MXPA99005173A - Treatment of highly vascular tumours - Google Patents

Abstract

This invention relates to the treatment of patients suffering from highly vascular tumours, and provides a method of treatment for patients suffering from Kaposi's sarcoma, which comprises administering dextrin sulphate to the patient. The treatment results in regression of the tumours and the improvement persists for a considerable time after completion of the treatment.

Description

TREATMENT OF HIGHLY VASCULAR TUMORS DESCRIPTIVE MEMORY This invention relates to the treatment of patients suffering from highly vascular tumors. Such tumors have an extensive formation of well formed and malformed new blood vessels, with numerous capillaries and longer channels that are composed mainly of an endothelium layer supported by cells of different types (eg, small spindle cells, plasma cells, lymphocytes) that can be abnormal. The invention is particularly directed to a condition that is known as Kaposi's sarcoma. A sarcoma is a malignant tumor of connective tissue of mesenchymal origin. The condition known as Kaposi's sarcoma (KS) is a multifocal, reactive, vascular proliferation that, in turn, may acquire some of the characteristics associated with a malignant tumor. Kaposi's sarcoma is usually seen in immunosuppressed patients and occurs in various clinical forms, which include: (i) Sporadic Kaposi's sarcoma (classic). This was the first form of Kaposi's sarcoma that was observed. It was observed many years ago (by Kaposi) in Jewish communities in Eastern Europe. (ii) Endemic Kaposi's sarcoma (African). It occurs in the region of Africa that is below the Sahara. (iii) Epidemic Kaposi's sarcoma (AIDS). It occurs in patients with AIDS. (iv) iatrogenic Kaposi's sarcoma. It occurs mainly in transplant patients who have received immunosuppressive medications. Until now, it was not possible to establish the clear biological or histopathological differences that would serve to explain these different clinical and pathological forms of Kaposi's sarcoma. The evolution of Kaposi's sarcoma of both skin and lymphadenopathy from early angiomatous lesions to the plaque and nodular stages of Kaposi's sarcoma are characterized by a progressive increase in the number of spindle cells. The highly vascular nature of this tumor may suggest that it develops from an aberrant lymphatic-venous connection that, in early vascular lesions, is covered by cells that are phenotypically similar to the lymphatic epithelium. However, there are still questions about the histocytogenic origin of fusiform cells and the pathogenic factors that lead to the proliferation of these cells during the evolution of Kaposi's sarcoma. These questions revolve around whether the Kaposi's sarcoma lesion constitutes a malignant clonal proliferation or a hyperproliferative "reactive" response to a stimulus or unknown stimuli. It is possible that the proliferation of mixed cells is produced by a minority of tumor cells that have constitutive or aneuploid genetic abnormalities. The heterogeneity of proliferating cells in a Kaposi sarcoma lesion suggests a complex network of cell stimulation in the case of spindle cells derived from Kaposi's sarcoma that have been cultured in vitro, it has been shown that various cytokines with autocrine growth properties and paracrine (for example, beta-FGF, IL-1, GM-CSF, platelet-derived growth factor, and oncostatin-M) cause local angiogenesis in the skin in an assay with hairless mice and on a choriolantoic membrane. Current clinical approaches to Kaposi's sarcoma treatments have found that early skin lesions respond to radiation therapy. But the most severe and widespread disease requires treatment with cytotoxic chemotherapeutic agents such as doxorubicin, vincristine and bleomycin which must be administered intravenously. These treatment regimens are often associated with severe clinical toxicity in already weak and immunosuppressed patients. Neutropenia is one of the most common reasons for stopping cycles of chemotherapy during the course of treatment of Kaposi's sarcoma with anthracyclic drugs (for example, adriamycin). More recently, administration of liposomal preparations of daunorubicin and doxorubicin has also resulted in a rapid regression of Kaposi's sarcoma lesions. For those Kaposi sarcoma lesions seen in patients with iatrogenic immunosuppression, the tumor returns when the degree of immunosuppression is reduced. The number of cases of Kaposi's sarcoma related to AIDS has increased greatly in recent years. It has been postulated that the growth of the fusiform cell of Kaposi's sarcoma in vitro and in vivo may be modulated by HIV-1. However, both immunohistochemistry for HIV-1 proteins and PCR for HIV-1 DNA have not found any evidence that HIV-1 is found in the population of spindle cells of Kaposi's sarcoma lesions. epidemic In addition, the treatment of Kaposi's sarcoma lesions is performed with drugs known to substantially reduce the HIV-1 viral load in the blood, such as zidovudine (AZT), didanosine (ddl) and / or zalcitabine (dd) , does not result in regression or relief of Kaposi's sarcoma lesions. Thus, it seems that Kaposi's sarcoma is not caused simply by the presence of HIV-1, particularly because Kaposi's sarcoma can appear in patients who do not show signs of that virus. Obviously, therefore, the fact that it is known that a drug has an anti-HIV activity is not an indicator that it is useful for the treatment of Kaposi's sarcoma. It has been discovered that the administration of dextrin sulfate in patients who have highly vascular tumors, in particular lesions of Kaposi's sarcoma, results in the regression of the tumors.

The present invention provides a method of treating a patient having a highly vascular tumor, especially Kaposi's sarcoma, which comprises administering dextrin sulfate to the patient. Dextrin sulfates are known compounds. They are produced by the sulfation of dextrin, which are mixtures of glucose polymers produced by hydrolysis of starch. These glucose polymers have a wide polymerization margin. The degree of polymerization (G.P.) varies from 1 (monomer, glucose) to very high values, for example up to hundreds of thousands or more glucose units. Typically, the direct result of the hydrolysis of a starch is a dextrin which contains a high proportion of polymers of relatively low molecular weight and may contain, for example, up to 60% by weight of glucose polymers of G.P. less than 12. The dextrin sulfates which are used in the present invention may have a wide range of composition, but preferably are dextrin derivatives containing at least 50% by weight, preferably more than 90%, of higher glucose polymers of 12, and / or containing less than 10%, preferably less than 5%, by weight of the GP glucose polymers less than 12. The weight average molecular weight of dextrin may be, for example, between 10,000 and 35,000, preferably between 15,000 and 25,000. (The technique used to determine the molecular weight of dextrin is a high-pressure liquid chromatography using chromatographic columns calibrated to dextran standards, as indicated in Alsop et al., J. Chromatography 246, 227-240 (1989). Preferably, the dextrin contains no more than 10%, preferably less than 5%, by weight of polymers of molecular weight greater than 40,000.The desired average molecular weight in weight and polymer profile is achieved by subjecting a dextrin to fractionation, using known techniques , including solvent precipitation and membrane fractionation Among the dextrins from which the dextrin sulfates suitable for use in the present invention can be derived are those described in the specifications of European Patent No. 115911, 153164 and 207676. Dextrin sulfates have been used pharmaceutically previously, for example, the British patent specification 8 71, 590 describes the use of certain dextrin sulfates as anti-lipemic agents, and U.S. patent specification 5,439,892 describes the use of certain dextrin sulfates as anti-HIV agents. These references also describe the processes for the production of dextrin sulfates; This document incorporates descriptions by reference. The Scandinavian Journal of Immunology, Volume 29 (2) p. 181-92, 1989 describes the regression of a tumor after a treatment with aminated β1-3D polyglucose. In the method of the invention dextrin sulfate can be administered to the patient by any route, enteral or parenteral, at the discretion of the physician. The intraperitoneal administration is particularly effective, but dextrin sulfate for example, can also be administered orally or intravenously, or injected directly into the lesions of the tumor at a lesion base by injury, or it can be applied topically. The dose level should be determined by the doctor. The dextrins can be sulphated at positions 2, 3 and 6, and therefore a sulfated dextrin completely contains three sulfate groups per glucose unit. The dextrin sulfate which is used in the present invention can have any degree of sulfation, but preferably contains at least two sulfate groups per glucose unit, most preferably from 0.5 to 1.5. Also, dextrin sulfate is preferably dextrin 2-sulfate, dextrin 6-sulfate or a mixture thereof. The following example is provided by way of illustration of this invention.

EXAMPLE A composition was prepared for use in the administration of dextrin sulfate intraperitoneally in the form of a sterile aqueous solution containing: Dextrin sulfate 100 micrograms / ml Mix of glucose polymer 10 grams / liter Na 132 mmoles / liter Ca 1.75 mmoles / liter Mg 0.75 mmoles / liter Lactate 35 mmoles / liter The dextrin sulfate was dextrin 2-sulfate, prepared as described in Example 3 of the U.S. Patent 5,439,892. The glucose polymer mixture, present in the solution as an osmotic agent, was the glucose polymer mixture described in Example 2 of European specification 153164; contained 91.9% polymers with G.P. greater than 12, and 7.9% polymers with G.P. from 2 to 10, and with an average molecular weight of 23,700. The above solution was administered intraperitoneally to three patients with widely disseminated Kaposi multifocal sarcoma and in an advanced stage of AIDS. 1.5 liters of the solution was administered daily in the peritoneal cavity of the patient through a resident catheter. The solution was left in the peritoneal cavity for twenty-four hours, then replaced by fresh solution. That treatment was continued for thirty days. Regression of Kaposi's sarcoma lesions was observed. This response to treatment was observed both on the skin and on mucous membranes (ie, inside the mouth) with lesions. The response was slow and occurred over a period of months, even though the treatment period was only thirty days. The improvement of the patient's condition, which received no further treatment, persisted for a considerable time. So far, there are no formally accepted criteria for the stages of Kaposi's sarcoma. However, the improvement in the patient's condition was evaluated in accordance with the guidelines issued by the AIDS Clinical Triais Group Oncology Committee (oncology committee, clinical trial group on AIDS), which suggests the following criteria: (a) Nodular lesions become flat. (b) the color of the lesions is obscured (ie, mallow) (c) the epithelium is desquamated (d) the edema associated with the tumor resolves (e) the lymphedema is resolved (f) the lesions alleviated develop a halo brown / skin color (g) Previously ulcerated areas of large lesions of Kaposi's sarcoma that had not yielded to any other form of current therapy have healed. In the case of the three patients treated as described in the previous relief process, it was slow and took months instead of weeks. During the last phase of the process of relief of the lesions that were present before the start of the administration of dextrin sulfate, the appearance of new lesions was observed. However, they were morphologically different from those that had been observed before treatment in that they were very small (measured in millimeters instead of centimeters), pink and flat. Also, they grew very slowly and were sometimes associated with a small number of satellite lesions. This is an unusual presentation of Kaposi's sarcoma in patients in advanced stages of AIDS. In the previous example, dextrin sulfate was administered to the patients in a transporting solution that was removed from the peritoneal cavity of the patients and replaced with fresh solution daily. Other treatment regimens are also feasible, also using intraperitoneal administration. If the transporter solution is left inside the peritoneal cavity, and is not removed, the body removes it from the peritoneal cavity, mainly towards the lymphatic circulation. A complete elimination is normally carried out in approximately forty-eight hours. Therefore, it is possible to use treatment regimens where the removal step of carrier liquid in the patient is omitted; for example, (a) dextrin sulfate can be administered daily in a volume of liquid transporter comparable with the volume of daily elimination, or (b) dextrin sulfate can be administered to the patient at a frequency less than daily, perhaps two or three times a week, depending on the elimination rate. Because the etiology and pathogenesis of Kaposi's sarcoma has not been understood, the mechanism of action of dextrin sulfate in Kaposi's sarcoma lesions is not yet known. Therefore, the ideal treatment regimen remains to be determined and certainly varies from patient to patient. However, as is evident from the previous example, dextrin sulfate does not have to be continuously present to show improvement of Kaposi's sarcoma. Therefore, it may be suitable for patients receiving dextrin sulfate less frequently than on a daily basis, perhaps once a week.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of dextrin sulfate in the manufacture of a drug to treat a highly vascular tumor.

2. The use of dextrin sulfate according to claim 1, further characterized in that said highly vascular tumor is Kaposi's sarcoma.

3. The use of dextrin sulfate according to claim 1, further characterized in that the dextrin sulfate is derived from a dextrin having at least 50% by weight of glucose polymers of G.P. greater than 12.

4. The use of dextrin sulphate according to any of claims 1 to 3, further characterized in that the dextrin sulfate is derived from a dextrin having more than 90 wt.% glucose polymers of G.P. greater than 12.

5. The use of dextrin sulfate according to any of claims 1 to 4, further characterized in that the dextrin sulfate is derived from a dextrin which contains less than 10% by weight of glucose polymers of G.P. less than 12.

6. The use of dextrin sulfate according to claims 1 to 4, further characterized in that the dextrin sulfate is derived from a dextrin which contains less than 5% by weight of glucose polymers of G.P. less than 12.

7. The use of dextrin sulfate according to any of claims 1 to 6, further characterized in that the dextrin sulfate is derived from a dextrin having an average molecular weight weight of 10,000 to 35,000 preferably 15,000 to 25,000.

8. The use of dextrin sulfate according to any of claims 1 to 6, further characterized in that the dextrin sulfate is derived from a dextrin which contains less than 10% by weight of glucose polymers of molecular weight greater than 40,000. .

9. The use of dextrin sulfate according to any of claims 1 to 6, further characterized in that the dextrin sulfate is derived from a dextrin which contains less than 5% by weight of glucose polymers of molecular weight greater than 40,000. .

10. The use of dextrin sulfate according to any of claims 1 to 9, further characterized in that the dextrin sulfate contains at most two sulphate groups per unit of glucose.

11. The use of dextrin sulphate according to claim 10, further characterized in that the dextrin sulfate contains between 0.5 and 1.5 sulfate groups per glucose unit.

12. The use of dextrin sulphate according to any of claims 1 to 11, further characterized in that the dextrin sulfate is dextrin 2-sulfate or dextrin 6-sulfate or a mixture thereof.