Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-10-24
2002-06-18
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S693000, C514S699000
Reexamination Certificate
active
06407071
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method and composition for treating malignant cells.
BACKGROUND OF THE INVENTION
Control of cell growth is one of the most important aspects of an animal's physiology. The cells of an adult must divide frequently enough to allow tissues to remain in a steady state, and division must be stimulated at wounds or when special requirements are placed on the tissues. There must be many circulating cell-specific factors that signal individual cell types whether to divide or not. However, uninhibited cell growth results in malignant tumors.
One of the greatest problems associated with treatment of cancers is delivery of a cytotoxic agent directly to the tumor or cancer cells without affecting normal cells of the body. Although it was hoped that monoclonal antibodies could be used as delivery agents for cytotoxic drugs to treat cancers and to inhibit metastasis of existing cancers, monoclonal antibodies have not lived up to their promise. One reason for this is that there is a very high density of receptors on the surface of cancer cells. Since monoclonal antibodies are relatively large compounds, it is impossible to provide sufficient amounts of monoclonal antibodies at the cell surface to effectively destroy the cells. In other words, the monoclonal antibodies are so large that only a very few can be present at the surface of a cell at any one time.
There have been many reports in the literature relating to the general concept of providing direct transport of an agent which is toxic to tumor cells directly to tumors having &bgr;-glucuronidase activity by conjugating the agent with glucuronic acid. Among such reports are Von Ardenne et al.,
Agressologie,
176(5):261-264 (1976); East German Patent No. 122,386; German Offenlegungsschrift 22 12 014; Sweeney et al.,
Cancer Research,
31:477-478 (1971); Baba et al.,
Gann,
69:283-284; and Ball,
Biochem. Pharm.,
23:3171-3177 (1974).
Von Ardenne et al. suggest many types of aglycones which may be conjugated to glucuronic acid and will be active at the tumor site. These include, broadly, alkylating groups, antimetabolites, cytotoxins, membrane-active (lytic) groups, glycolysis stimulators, respiration inhibitors, inorganic and organic acids, and cell cycle stoppers. East German Patent No. 122,386 also suggests many such combinations, including 5-fluorourcil-glucuronide, aniline mustard-glucuronide, and many others. German offenlegungsschrift also mentions a large number of glucuronides. Sweeney et al. disclose the anti-tumor activity of mycophenolic acid-&bgr;-glucuronides. Baba et al. note the antitumor activity of 5-fluorouracil-O-&bgr;-D-glucuronide, and Ball discloses the anti-tumor activity of p-hydroxyaniline mustard glucuronide.
Kneen, in European Patent application 054,924, discloses phenyl ether compounds which can be used to make tumors more sensitive to radiotherapy.
Rubin, in U.S. Pat. Nos. 4,337,760 and 4,481,195, discloses methods for treating tumors having high &bgr;-glucuronidase activity with glucuronides with aglycones toxic to the tumor cells while protecting the rest of the body by first administering an alkalizing agent in an amount sufficient to maintain the pH level of non-tumor tissues at approximately 7.5 during the glucuronide treatment to inactivate &bgr;-glucuronidase activity in the rest of the body. Thus, the toxic agent is released only at the cancer cells, rather than to all of the healthy cells of the body, since the aglycone is only released at the site of the cancer. Tumors having high glucuronidase activity can be identified by assaying tumor cells obtained in a biopsy for &bgr;-glucuronidase activity, or by administering a glucuronide whose aglycone has been labelled with a radioactive isotope. If, upon a full body scan, it is found that the radioisotope has accumulated at any specific areas of the body, this will indicate not only the location of the tumor but the fact that the tumor has sufficient &bgr;-glucuronidase activity to deconjugate the glucuronide.
Rubin, in U.S. Pat. Nos. 5,649,737 and 5,476,842 discloses a variety of other compositions and methods of treating cancer cells using the high &bgr;-glucuronidase activity of many malignant cells. All of these patents are hereby incorporated in their entirety by reference.
Para-methoxy phenol, or 4-hydroxy anisole, has been used for treating melanoma because the only cells in vertebrates that contain tyrosinase are melanocytes. 4-Hydroxyanisole inhibits DNA synthesis, but by itself shows little toxicity. However, 4-hydroxyanisole is oxidized by tyrosinase to form highly cytotoxic products, and consequently, 4-hydroxyanisole is preferentially toxic to those melanoma cells that contain the enzyme tyrosinase [Riley,
Phils. Trans. R. Soc.
(
Biol.
), 311: 679, (1985)]. Morgan et al., in
Clinical Oncology,
7:227-231, (1981), also noted that 4-hydroxyanisole, which is oxidized by tyrosinase, gives rise to cytotoxic oxidation products. The specific melanocytotoxic action of this agent is of particular interest because of its use in treatment of malignant melanoma. It was found that localized malignant melanomas treated by intra-arterial infusion of 4-hydroxyanisole underwent regression, although intravenous administration of the drug was not therapeutically effective. The need to use the intra-arterial route of administration imposes certain limits on the use of 4-hydroxyanisole, since it is not always possible to perfuse the site occupied by a tumor. However, it is believed that, as an adjunct to the conventional treatment of primary melanoma in accessible sites, 4-hydroxyanisole infusion will reduce the dissemination of metastases.
Kanclerz et al., in
Br. J. Cancer,
54:693-698 (1986), reported that animal studies on experimental melanomas have yielded variable results with respect to the therapeutic efficacy of phenolic depigmentation agents. The most active melanocytotoxic agent was found to be an analog of tyrosine, 4-hydroxyanisole. However, evidence for an antitumor effect of 4-hydroxyanisole on melanoma in vivo was found to be variable and not conclusive.
Unfortunately, intra-arterial infusion of 4-hydroxyanisole has serious clinical drawbacks, including difficulties in placing and maintaining the patency of intra-arterial catheters. Clogging and/or clotting frequently occurs, and, furthermore, 4-hydroxyanisole has a short half life in blood, only about nine minutes, following intra-arterial injection.
Saari, in U.S. Pat. No. 4,812,590, discloses that certain carbamates of 4-hydroxyanisole are suitable substitutes for 4-hydroxyanisole in melanoma treatment. These carbamates can be delivered by, for example, intravenous injection, and provide increased levels of 4-hydroxyanisole at the tumor site. This delivery of 4-hydroxyanisole is more convenient and is safer than many other methods for delivering 4-hydroxyanisole. However, because serum tyrosinase levels may be elevated in patients having tumors with high tyrosinase activity, the metabolic products of 4-hydroxyanisole may be present in locations other than the tumor site.
Pavel et al., in
Pigment Cells Research,
2:241-241 (1999), reported an investigation of the human metabolism of 4-hydroxyanisole using urine samples from melanoma patients treated with 4-hydroxyanisole. The most important metabolite of 4-hydroxyanisole was found to be 3,4-dihydroxyanisole, although other metabolic products included 3-hydroxy-4-methoxyanisole and 4-hydroxyanisole-3-methoxyanisole, as well as quinone. These compounds were excreted predominantly as sulfates and glucuronides. Unfortunately, when tyrosinase oxidizes 4-hydroxyanisole in the body, the product, 4-methoxybenzoquinone, is extremely toxic. Because the 4-hydroxyanisole is not confined to the tumor site, and because the serum level of tyrosinase of patients suffering from tyrosinase-active tumors tends to be elevated, there is always the danger in administering 4-hydroxyanisole to such patients that an excess of the metabolic products of 4-hydroxyansole will be present in
Browdy and Neimark
Co-Enzyme Technology Ltd.
Peselev Elli
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