) and are even superior to edatrexate (“ETX”), a more recent clinical candidate. Moreover, 10-propargyl-10dAM showed a surprising ability to cure tumors such that there was no evidence of tumor growth several weeks after the cessation of therapy. Thus, highly purified composition containing 10-propargyl-10dAM can be used in accordance with the invention to treat tumors, including both solid tumors and leukemias. The composition is illustrated in the parent application for use in treatment of human mammary tumors and human lung cancer.
SUMMARY OF THE INVENTION
Preliminary clinical studies in humans have now been done which show both the efficacy of 10-propargyl-10dAM and a preferred dosage schedule for such treatments. In addition, it has now been determined that combinations of 10-propargyl-10-deazaaminopterin (preferably the highly purified forms, substantially free of 10-deazaaminopterin) with taxols exhibit synergistic effectiveness in the treatment of tumors. 10-propargyl-10-deazaaminopterin and a taxol in therapeutically effective amounts can be administered concurrently, one right after the other, or with a period of time in between.
REFERENCES:
patent: 5066828 (1991-11-01), Bey et al.
patent: 5286726 (1994-02-01), Bey et al.
patent: 5354751 (1994-10-01), DeGraw et al.
patent: 6100411 (2000-08-01), Ojima
Starling, et al., Cancer Chemotherapy Reports, Part 1, col. 58, No. 5, Sep./Oct. 1974.
J. I. DeGraw, W.T. Colwell, JR. Piper, F.M. Sirotnak, “Synthesis and Antiumor Activity of 10-Propargyl-10-deazaaminopterin”, J. Med. Chem., 1993, vol. 36, pp. 2228-2231.
Colwell William T.
DeGraw Joseph I.
Piper James R.
Sirotnak Francis M.
Kifle Bruck
Oppedahl & Larson LLP
Sloan-Kettering Institute for Cancer Research
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