Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1995-05-09
1998-03-17
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514151, 514183, 514256, 514274, 514275, 514449, 514245, A61K 31335
Patent
active
057286876
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to combinations of taxol, Taxotere and their analogues and substances which are therapeutically useful in the treatment of neoplastic diseases.
BACKGROUND OF THE INVENTION
Taxol, Taxotere and their analogues, which possess noteworthy antitumor and antileukaemic properties, are especially useful in the treatment of cancers of the ovary, breast or lung.
The preparation of taxol, Taxotere and their derivatives form the subject, for example, of European Patents EP 0,253,738 and EP 0,253,739 and International Application PCT WO 92/09,589.
Generally, the doses used, which depend on factors distinctive to the subject to be treated, are between 1 and 10 mg/kg administered intraperitoneally or between 1 and 3 mg/kg administered intravenously.
DESCRIPTION OF THE INVENTION
It has now been found, and this forms the subject of the present invention, that the efficacy of taxol, Taxotere and their analogues may be considerably improved when they are administered in combination with at least one substance which is therapeutically useful in anticancer treatments and has a mechanism identical to or different from this of taxane derivatives.
Among substances which may be used in association or in combination with taxol, Taxotere or their analogues, there may be mentioned alkylating agents such as cyclophosphamide, isosfamide, melphalan, hexamethylmelamine, thiotepa or dacarbazine, antimetabolites such as pyrimidine analogues, for instance 5-fluorouracil and cytarabine or its analogues such as 2-fluorodeoxycytidine, or folic acid analogues such as methotrexate, idatrexate or trimetrexate, spindle poisons including vinca alkaloids such as vinblastine or vincristine or their synthetic analogues such as navelbine, or estramustine or taxoids, epidophylloptoxins such as etoposide or teniposide, antibiotics such as daunorubicine, doxorubicin, bleomycin or mitomycin, enzymes such as L-asparaginase, topoisomerase inhibitors such as camptothecin derivatives chosen from CPT-11 and topotecan or pyridobenzoindole derivatives, and various agents such as procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin or carboplatin, and biological response modifiers or growth factor inhibitors such as interferons or interleukins.
Moreover, since the activity of the products depends on the doses used, it is possible to use higher doses and to increase the activity while decreasing the toxicity phenomena or delaying their onset by combining growth factors of the haematopoietic type such as G-CSF or GM-CSF or certain interleukins with taxol, Taxotere, their analogues or their combinations with other therapeutically active substances.
The combinations or associations according to the invention enable the phenomena of pleiotropic resistance or "multi-drug resistance" to be avoided or delayed.
More especially, the invention relates to combinations of taxol, Taxotere and their analogues with vinca alkaloids, cyclophosphamide, 5-fluorouracil, doxorubicin, cisplatin and etoposide.
The improved efficacy of a combination according to the invention may be demonstrated by determination of the therapeutic synergy.
The efficacy of a combination according to the invention may also he characterized by adding the actions of each constituent.
A combination manifests therapeutic synergy if it is therapeutically H. CORBETT et al., Cancer Treatment Reports, 66, 1187 (1982)!.
To demonstrate the efficacy of a combination, it may be necessary to compare the maximum tolerated dose of the combination with the maximum tolerated dose of each of the separate constituents in the study in question. This efficacy may be quantified, for example by the log.sub.10 cells killed, which is determined according to the following formula: mean time in days for the tumours of the treated group (T) and the tumors of the treated group (C) to have reached a predetermined value (1 g for example), and T.sub.d represents the time in days needed for the volume of 40, 2660.2680 (1977); F. M. SCHABEL et al., Cancer Dr
REFERENCES:
patent: 5262409 (1993-11-01), Margolis et al.
patent: 5494683 (1996-02-01), Liversidge et al.
Krass Frederick
Rhone-Poulenc Rorer S.A.
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