Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-10-03
2002-10-08
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S649000
Reexamination Certificate
active
06462087
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel antitumor or anti-neoplastic agent, composition and treatment. More particularly, it is directed to compositions comprising a stilbene derivative and a platinum coordination compound, such as the drug Cisplatin. Such compositions have been discovered to be safe and highly effective anti-neoplastic agents and are thus useful for the prevention, amelioration, treatment or cure of neoplasms, cancer, and tumors, particularly malignant or solid tumors. These compositions may optionally include other therapeutic compounds or agents. The invention is also directed to methods of using a composition comprising a stilbene derivative and a platinum coordination compound, and to methods of co-administration of these compounds to prevent, ameliorate, treat, or cure neoplasms, cancer or tumors.
2. Discussion of the Background
There is a pronounced need for safe and more efficacious anti-tumor agents. While a wide variety of chemotherapeutic agents are presently used for the treatment, suppression and prevention of tumors, tumors may develop a resistance to such agents, especially highly malignant or solid tumors. Thus, tumor relapse is a common problem. Also, existing agents, even if effective, may be inconvenient to administer in effective dosages and have inadequate therapeutic indexes. Thus, patients may suffer from pain and other side-effects of their administration, especially from the administration of high doses of anti-tumor agents with relatively low potencies.
Platinum coordination compounds, such as Cisplatin and other diamino-platinum complexes, have been widely used in humans as chemotherapeutic drugs. The platinum coordination compound used in the present invention is such a compound which gives platinum preferably in an ionic form, and preferably is a compound exhibiting substantial anti-tumor activity, more preferably a platinum coordination compound exhibiting tumor cell proliferation preventative or inhibiting properties. Many platinum coordination compounds used in the present invention are commercially available or may be manufactured by known or routinely used techniques. However, these compounds are not therapeutically effective for all patients or all types of tumors. For instance, numerous attempts have been made to improve Cisplatin-based therapy by using Cisplatin in combination with other drugs. Although some attempts have achieved improvements in efficacy, these compositions were not sufficiently effective in treating tumors, reducing tumor burden, or in relieving the pain and other complications suffered by tumor patients. Thus, there is a need to discover other agents which together with a platinum coordination compound would be more efficacious in treating tumors.
Cisplatin or cis-diamminedichloroplatinum (II) has been successfully used for long as a chemotherapeutic drug in the therapy of various malignant tumors in the human being.
More recently, other diamino-platinum complexes have shown efficacy as chemotherapeutic drugs in curing various malignant tumors in the human being. Examples of the diamino-platinum complexes may be spiroplatinum and carboplatinum.
Cisplatin and other diamino-platinum complexes have been widely used as chemotherapeutic drugs in the humans. However, these are not therapeutically efficient for all patients or all sorts of tumors. In expectation of possibly increasing therapeutic efficacy, numerous attempts have been made towards using Cisplatin in combination with Vindesine, see Garalla, R. J. etal., Ann. Intern. Med. 95: 414-420 (1980) or using Cisplatin in combination with VP-16, see Congeval, E. et al., Cancer, 51: 2751-2756 (1982). Although such combined application has achieved certain improvement in the efficacy ratio, it cannot be said that the tumor burden or pains of tumor-bearing patients has been completely relieved by these measures.
Stilbene derivatives which have cis-stilbene as a fundamental skeleton, are known to strongly inhibit mitosis and cause cytotoxicity. However, existing stilbene derivatives have not been available or practical as pharmaceutical agents for a number of reasons, including their low solubilities in water.
Recently, certain stilbene derivatives which inhibit tubulin polymerization and having improved solubility in water have been investigated, for instance, the phosphorylated pro-drug Combretastatin-A4, see U.S. Pat. No. 5,561,122. Other stilbene derivatives having improved solubility in water have been proposed as drugs, such as those of the present Assignee as described for instance in Japanese Pat. Kokai Publications JP-A-7-228558 and JP-A-8-301831.While such stilbene derivatives are promising, alone they may exert insufficient anti-tumor activity. Thus, it is desired to enhance the antitumor efficacy and safety of compositions containing stilbene derivatives.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to develop a superior antitumor agent, specifically, to develop a pharmaceutical preparation which improves the efficacy of a stilbene derivative and, in particular, to develop and provide an antitumor agent exhibiting superior safety and anti-tumor efficacy for reducing the severity, preventing, treating or curing tumors and other neoplasms, particularly solid or highly malignant tumors.
The present inventors have persistently and methodically conducted research with the above objectives in mind in order to overcome the recognized problems of the prior art compounds and therapies. Through these efforts, it has been discovered that a stilbene derivative when administered together with a platinum coordination compound, such as Cisplatin, provide enhanced or synergistic anti-neoplastic or anti-tumor effects and significantly enhance the tumor-inhibiting properties of either or both compounds.
Addition of a stilbene derivative to a therapeutic platinum coordination compound can provide superior anti-neoplastic or anti-tumor effects compared to combinations of other chemotherapeutic drugs with a platinum coordination compound, such as Cisplatin. Such stilbene-containing compositions thus provide a chemotherapeutic drug higher in efficacy useful to treat tumor or cancer patients. For instance, enhanced or synergistic effects are achieved by employing a stilbene derivative in combination with platinum coordination compound, such as Cisplatin. Such compositions are used to more efficaciously and safely to treat or cure tumors and solid cancers.
The present inventors have found that, by combining a stilbene derivative, most preferably one having in-vitro tubulin polymerization inhibiting activity with a platinum coordination compound such as Cisplatin, it is possible to completely cure tumors and prevent decreases in body weight. For instance, it is demonstrated that the present invention cures mice of malignant engrafted tumors. These studies show that the inventive compositions are highly effective chemotherapeutic agents against cancer and tumors, and thus may find successful application for treating or curing various solid cancers or tumors, such as pulmonary or lung cancer.
Vincristine, Vindesine, and Vinblastine are examples of currently known therapeutic agents having tubulin polymerization inhibiting activities. These agents are used for treatment of solid cancers in multi-drug or polypharmacy therapeutic approaches. They may be used in combination with drugs such as Cisplatin. However, complete curing of tumors in mice has not been observed after simultaneous administration of Vindesine and Cisplatin. Further, the combination of Vindesine and Cisplatin is shown to result in significant decreases in body weight, and thus such combinations may be toxic and unsafe.
On the other hand, the inventive combination of Cisplatin and a stilbene derivative results in complete curing of tumors in mice and this effect is attributed to -the combined, enhanced or synergistic action of the compositions of the present invention. Further, combinations of a stilbene derivative and Cisplatin have im
Morinaga Yoshihiro
Nihei Yukio
Ohishi Kazuo
Okano Akira
Suga Yasuyo
Ajinomoto Co. Inc.
Goldberg Jerome D.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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