MXPA00003655A

MXPA00003655A - Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds

Info

Publication number: MXPA00003655A
Application number: MXPA/A/2000/003655A
Authority: MX
Inventors: Ralph M Ellison; Fred H Mermelstein
Original assignee: Polarx Biopharmaceuticals Inc
Priority date: 1997-10-15
Filing date: 2000-04-14
Publication date: 2001-12-04

Abstract

The invention relates to the use of arsenic compounds to treat a variety of neoplastic diseases (see the dose response curves in the Figure). Further, the arsenic compounds may be used to treat metastatic neoplastic diseases.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF PRIMARY AND METASTASIC NEOPLASTIC DISEASES USING COMPOUNDS OF ARSENIC 1. FIELD OF THE INVENTION The present invention relates to methods and compositions for the treatment of primary and metastatic neoplastic diseases, including, but not limited to, these diseases, sarcomas, carcinomas and human hematopoietic disorders. In the practice of cancer treatment, compositions containing arsenic compounds are used to arrest and reverse neoplastic growth. More specifically, the present invention relates to novel chemotherapeutic methods - novel uses of arsenic compounds for the treatment of primary and metastatic tumors; primary and metastatic tumors of the central nervous system; refractory primary and metastatic tumors of the central nervous system; breast, lung, bladder and prostate cancer; Breast, lung, bladder and prostate cancer refractory to mention a few. 2. ATTACHMENTS OF THE INVENTION In 1997, more than one million people will develop some type of cancer in the United States of America.

Approximately 500,000 will be cured or in a state of remission. These figures represent an improved cure rate compared to the last decade that is largely due to earlier detection, better treatment and progress in chemotherapy. Particularly, advances in chemotherapy include specific pharmacological therapy and focused on where a drug is developed specifically for the treatment of a certain type of cancer. This "disease-oriented" approach is designed to identify compounds that exert selective effects in vitro on particular types of tumors and to monitor these advances in vivo using cell lines (Fiebig et al., Cancer Treatment Reviews 17: 109-117 (1990)). However, the incidence of cancer continues to grow as our population ages and as new cancers develop or occur more frequently, such as in the case of patients infected with the AIDS virus. Thus, it is clear that there is a significant demand for additional regimens to treat patients with cancer. 2.1 Cancer pathobiology Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic spread or in the blood of malignant cells to regional lymph nodes and towards distant sites (metastasis). Clinical data and molecular biological studies indicate that cancer is a multi-stage process that begins with minor preneoplastic changes, which can, under certain conditions, progress to a neoplasm. The growth of abnormal premalignant cells is exemplified by hyperplasia, metaplasia, or more particularly, dysplasia (for a review of such abnormal growth conditions, see Robbins and Angeli, 1976, Basic Pathology, 2nd Edition, WB Saunders Co., Philadelphia, pages 68-79). Hyperplasia is a form of controlled cell proliferation that involves an increase in the number of cells in a tissue and organ, without significant alteration of structure or function. Only by way of example, endometrial hyperplasia frequently precedes endometrial cancer. Metaplasia is a form of controlled cell growth where one type of adult or totally differentiated cell replaces another type of adult cell. Metaplasia can occur in cells of epithelial or connective tissue. An atypical metaplasia involves a relatively disorderly metaplastic epithelium. Dysplasia is often a precursor to cancer and is found mainly in the epithelia; it is the most disordered form of non-neoplastic cell growth, involving a loss of uniformity of individual cells and the architectural orientation of the cells. Dysplastic cells often have abnormally large nuclei, deeply tinged, and show pleomorphism. Dysplasia characteristically occurs when there is chronic irritation or inflammation, and is frequently found in the cervix, respiratory passages, oral cavity, and gallbladder. The neoplastic lesion can evolve clonally and develop an increased capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape surveillance of the host's immune system (Roitt, I., Brostoff, J and Kale, D., 1993, Imology, 3rd edition, Mosby, St. Louis, pages 17.1-17.2). 2.2 Non-Hodgkin lymphoma related to AIDS Since the discovery of AIDS, the disease has had a close relationship with an interesting spectrum of cancers.

In addition, the types of diseases and their incidence rates are growing as the development of effective antiretroviral therapies and prophylactic treatments against opportunistic infections cause a prolonged survival in the immunodeficient state in the case of patients with AIDS (Karp and Broder, Cancer Res. 51: 4747-4756 (1991)). Non-Hodgkin's lymphoma related to AIDS was found in patients with AIDS only after 1981. Non-Hodgkin's lymphoma related to AIDS is a very aggressive disease with a very high incidence of involvement of the central nervous system. It is growing in its incidence in the population with AIDS. As patients infected with the AIDS virus live longer because they are not dying from common infections, they are developing lymphoma at an increasing rate. The characteristics of AIDS-related non-Hodgkin's lymphoma are detailed in an article by Karp and Broder, (1991), supra. The problems faced by the oncologist when treating patients with AIDS-related lymphomas is the predilection recently described in the sense of the occurrence of lymphoma in the central nervous system (in the brain and surrounding meninges) and the fact that the patient with AIDS You have a very weak bone marrow that can not tolerate a standard chemotherapy treatment. This complicates the treatment of lymphoma in patients with AIDS because standard chemotherapeutic agents are usually very suppressive of the bone marrow and do not cross the blood-brain barrier (to treat central nervous system disease). 2.3 Primary and metastatic central nervous system tumors The incidence of primary and metastatic brain tumors is growing in the United States of America. In fact, the arsenal of chemotherapeutic agents for these types of cancers is minimal while the need for such therapeutic agents is high. Glioblastoma multiforme and other primary and metastatic tumors of the central nervous system are devastating diseases. The treatment of these tumors includes surgical intervention, radiation therapy and treatment with agents such as BCNU nitrosurea. Other chemotherapeutic agents employed include procarbazine, vincristine, hydroxyurea and cisplatin. Unfortunately, even when these three modalities are used (surgical intervention, radiation therapy, and chemotherapy) the average survival of patients with central nervous system cancers is only about 57 weeks. Clearly, new therapeutic approaches are required both for patients with newly diagnosed and metastatic primary central nervous system tumors, as well as for patients with such tumors who are refractory to the modalities presented above. The discovery of novel agents of this type has been complicated by the fact that there is no animal model that seems to predict which agent will be clinically effective against primary and metastatic tumors of the central nervous system. 2.4. Breast, lung, bladder and prostate cancers It is known that breast cancer occurs in approximately one of 8-9 women in the United States of America. Treatment for initial breast cancer is surgical intervention, with or without radiation therapy, or surgical intervention, with or without radiation therapy, plus chemotherapy and / or hormone therapy. Despite the best efforts of doctors there are still more than 80,000 deaths each year caused by breast cancer and the incidence continues to increase. Current chemotherapy for patients with primary or etastatic breast cancer includes treatment with cyclophosphamide, methotrexate, doxorubicin, 5-fluorouracil, cisplatin, vinblastine, taxol, taxotere, mitomycin C, and occasionally other agents. Unfortunately, even with these agents, almost all women who develop metastatic breast cancer die. A particular place where metastatic breast cancer metastasizes is the central nervous system. When metastases occur in the central nervous system, the usual treatment is surgical intervention (in the case of a solitary metastasis) or radiation, or surgical intervention plus radiation therapy. Currently there is no chemotherapy that can help in this situation. Lung cancer is responsible for more than 150,000 deaths each year in the United States of America. Most patients with lung cancer have a tumor that has already metastasized to several organs, including the lung, liver, adrenal gland, and other organs. Current treatment for metastatic lung cancer is not yet standardized (Ihde, Daniel C, "Chemotherapy of Lung Cancer", The New England Journal of Medicine 327: 1434-1441, November 1992, 12th issue). However, regimens with chemotherapy that are used include treatment with cisplatin plus etoposide, combinations of cyclophosphamide plus doxorubicin plus cisplatin, and single agents alone or in combination, including ifosfamide, teniposide, vindesine, carboplatin, vincristine, taxol, nitrogen mustard, methotrexate, hexamethylmelamine and others. Despite these chemotherapeutic regimens, the average patient with metastatic lung cancer survives only for 7-12 months. A particularly worrisome place for lung cancer metastasis is the central nervous system. Treatment of central nervous system metastases includes surgical intervention (to remove a solitary lesion), radiation therapy, or a combination of both. Unfortunately - there is no standard chemotherapy that can help in this situation. Each year approximately 11,000 patients die of bladder cancer in the United States of America. Even when, when the disease occurs, it is usually localized, most patients develop distant metastatic diseases. The most recent advances have been in the area of chemotherapy for patients with metastatic disease of this type. An effective regime is known as the MVAC regime. It consists of treatment with methotrexate plus vinblastine plus adriamycin (doxorubicin) plus cisplatin. Even when the response rate is high to this chemotherapeutic regimen, oncologists are observing that one place that presents problems with metastases is the central nervous system. Unfortunately, there is no standard therapy that can help in this situation. It is estimated that more than 100,000 men will be diagnosed with prostate cancer this year and more than 30,000 patients will die of the disease. The most common sites of metastasis in patients with prostate cancer are the bones and lymph nodes. Metastases in bones are particularly worrisome insofar as they can cause severe pain to the patient. Current treatment for metastatic prostate cancer includes treatment with flutamide, leuprolide, diethylstilbestrol and other hormonal manipulations, as well as chemotherapy (doxorubicin, estramustine phosphate, vinblastine, suramin, cisplatin, and others). Unfortunately, none of these agents consistently helps in the case of this disease. In addition, since patients with prostate cancer live longer with their disease, they are more likely to develop a higher incidence of metastasis to the central nervous system (including spinal cord). In general, as patients live longer with common cancers such as breast cancer, lung cancer, bladder cancer, prostate cancer, and several other cancers (due to control of their systemic disease with surgical intervention, radiation and chemotherapy), oncologists are observing that patients are developing an increasing incidence of metastatic tumors in the central nervous system, including the brain. This is probably due to the fact that the majority of chemotherapies currently available do not cross the blood-brain barrier. When the patient (who has his tumor controlled in places outside the brain) develops brain metastasis, it is a very difficult situation. The options for this patient are usually limited to surgical intervention in the case of a solitary metastasis and / or radiation therapy. However, when these modalities fail, usually the patient has no other options. For each of the aforementioned indications (primary tumors of the brain and metastases to the brain from other common tumors such as breast, lung, bladder and prostate cancers), there is a strong need for more effective treatment and / or more effective methods to improve the quality of the patient. 2.5 Esophageal cancer In the United States of America, carcinoma of the esophagus accounts for approximately 6% of all cancers of the gastrointestinal tract but causes a disproportionate number of deaths from cancer. (Boring, C.C., et al .: Cancer statistics, 1993. CA Cancer J. Clin 43: 7, 1993). These cancers usually arise from the epithelial layer of the esophagus and are either squamous cell carcinomas or squamous cell adenocarcinomas. Overall, survival at 5 years is approximately 5%. Squamous cell carcinoma usually occurs after age 50 and is more common in men than in women. The incidence varies greatly from country to country and between regions within the same country. In the United States of America, the incidence is between 2 and 8 people per 100,000 inhabitants and is more prevalent in blacks than in whites. Adenocarcinoma accounts for 25% of all esophageal cancers in the United States of America. It is usually located in the distant third of the esophagus and may invade the adjacent gastric cardia. It tends to occur in people over 40 and is more common in men than in women. It is more common in whites than in blacks. 2.6 Arsenic and its uses in medicine Arsenic has long been considered a poison and a drug in both Western and Chinese medical practices. In the latter part of the 19th century, arsenic was frequently used in attempts to treat blood diseases in the western world. In 1873, it was reported that the treatment of a patient affected by leukemia with a solution of Fowler (a solution of potassium arsenite) markedly reduced the white blood cell count (Cutler and Bradford, Am. J. Med. Sci., January of 1878, 81-84). Additional interests in the use of Fowler's solution as a palliative agent to treat chronic myelogenous leukemia (CML) was described by Forkner and Scott in 1931 (J. Am. Med. Assoc. 1931, iii, 97), and was later confirmed by Stephens and Lawrence in 1936 (Ann Intern. Med. 9, 1488-1502). Typically, the Fowler solution was administered orally to patients with leukemia in the form of a solution until the level of white blood cells was suppressed to an acceptable level or until the development of toxicities (such as cutaneous keratosis and hyperpigmentation)., while patients enjoyed varying periods of remission. In the 1960s, Fowler's solution was still used occasionally in attempts to treat CML, however, most patients with CML were treated with other chemotherapeutic agents, such as busulfan and / or through radiation therapy ( Monfardini et al., Cancer, 1973, 31: 492-501). Paradoxically, one of the long-recognized effects of exposure to arsenic, whether its source is environmental or medical, is skin cancer (Hutchinson, 1888, Trans. Path. Soc. Lond., 39: 352; Neurauer, 1947, Br. J. Cancer, 1: 192). Epidemiological data suggesting that the use of the Fowler solution over long periods of time could lead to an increased incidence of cancer and internal sites (Cuzick et al., Br. J. Cancer,, 1982, 45: 904-911). Kaspar et al., J. Am. Med. Assoc, 1984, 252: 3407-3408). The carcinogenicity of arsenic has been demonstrated by the fact that it can induce a chromosomal aberration, gene amplification, sister chromatid exchanges as well as cell transformation (see, for example, Lee et al., 1988, Science, 241: 79-81; and Germolec et al., Toxicol, Applied Pharmacol., 1996, 141: 308-318). Due to the known carcinogenic effect of arsenic, its only therapeutic use in humans in western medicine today is in treatment of tropical diseases such as African trypanosomiasis (melarsoprol, or Arsobal® by Rhone Poulenc Rorer, Collegeville, PA; see Goodman &Gilman's The Pharmacological Basis of Therapeutics, (the pharmacological basis of therapy), 9th edition, chapter 66, 1659-1662, 1997). In traditional Chinese medicine, arsenic acid or arsenic trioxide paste has been used to treat tooth marrow disease, psoriasis, syphilis and rheumatosis (Chen et al., 1995, in the Manual of Clinical Drugs, Clinicians), Shanghai, China, Shanghai Institute of Science and Technology, page 830). In the 1970s, arsenic trioxide has been applied experimentally to treat acute promyelocytic leukemia (APL) in China (discussed by Mervis, 1996, Science, 273: 578). Clinical efficacy of arsenic trioxide has recently been reinvestigated in 14 of 15 patients with refractory APL, where the use of an intravenous dose of 10 mg / day for 4-9 weeks was reported as resulting in a complete morphological remission without associated suppression of bone marrow (Shen et al., 1997, Blood, 89: 3354-3360). It was also reported that arsenic trioxide induced apoptosis (programmed cell death) in vitro in NB4 cells, a cell line of APL, and that apoptosis was apparently associated with a down-regulation of the bcl-2 oncogene, and intracellular redistribution of the unique PML / RARáquimérica protein for APL cells (Chen et al., 1996, Blodd, 88: 1052-1061; Andre et al., 1996, Exp. Cell Res. 229: 253-260). Similarly, it has been reported that melarsoprol induces apoptosis in cell lines representative of chronic B-cell leukemia (Kong et al., 1997, Blood 90: 562-570). The fact of determining whether apoptosis is induced in patients with APL is currently unclear, but some consider it to be one of the possible mechanisms of the therapeutic effects of certain arsenic compounds. Even though arsenic is well known as a poison and as a carcinogenic agent, there are numerous reports on the use of arsenic in medical treatment. The identification or comments of the prior art that were presented above should not be considered as an admission that the prior art is so. In addition, from the comments above, it should be understood that there are many different types of cancers, each of which requires a single treatment protocol. Thus, the development of a broad spectrum anticancer agent is highly desirable. At a minimum, effective additional anticancer agents are required for their addition to the existing arsenal against cancer. 3. COMPENDIUM OF THE INVENTION Regardless of the conflicting reports in the art regarding the benefits and risks of arsenic administration to patients, applicants have discovered that arsenic compound has a wide application possibility in the treatment of various cancers , including solid tumors and blood disorders. For example, the present invention encompasses the use of arsenic in the form of a salt, complex, organic compound or ionic solution to treat tumors of epithelial tissue, connective tissue, central nervous system, lymphoid tissue, hematopoietic cells and tumors associated with oncogenic viruses. . In addition, the present invention encompasses the use of arsenic compounds to treat mammals suffering from a primary and metastatic neoplastic disease as well as infectious diseases related to said disease. In addition, this invention also encompasses the use of arsenic compounds to treat primary and metastatic breast, lung, bladder and prostate cancers in humans. This invention also encompasses the treatment of hematopoietic disorders in mammals by the administration of one or several arsenic compounds to said mammal. The hematopoietic disorders to be treated include, but are not limited to, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease including follicular lymphoma, diffuse lymphoma, lymphoblastic lymphoma, small lymphocytic lymphoma, acute lymphocytic leukemia, hairy cell leukemia, myeloid metaplasia, syndrome myeloid dysplastic, multiple myeloma and plasmacytoma. According to the present invention, arsenic compounds can be used alone or in combination with other known therapeutic agents (including chemotherapeutic, radioprotective and radiotherapeutic agents) or techniques to improve the quality of life of the patient or to treat the primary neoplastic disease . For example, the arsenic compounds can be used before, during or after the administration of one or more antitumor agents including, but not limited to, mustard, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, 6-mercaptopurine, 6- thioguanine, cytarabine, 5-fluorouracil, floxuridine, methotrexate, vincristine, vinblastine, taxol, etoposide, temiphoside, dactinomycin, daunorubicin, dxxorubicin, bleomycin, mitomycin, cisplatin, carboplatin, estramustine phosphate, hydroxyurea, BCNU, prccarbazine, VM-26 ( vumon), interferons as well as all trans retinoic acid (ATRA), (see for example, the Physician Desk references). In addition, arsenic compounds can be used before, during or after treatment with radiation. For the treatment of patients infected with HIV, the arsenic compounds can be used alone or in combination with AZT, ddI, ddA, ddC, d4T, 3TC and other known antiviral agents. The invention described herein encompasses a method for the treatment of primary and metastatic neoplastic diseases, a method for the treatment of solid tumors, a method for the treatment of leukemias, a method for the treatment of cancers related to bcl-2 (oncogene), each of which comprises administering a therapeutically effective and non-lethal amount of one or more arsenic compounds to a mammal in need of such therapy. The invention, in accordance with what is mentioned above, also encompasses the use of a combination therapy to treat the aforementioned diseases. In a particular embodiment, the arsenic compounds are used within a method to treat cancers of the breast, lung, colon, ovary, kidney, non-small cell lung, central nervous system, bladder, prostate, and head and neck by administration of an effective amount of one or more arsenic compounds alone or in combination with other antineoplastic agents or therapeutic techniques including radiotherapy and surgical intervention. Without being limited to any theory, the inventors believe that the arsenic compounds of the present invention may have one or several mechanisms of action in relation to the methods described herein. For example, arsenic compounds can act as a phosphorus analog that interferes with the phosphorylation events that occur in signal transduction involved in apoptosis. Arsenic can also act as an inhibitor of angiogenesis, that is, the formation of new blood vessels, thus limiting blood flow to masses of proliferating preneoplastic cells, tumors and metastases. As is well known in the art, if a tumor is not invaded by blood capillaries, it would have to depend on the diffusion of nutrients from the surrounding areas and can not grow beyond a certain size. Arsenic can also function as a differentiating agent that causes the division of preneoplastic and / or cancerous cells that present an undifferentiated or subdifferentiated phenotype to develop into terminally differentiated cells, and die after a finite number of cell divisions. Finally, arsenic can also act to sensitize cancer cells to radiation and / or chemotherapy. Accordingly, the arsenic compounds of the present invention are described as being useful against various cancers. Specific therapeutic regimens, specific pharmaceutical compositions as well as sets of elements are also provided by the present invention, thus, the invention also encompasses pharmaceutical compositions comprising one or more arsenic compounds and a pharmaceutically acceptable carrier. The compositions are sterile solutions suitable for intravenous injection or infusion. In another embodiment, the invention encompasses a composition suitable for oral administration; comprises one or more arsenic compounds and a pharmaceutically acceptable excipient or carrier. In another embodiment, the invention also includes compositions suitable for topical or dermal administration. Particular compositions of the present invention and their properties are described in the following sections and subsections. 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1A-1I. Dose response curves showing the percentage growth of several cancer cell lines after continuous exposure to 10"5 to 10" 9 μg / ml arsenic trioxide for 2 days. Figure IA. Leukemia cell lines CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226, SR. Figure IB. Non-small cell lung cancer cell lines A549 / ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-8322M, NCI-H460, NCI-H522. Figure 1C. Colonic cancer cell lines COLÓ 205, HCT-116, HCT-15, HT29, KM12, SW620. Figure ID. Central nervous system cancer cell lines SF-268, SF-295, SF-539, SNB-19, SNB-75 U251. Figure 1E. Melanoma cell lines LOX 1MV1, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62. Figure IF. Ovarian cancer cell lines IGROV1, OVCAR-3, OVCAR-5, OVCAR-8, SK-OV-3. Figure 1G. Renal cancer cell lines A498, CAKI-1, RXE 393, SN12C, TX-10, UO-31. Figure 1H. Lines of cancer cells of the prostate PC-3, DU-145. Figure II. Breast cancer cell lines MCF7, NCI / ADR-RES, MDA-MB-435, MDA-N, BT-549, T-47D. Figure 2. Graph of means showing selectivity patterns in each of the main response parameters for all cell lines tested after continuous exposure to IO "0 to 10 ~ 9 μg / ml arsenic trioxide for 2 days Figure 3A-3I: Dose response curves showing the percentage growth of several cancer cell lines after continuous exposure to 10 ~ 5 to 10"9 μg / ml of arsenic trioxide for 6 days. Figure 3A. Leukemia cell lines CCCRF-CEM, K-562, MOLT-4, RPMI-8226. Figure 3B. Non-small cell lung cancer cell lines EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI-H522. Figure 3C. Colonic cancer cell lines COLÓ 205, HCT-116, HCT-15, HT29, KM12, SW-620. 3D figure. Cancer cell lines of the central nervous system SF-268, SF-295, SF-539, SNB-75, U251. Figure 3E. Melanoma cell lines LOX IMVI, MALMI-3M, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62. Figure 3F. Ovarian cancer cell lines IGROVI, OVCAR-3, OCAR-5, OVCAR-8, SK-OV-3. Figure 3G. Renal cancer cell lines 786-0, A498, CAKI-1, RKX 393, S12C, TK-10. Figure 3H. Prostate cancer cell lines DU-145. Figure 31. Breast cancer cell lines MCF7, NCI / ADR-RIS, MDA-MB-231 / ATCC, HS 578T, MDA-MB-435, MDA-N, BR-549, T-47D. Figure 4. Mean graphs showing the selectivity patterns in each of the main response parameters for all cell lines tested after continuous exposure to 10"5 to 10 ~ 9 μg / ml of arsenic trioxide for 6 days 5. DETAILED DESCRIPTION OF THE INVENTION The following describes methods and compositions for the treatment of primary and metastatic neoplastic diseases The invention is based, in part, on a dosage regimen for the administration of compositions comprising arsenic. also in part in the potency of the arsenic compounds of the invention against certain cancers This invention includes a method for the treatment of primary solid tumors in a mammal comprising administering to a mammal requiring said therapy a therapeutically effective amount. and non-lethal one or several arsenic compounds. and also a method for the treatment of metastatic tumors in a mammal, comprising administering to a mammal a therapeutically effective and non-lethal dose of one or more arsenic compounds. The invention includes a method for the treatment of blood disorders in a mammal, comprising the administration of one or more arsenic compounds in a therapeutically effective and non-lethal amount. The arsenic compound of the present invention can be used in various known ways; for example, arsenic can be administered in the form of a salt, an organic or inorganic complex, an organic chelate, an organic compound or an organic or inorganic solution. It is preferred that the form be chosen to reduce toxicity and improve efficiency. In addition, the chosen form may also depend on the type and location of the tumor in question. Forms of inorganic arsenic salts are preferred. For example, inorganic salts such as arsenic triiodide, arsenic bromide (III), arsenic chloride (III), arsenic pentoxide, arsenic trioxide, Fowler's solution (potassium arsenite), sodium arsenite, and arsenite calcium can be used. Arsenic trioxide is especially preferred. Both arsenic acids and arsenites as well as arsenic acids and arsates can be employed within the present methods. Aqueous solutions containing arsenite ions are preferred. In addition, arsenic sulphides such as arsenic sulphide, arsenic sulfide, arsenic pentasulfide, tetra-arsenic trisulfide and tetra-arsenic pentasulfide can be used. Without being limited to any theory, some of these arsenic compounds can be prodrugs for an active species. Generally, the person skilled in the art will recognize that the arsenic form to be used must be therapeutically effective without presenting an unreasonable toxicity. The toxicity depends on the dose, the dosage form, the mode of administration and the frequency of administration. Generally, the person skilled in the art can choose between the following known forms of arsenic: arsenic halides, arsenic oxides, arsenic acids, arsenic sulfides and the like. Arsenic can also be easily combined with carbon to form a wide range of organic compounds. These compounds include, but are not limited to, primary and secondary arsines, tertiary arsines, haloarsines, dihaloarsins, cyclic and polymeric substances containing arsenic; Specific examples of organic arsenic compounds include, but are not limited to, 3-nitro-4-hydroxyphenylarsonic acid, arsanilic acid, sodium hydrogen 4-aminophenylarsenate, melarsoprol, melarsonilpotasium, carbarsone, arsphenamine arsenamide and sodium arsanilate. As used herein, the term "arsenic compound" refers to a pharmaceutically acceptable form of arsenic including salts, solutions, complexes, chelates and organic and inorganic compounds that incorporate arsenic. It will be recognized that the invention includes prodrugs of arsenic or compounds converted in vivo into biologically active forms of arsenic. Such prodrugs can be used to reduce or avoid the well-known toxicity potential of arsenic. The arsenic compounds of the present invention can be synthesized or purchased commercially. For example, the compounds can be prepared from well-known chemical techniques. (See, for example, Kirk-Othmer, Encyclopedia of Chemical Technology, 4th edition, volume 3, pages 633-655 John Wiley &Sons). In one embodiment, the arsenic compound of the present invention is arsenic trioxide dissolved in an aqueous solution of sodium hydroxide, with the pH adjusted to a physiologically acceptable range, for example, a pH of about 6-8. Any suitable mode of administration can be employed in accordance with the present invention, including without limitation, parenteral administration such as for example intravenous, subcutaneous, intramuscular as well as intrathecal administration; oral, intranasal, rectal or vaginal administration may also be employed; directly in the tumor; transdermal parts; implanted devices (especially for delayed release); finally, topical administration can be employed. The mode of administration may vary according to the type of arsenic compound being used and the disease to be treated. The pharmaceutical compositions to be used may be in the form of physiologically acceptable sterile solutions (aqueous or organic solutions), colloidal suspensions, creams, ointments, pastes, capsules, tablets and dragees. Pharmaceutical compositions comprising arsenic compounds of the present invention can be found in sealed sterile glass containers and / or ampoules. In addition, the active ingredient may be microencapsulated, encapsulated in a liposome, or lipoespuma alone or in combination with targeting antibodies. It will be recognized that slow or sustained delayed release forms are also included. The arsenic compounds of the present invention can be used against a number of primary and metastatic neoplastic diseases including, but not limited to, primary and metastatic tumors of the central nervous system, breast, colon, ovaries, kidneys, lung, bladder, prostate and head and neck. . More specifically, the arsenic compounds of the present invention can be used to treat tumors of epithelial origin including, but not limited to, squamous cell carcinoma basal cell carcinoma melanoma epithelial lining tumors of glands or ducts: adenocarcinoma papillary carcinoma papillary adenocarcinoma Liver and biliary tract: hepatocellular carcinoma Gastrointestinal tract tumors: squamous cell carcinoma of the esophagus esophageal carcinoma of the esophagus colorectal carcinoma (colon cancer) gastric carcinoma (stomach cancer) respiratory tract tumors: bronchogenic carcinoma small cell carcinoma cell carcinoma large tumors of the urogenital tract: transitional cell carcinomas of the bladder squamous cell carcinoma of the bladder carcinoma of the prostate carcinoma of the cervix breast tumors tumors of blood cells and related cells (leukemia): leuc acute and chronic lymphocytic emia polycythemia vera lymphoid tissue cancers malignant lymphomas - Hodgkins lymphoma non-Hodgkin's lymphoma - follicular lymphoma diffuse lymphoma small lymphocytic lymphoma large-cell lymphoma lymphoblastic lymphoma multiple myeloma connective tissue tumors bone cancers osteosarcoma nervous system tumors neuroblastoma retinoblastoma oligodendroglioma glioblastoma tumors associated with oncogenic virus human papillomavirus - squamous cell carcinoma of the cervix Ebstein-Barr virus - Burkitts lymphoma B-cell lymphoma in immunocompromised patients »<;, nasopharyngeal carcinoma, hepatitis B virus - hepatocellular carcinoma, herpes virus 8 or Herpes virus of Sarcoma Kaposi (KSHV) - Kaposi's sarcoma, and the like. Other neoplastic diseases known to the person skilled in the art are also encompassed within the scope of the present invention including cancer of the oral cavity, larynx, kidneys, testes and ovaries. The person skilled in the art will recognize that other cancers can be treated in accordance with the present invention. The term "a method for treating primary and metastatic tumors of the central nervous system" as used herein refers to the fact that the disease and symptoms associated with the disease are alleviated, reduced, cured or placed in a state of remission in another way. As used herein, the term "a method for the treatment of primary or metastatic breast, lung, bladder or prostate cancer" and "a method for the treatment of breast, lung, bladder or prostate cancer metastasis" indicates that the Illness and the symptoms associated with the disease are relieved, reduced, cured or placed in a state of remission. In addition, the term "a method for the treatment of metastases from breast, lung, bladder or prostate cancer" indicates that metastatic tumors and symptoms associated with the disease are relieved, reduced, cured or placed in a state of remission. The term "refractory" when used herein indicates that the cancer is generally resistant to treatment or cure. The term "refractory" when used in the above terms, indicates that cancers that are generally resistant to treatment or cure are relieved, reduced, cured or placed in a state of remission. As used, the terms "a therapeutic agent", "therapeutic regimen", "radioprotective", "chemotherapeutic" refer to conventional drugs and pharmacological therapies, including vaccines, for the treatment of cancer, viral infections and other known diseases of the subject matter experts. "Radiotherapeutic" agents or well known in the art. As used herein, "a method for the treatment of cancer" or "a method for the treatment of solid tumors" or "a method for the treatment of neoplastic diseases" refers to the disease and the symptoms associated with the disease are relieved, reduced, cured or placed in a state of remission. In addition, tumor growth is inhibited and / or tumor size is reduced.

As used herein, a "preneoplastic" cell refers to a cell that is in a transition from a normal to a neoplastic form; and morphological evidence, increasingly supported by molecular biological studies, indicates that preneoplasia progresses through a series of steps. The growth of non-neoplastic cells commonly consists of hyperplasia, metaplasia, or more especially dysplasia (for a review of such abnormal growth conditions see Robbins and Angeli, 1976, Basic Pathology, 2nd edition, WB Saunders Co., Philadelphia, pages 68-79). Hyperplasia is a form of controlled proliferation of cells that involves an increase in the number of cells in a tissue or an organ, without significantly altering its structure or function. Just by way of example, endometrial hyperplasia frequently precedes endometrial cancer. Metaplasia is a form of controlled growth of cells in which one type of adult or totally differentiated cells substitute another type of adult cells. Metaplasia can occur in cells of epithelial or connective tissue. An atypical metaplasia includes a relatively disorderly metaplastic epithelium. Dysplasia is often a precursor to cancer, and is found mainly in the epithelia; it is the most disordered form of non-neoplastic cell growth, involving a loss of uniformity of individual cells and the architectural orientation of the cells. Dysplastic cells often have deeply stained, abnormally large nuclei, and show pleomorphism. Dysplasia typically occurs when there is chronic irritation or chronic inflammation and is frequently found in the cervix, respiratory tract, oral cavity, as well as gallbladder. Although preneoplastic lesions may progress to the neoplasm, they may also remain stable for long periods of time and may regress, particularly if the triggering agent is removed or if the lesion succumbs to an immune attack by the host. The therapeutic regimens and pharmaceutical compositions of the invention may be employed with additional immune response enhancers or biological response modifiers including, but not limited to, the cytokines IFN-α, IFN- ?, IL-2, IL-4, IL-6, TNF, or other immunostimulants / immunomodulators. In accordance with this aspect of the invention, the arsenic compounds are administered in combination therapy with one or more of these agents. 5.1 Formulation The arsenic compounds of the present invention can be formulated into pharmaceutical preparations for administration to mammals for the treatment of cancer. Compositions comprising a compound of the present invention formulated in a pharmaceutically compatible carrier can be prepared, packaged, labeled for treatment and used for the treatment of the indicated tumor, such as for example human sarcomas and carcinomas, for example, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, 1infangiosarcoma, lymphangioendotheliosarcoma, sinovioma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma , basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, cebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, carcinoma embryonal oma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, hepithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniofaringioma, ependymoma, pinealoma, hemagioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblast a, retinoblastoma; leukemias, such as acute lymphocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia and chronic lymphocytic leukemia; lymphocythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, as well as heavy chain disease. Alternatively, it can be labeled for the treatment of the appropriate infectious disease. Alternatively, pharmaceutical compositions for the treatment of appropriate infectious diseases can be formulated. If the complex is soluble in water, then it can be formulated in an appropriate regulator, for example, phosphate-buffered saline or other physiologically compatible solutions. Alternatively, if the resulting complex has a limited solubility in aqueous solvents, then it can be formulated with a non-ionic surfactant, such as for example Tween, polyethylene glycol or glycerin. Thus, the compounds and their physiologically acceptable solvates can be formulated for administration by inhalation or insufflation (either through the mouth or nose) or oral, buccal, parenteral, topical, dermal, vaginal, administration devices. of drug, for example porous or viscous material such as for example lipoespuma, rectal administration or in the case of tumors, can be injected directly into a solid tumor. For oral administration, the pharmaceutical preparations may be in liquid form, for example, solutions, syrups or suspensions, or may have a pharmaceutical-type presentation for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hydroxybenzoates or sorbic acid). The pharmaceutical compositions may take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate, lubricants (for example, magnesium stearate, talc or silica), disintegrants (for example, potato starch or sodium starch glycolate); wetting (eg, sodium sulphate lauryl) The tablets may be coated by methods well known in the art Preparations for oral administration may be suitably formulated to provide a controlled release of the active compound. the compositions may take the form of conventionally formulated tablets or dragees For administration by inhalation, the compounds for use in accordance with the present invention are conveniently administered in the form of an aerosol-type spray presentation from presentations under pressure or atomizer, with the use of a propulsion agent ad Eq., for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of an aerosol under pressure, the dosage unit can be determined by providing a valve to supply a measured quantity. Capsules and cartridges, for example, of gelatin for use in an inhaler or insufflator can be formulated which contain a powder mixture of the compound and a suitable powder base such as for example lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or by continuous infusion. Such formulations are sterile. Formulations for injection can be presented through a unit dosage form such as, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may have the forms such as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as for example suppositories or retention enemas, which contain, for example, conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds may also be formulated as a prolonged release type preparation. Such long-acting formulations can be administered by implant (for example, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, as a Slightly soluble salt. Liposomes and emulsions are well known examples of delivery vehicles for hydrophilic drugs. The compositions may, if desired, be presented in a packaging or dispensing device which may contain one or more unit dosage forms containing the active ingredient. The package may comprise, for example, a sheet of metal or plastic, such as a blister-type package. The dispensing device or packaging may be accompanied by instructions for its administration. The invention also offers sets of elements for carrying out the therapeutic regimens of the invention. Such sets of elements comprise in one or more containers therapeutically effective amounts of the arsenic compounds in a pharmaceutically acceptable form. The arsenic compound in a bottle of a set of elements of the invention may be in the form of a pharmaceutically acceptable solution, for example, in combination with a sterile saline solution, dextrose solution, or either a regulated solution or another pharmaceutically sterile fluid. acceptable. Alternatively, the complex can be lyophilized or well-dissected; in this case, the set of elements further comprises in addition in a container a pharmaceutically acceptable solution (eg, saline, dextrose solution, etc.), preferably sterile solution, to reconstitute the complex to form a solution for of injection. In another embodiment, a set of elements of the invention further comprises a needle or syringe, preferably packed in a sterile form, for injecting the complex, and / or a packed alcohol cushion. Instructions are optionally included for the administration of arsenic compounds by a physician or by the patient. The magnitude of a therapeutic dose of an arsenic compound in the acute or chronic management of cancer will vary according to the severity of the condition to be treated and the route of administration. The dose, and perhaps the frequency of administration will also vary according to the age, body weight, condition and response of the individual patient. In general, the total daily dose is within a range for the conditions described herein which is generally from about 10 μg to about 200 mg which is administered in divided doses either parenterally or orally or topically. A preferred total daily dose is from about 0.5 mg to about 70 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion of an arsenic compound in accordance with that determined by plasma levels. It will be noted that the physician will be informed as to how and when to terminate, discontinue or adjust the therapy to a lower dosage due to toxicity, or bone marrow, liver or kidney dysfunction. Conversely, the doctor will also know how and when to adjust the treatment to higher levels if the clinical response is not adequate (without causing toxic side effects). Again, any suitable route of administration may be employed to provide the patient with an effective dosage of an arsenic compound. For example, oral, rectal, vaginal, transdermal, parenteral (subcutaneous, intramuscular, intrathecal, and the like) administration can be employed. Dosage forms include tablets, dragees, dispersions, suspensions, solutions, capsules, patches, and the like. (See Remington's Pharmaceuticals Sciences.). The pharmaceutical compositions of the present invention comprise an arsenic compound as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients such as, for example, antivirals. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. The pharmaceutical compositions include compositions suitable for oral, rectal, mucosal, transdermal, parenteral (including subcutaneous, intramuscular, intrathecal and intravenous) administration, although the most appropriate route of administration in any given case will depend on the nature and severity of the condition that It is being treated. In the case where an intravenous infusion or injection composition is employed, a suitable dosage range for use is, for example, 0.5 mg to about 150 mg as the total daily dose. In addition, the arsenic carrier can be administered through charged and uncharged matrices employed as drug delivery devices such as cellulose acetate membranes, also through targeted delivery systems such as fusogenic liposomes fixed on antibodies or specific antigens. In practice, an arsenic compound can be combined as the active ingredient in an intimate mixture with a pharmaceutical carrier in accordance with conventional pharmaceutical composition techniques. The vehicle can acquire several forms according to the form of preparation desired for its administration, for example, oral or parenteral (including tablets, capsules, powders, intravenous injections or infusions). In the preparation of the compositions for oral administration form, any of the usual pharmaceutical media can be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, and the like.; in the case of oral liquid preparations, for example, suspensions, solutions, elixirs, liposomes and aerosols; starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like in the case of oral solid preparations, for example powders, capsules and tablets. To prepare the compositions for parenteral dosage form, such as intravenous injection or infusion, similar pharmaceutical media can be employed, for example, water, glycols, oils, regulators, sugars, preservatives, and the like as known to those skilled in the art. Examples of such parenteral compositions include, but are not limited to, 5% w / v dextrose, normal saline or other solutions. The total dose of the arsenic compound can be administered in an intravenous fluid bottle, for example, which is within a range of about 2 ml to about 2000 ml. The volume of fluid in dilution will vary according to the total dose administered. . 2 White Cancers Cancers that can be treated by the methods of the present invention include, but are not limited to, human sarcomas and carcinomas, eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovitis, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adrenocarcinoma, gland carcinoma sudoriparous, carcinoma of cebaceous glands, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, pulmonary carcinoma, small cell lung carcinoma nails, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharynx, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, rstinoblastoma; leukemias such as acute lymphocytic leukemia (myeloblastic, myelomonocytic, monocytic and erythroleukemia); as well as chronic lymphocytic leukemia; and polycythemia vera, lymphoma (Hodgkin's disease as well as non-Hodgkin's disease), multiple myeloma, Wa ± denstrom's macroglobulinemia, and heavy chain disease. Specific examples of such cancers are described in the following sections. In a specific embodiment, the cancer is metastatic, in another specific embodiment, the patient having a cancer is immunosuppressed because he has undergone anticancer therapy (eg, chemotherapy radiation) prior to the administration of the arsenic compounds of the invention. In a specific embodiment, the present invention offers compositions and methods for increasing tumor-specific immunity in individuals suffering from colorectal cancer with liver metastases, in order to inhibit the progression of the neoplastic disease. Preferred methods of treatment of these neoplastic diseases comprise the administration of an arsenic composition that elicits an immunological response against the tumor cells. In another specific embodiment, the present invention offers compositions and methods for increasing specific immunity in patients suffering from hepatocellular carcinoma in order to inhibit the progression of the neoplastic disease and finally to irradiate all the preneoplastic and neoplastic cells. In a specific embodiment, the present invention offers hsp compositions and methods for increasing specific immunity to preneoplastic and neoplastic mammary cells in women. The present invention also provides compositions and methods for inhibiting cancer cell proliferation and metastasis. These compositions can be applied alone or in combination with each other or with biological response modifiers. 6. WORK EXAMPLES The following subsections describe the test of a pharmaceutical composition comprising arsenic trioxide in vitro using a panel of cancer cell lines used by the National Cancer Institute (NCI) (Institute National Cancer). The results demonstrate that arsenic trioxide is effective in inhibiting the growth of a wide range of leukemia cells and cancer cells in vitro. 6.1 METHODS AND MATERIALS Arsenic trioxide (1 mg / ml, 10 mg / pole, manufactured by Taylor Pharmaceuticals, Decatur, Illinois) was tested in five concentrations each in 10-fold dilutions, ie 10"5, 10"6, 10" 7, 10 ~ 8, and 10"9 μg / ml. In vitro tests were performed by incubating the test cells in the presence of the indicated concentration of arsenic trioxide under standard culture conditions for a designated period of time, which is followed by a trial with sulforhodamine B protein (SRB) to estimate cell viability or growth. The cell lines are organized in subpanels according to the origin of the cell lines, for example, leukemia, breast cancer, etc. A description of the cell lines and the test method is presented in Monk et al. (1997, Anticancer Drug Des. 12: 533-41) and Weinstein et al., (1997, Science 275: 343-9), which are incorporated herein by reference in their entirety. Below we describe the procedures for data analysis and presentations. The measurement of an effect is expressed in percentage growth (PG). The measured effect of the compound on a cell line is calculated according to one or both of the following two expressions: If (OD average mean - 0DZero) D 0, then PG = 100 x (0D test average - 0Dzero average) / (0Dctri average - 0Dzero average) Yes (0DOdo average - ODZero media) <; 0, then PG = 100 x (OD average test - 0Dzero average) / (ODzero media) where ODzero mean = the mean of the optical density measurements of color derived from SRB just before exposure of the cells to the test compounds; ODtest average = the mean of the optical density measurements - ^ aft- of color derived from SRB after exposure of the cells to the test compound for a designated period of time; and ODctri mean = the mean of the optical density measurements of SRB-derived color after no exposure of the cells to the test compound for a designated period of time. Tables 1 and 2 present the experimental data collected against each cell line. The first two columns describe the subpanel (for example, leukemia) and the cell line (for example, CCRF-CEM) involved. The next two columns present a list of the average ODzero and ODctri media; The next five columns present a list of the average ODPR for each of five different concentrations. Each concentration is expressed as logio (molar or μg / ml). The next five columns present a list of the PGs calculated for each concentration. The response parameters GI50, TGI and LC50 are interpolated values representing the concentrations in which the PG is +50, 0, and -50, respectively. Sometimes these response parameters can not be obtained by interpolation. If, for example, all PGs in a given row exceed +50, then none of the three parameters can be obtained by interpolation. In a case of this type, the value given for each response parameter is the highest concentration tested and is preceded by a ">" symbol. This practice is used in the same way to other possible situations where a response parameter can not be obtained by interpolation. A dose-response curve (see Figures 1A-1I and 3A-3I) for the data set is created by plotting the PGs against the logio of the corresponding concentration for each cell line. Cell line curves are grouped by subpanel. Horizontal lines are provided in the PG value of +50, 0, and -50. The concentrations that correspond to points at which the curves cross these lines are GI50, TGI, and LC50, respectively. An average graph (Figures 2 and 4) facilitates the visual exploration of data to determine potential patterns of selectivity for particular lines of cells or for particular subpanels in relation to a selected response parameter. Differences in apparent selectivity patterns can occur for the same compound against the same cell lines when comparing different parameters, the average graphs page of the data package shows average graphs in each of the main response parameters: GI50, TGI , and LC50. Bars extending to the right represent the sensitivity of the cell line to the test agent in excess of the average sensitivity of all cell lines tested. Since the bar scale is logarithmic, a bar 2 units to the right implies that the compound reached the response parameter (eg, GI50) for the -JSfelular line at a concentration one hundredth of the average concentration required in all cell lines, and therefore the cell line is unusually sensitive to this compound. Bars that extend to the left therefore imply a lower than average sensitivity. If, for a particular drug and for a particular ce lular line it was not possible to determine the desired response parameter by interpolation, the bar length illustrated is either the highest concentration tested (and in the logio listing of the response parameter will be preceded by an ">" symbol) or the lowest concentration tested (and the logio listing will be preceded by a "<" symbol). The values in any of the limits (> or <) are also calculated in the mean used for the average graph. Therefore, the mean used in the average graph may not be the actual mean of the GI50, for example. For this reason, this value is known as MG_MID (for an average of average graph). 6.2 RESULTS The results of two sets of tests appear below. In the first set, cells from 56 different cancer cell lines were exposed to five concentrations of arsenic trioxide continuously for two days before carrying out the SRB assay. In the second set, the cells from 50 different cell lines (a subset of the first 56 cell lines, plus the renal cancer cell line 786-0) were exposed continuously for six days before the SRB assay. Table 1 Log Concentration 10 Average optical densities Zero Time Ctrl. -8.9 -7.9 -6.9 -5.9 -4.9 Leukemia CCRF-CEM 0.300 1.155 1.203 1.195 1.134 0.704 0.285 HL-60 (TB) 0.233 0.530 0.533 0.507 0.535 0.499 0.213 K-562 0.209 1.416 1.387 1.431 1.418 1.124 0.199 MOLT-4 0.134 0.438 0.465 0.454 0.454 0.368 0.146 RPMI-8226 0.257 0.893 0.868 0.848 0.813 0.670 0.204 SR 0.158 0.457 0.454 0.425 0.457 0.338 0.111 Lung cancer that does not affect small cells A549 / ATCC 0.015 0.477 0.479 0.486 0.476 0.516 0.336 EKVX 0.342 0.736 0.809 0.849 0.841 0.853 0.385 HOP-62 0.335 1.109 1.088 1.099 1.113 1.086 0.605 HOP-92 0.505 1.694 1.554 1.603 1.477 1.381 0.873 NCI-H226 0.560 0.932 0.967 0.918 0.967 0.967 0.904 NCI-H23 0.648 1.622 1.769 1.822 1.880 1.635 1.215 NCI-8322M 0.382 0.997 1.103 1.036 0.976 0.992 0.755 NCI-H460 0.296 1.235 1.132 1.186 1.234 1.157 0.757 NCI-H522 0.478 1.138 1.332 1.135 1.189 0.892 0.378 Colon cancer COLÓ 205 0.328 1.394 1.425 1.414 1.576 1.434 0.935 HCT-116 0.301 1.574 1.508 1.480 1.488 1.391 0.685 HCT-15 0.219 1.623 1.800 1.627 1.673 1.522 0.504 HT29 0.095 0.578 0.637 0.599 0.580 0.479 0.169 KM12 0.189 0.741 0.744 0.728 0.777 0.737 0.567 SW-620 0.153 0.886 0.898 0.868 0.857 0.779 0.267 CNS cancer SF-268 0.203 0.767 0.821 0.736 0.815 0.767 0.334 SF-295 0.249 1.007 0.951 0.978 0.938 0.938 0.639 SF-539 0.132 0.462 0.491 0.516 0.506 0.435 0.110 SNB-19 0.176 0.905 0.857 0.880 0.887 0.883 0.437 SNB-75 0.501 1.051 0.925 1.049 1.134 0.703 0.438 U251 0.192 0.799 0.789 0.792 0.803 0.680 0.061 LOX Melanoma IMVI 0.173 1.304 1.175 1.170 0.974 0.997 0.319 MALME-3M 0.476 0.859 1.006 0.949 0.868 0.819 0.275 M14 0.123 0.613 0.602 0.635 0.592 0.549 0.136 SK-MEL-2 0.388 0.704 0.746 0.714 0.735 0.676 0.323 SK-MEL-28 0.513 1.090 1.088 1.107 1.093 1.057 0.546 iJsCfc SK-MEL-5 0.454 2.107 2.049 2.066 2.025 1.748 0.460 UACC-257 0.596 1.142 1.149 1.128 1.165 1.078 0.814 UACC-62 0.306 1.082 1.111 1.105 1.108 1.051 0.355 Ovarian cancer IGROVI 0.291 1.679 1.828 1.932 1.743 1.710 0.536 OVCAR-3 0.240 1.066 1.073 1.055 1.045 0.980 0.343 OVCAR-5 0.457 1.206 1.243 1.230 1.157 1.181 0.715 OVCAR-8 0.173 1.340 1.250 1.245 1.159 1.107 0.495 SK-OV-3 0.351 0.865 0.836 0.852 0.853 0.867 0.557 Kidney cancer A498 0.400 0.678 0.691 0.657 0.649 0.635 0.357 CAKI-1 0.372 0.942 1.058 0.960 1.103 0.819 0.325 RXE 393 0.743 1.243 0.860 1.114 1.290 1.077 0.776 SN12C 0.157 0.546 0.533 0.529 0.500 0.474 0.113 TX-10 0.355 1.027 1.014 1.002 1.042 0.999 0.727 UO-31 0.124 0.765 0.799 0.816 0.830 0.785 0.391 Prostate cancer PC-3 0.187 0.419 0.426 0.399 0.390 0.342 0.179 DU-145 0.384 1.151 1.081 1.389 1.194 1.119 0.873 Breast cancer MCF7 0.200 0.928 0.924 0.912 0.985 0.893 0.277 NCI / ADR-RES 0.328 1.386 1.576 1.376 1.425 1.298 0.801 MDA-MB- 231 / ATCC 0.304 0.644 0.635 0.651 0.674 0.667 0.314 HS 578T 0.369 1.255 1.338 1.296 1.219 1.300 0.742 MDA-MB-435 0.465 1.425 1.370 1.354 1.476 1.369 0.666 MDA-N 0.348 1.471 1.499 1.481 1.374 1.316 0.385 BT- 549 0.735 1.762 1.910 1.865 1.847 1.599 0.998 T-47D 0.464 1.007 0.941 1.054 1.184 0.905 0.419 Percent growth -8.9 -7.9 -6.9 -5.9 -4.9 GI50 Leukemia CCRF-CEM 106 105 98 47 -5 1.11E-06 HL-60 (TB) 101 92 102 90 -9 3.19E-06 K-562 98 101 100 76 -5 2.63E-06 MOLT-4 109 105 105 77 4 2.96E-06 RPMI-8226 96 93 87 65 -21 1.88E-06 SR 99 89 100 60 -30 1.63E-06 Lung cancer that does not affect small cells A549 / ATCC 100 102 100 108 69 > 1.26E-05 EKVX 119 129 127 130 11 5.91E-06 HOP-62 97 99 100 97 35 7.18E-06 HOP-92 88 92 82 74 31 4.50E-06 NCI-H226 109 96 109 109 92 > 1.26E-05 NCI-H23 115 121 127 101 58 > 1.26E-05 NCI-8322M 117 106 97 99 61 > 1.26E-05 NCI-H460 89 95 100 92 49 1.20E-05 NCI-H522 129 100 108 63 -21 1.79E-06 Colon cancer COLÓ 205 103 102 117 104 57 > 1.26E-05 HCT-116 95 93 93 86 30 5.53E-06 HCT-15 113 100 104 93 20 4.90E-06 HT29 112 104 100 80 15 3.63E-06 KM12 101 98 106 99 68 > 1.26E-05 SW-620 102 98 96 85 16 4.05E-06 Cancer SNC SF-268 110 94 108 100 23 5.63E-06 SF-295 93 96 91 91 51 > 1.26E-05 SF-539 109 117 113 92 -17 3.06E-06 SNB-19 93 97 98 97 36 7.38E-06 SNB-75 77 100 115 37 -13 8.54E-07 U251 98 99 101 80 -68 2.02E-06 Melanoma LOX IMVI 89 88 71 73 135 3.03E-06 MALME-3M 138 123 102 90 -42 2.51E-06 M14 98 105 96 87 3 3.45E-06 SK-MEL-2 113 103 110 91 -17 3.03E-06 SK-MEL-28 100 103 101 94 6 3.98E-06 SK-MEL-5 96 97 95 78 0 2.90E-06 UACC-257 101 97 104 88 40 7.78E-06 UACC-62 104 103 103 96 6 4.10E-06 Ovarian cancer IGROVI 111 118 105 102 18 5.22E-06 OVCAR-3 101 99 97 90 12 4.10E-06 OVCAR-5 105 103 93 97 34 7.07E-06 OVCAR-8 92 92 84 80 28 4.71E-06 SK-OV-3 94 97 98 100 40 8.59E-06 Kidney cancer A498 105 93 89 84 -11 2.90E-06 CAKI-1 120 103 128 78 -13 2.59E-06 RXE 393 23 74 109 67 7 SN12C 97 96 88 81 -28 2.44E-06 TX-10 98 96 102 96 55 > 1.26E-05 UO-31 105 108 110 103 42 9.20E-06 Prostate cancer PC-3 103 91 88 67 -4 2.17E-06 DU-145 91 131 106 96 64 > 1.26E-05 Breast cancer MCF7 99 98 108 95 11 4.31E-06 NCI / ADR-RES 118 99 104 92 45 9.69E-06 MDA-MB-231 / ATCC 97 102 109 107 3 4.43E-06 HS 578T 109 105 96 105 42 9.44E-06 MDA-MB-435 94 93 105 94 21 5.05E-06 MDA-N 102 101 91 86 3 3.44E-06 BT-549 114 110 108 84 26 4.82E-06 T-47D 88 109 133 81 -10 2.78E-06 TGI LC50 Leukemia CCRF-CEM 1. .00E-05 > 1 .26E-05 HL-60 (TB) 1.03E-05 > 1.26E-05 K-562 1.10E-05 > 1.26E-05 MOLT-4 > 1.26E-05 > 1.26E-05 RPMI-8226 7.23E-06 > 1.26E-05 SR 5.85E-06 > 1.26E-05 Lung cancer that does not affect small cells A549 / ATCC > 1.26E-05 > 1.26E-05 EKVX > 1.26E-05 > 1.26E-05 HOP-62 > 1.26E-05 > 1.26E-05 HOP-92 > 1.26E-05 > 1.26E-05 NCI-H226 > 1.26E-05 > 1.26E-05 NCI-H23 > 1.26E-05 > 1.26E-05 NCI-8322M > 1.26E-05 > 1.26E-05 NCI-H460 > 1.26E-05 > 1.26E-05 NCI-H522 7.08E-06 > 1.26E-05 Colon cancer COLÓ 205 > 1.26E-05 > 1.26E-05 HCT-116 > 1.26E-05 > 1.26E-05 HCT-15 > 1.26E-05 > 1.26E-05 HT29 > 1.26E-05 > 1.26E-05 KM12 > 1.26E-05 > 1.26E-05 SW-620 > 1.26E-05 > 1.26E-05 Cancer SNC SF-268 > 1.26E-05 > 1.26E-05 SF-295 > 1.26E-05 > 1.26E-05 SF-539 8.85E-06 > 1.26E-05 SNB-19 > 1.26E-05 > 1.26E-05 SNB-75 6.98E-06 > 1.26E-05 U251 4.37E-06 9.47E-06 Melanoma LOX IMVI > 1.26E-05 > 1.26E-05 MALME-3M 6.02E-06 > 1.26E-05 M14 > 1.26E-05 > 1.26E-05 SK-MEL-2 8.81E-06 > 1.26E-05 SK-MEL-28 > 1.26E-05 > 1.26E-05 SK-MEL-5 > 1.26E-05 > 1.26E-05 UACC-257 > 1.26E-05 > 1.26E-05 UACC-62 > 1.26E-05 > 1.26E-05 Ovarian cancer IGROVI > 1.26E-05 > 1.26E-05 OVCAR-3 M.26E-05 > 1.26E-05 OVCAR-5 > 1.26E-05 > 1.26E-05 OVCAR-8 > 1.26E-05 > 1.26E-05 SK-OV-3 > 1.26E-05 > 1.26E-05 Kidney cancer A498 9.71E-06 > 1.26E-05 CAKI-1 9.13E-06 > 1.26E-05 RXE 393 > 1.26E-05 > 1.26E-05 SN12C 6.96E-06 > 1.26E-05 TX-10 > 1.26E-05 > 1.26E-05 UO-31 > 1.26E-05 > 1.26E-05 Prostate cancer PC-3 1.10E-05 > 1.26E-05 DU-145 > 1.26E-05 > 1.26E-05 Breast cancer MCF7 > 1.26E-05 > 1.26E-05 NCI / ADR-RES > 1.26E-05 > 1.26E-05 MDA-MB-231 / ATCC > 1.26E-05 > 1.26E-05 HS 578T > 1.26E-05 > 1.26E-05 MDA-MB-435 > 1.26E-05 > 1.26E-05 MDA-N > 1.26E-05 M.26E-05 BT-549 > 1.26E-05 > 1.26E-05 T-47D 9.86E-06 > 1.26E-05 In the first set of tests, in accordance with the table 1 and the dose-response curves as shown in Figures IA to II, arsenic trioxide was effective in reducing cell growth against almost all of the cell lines tested. Particularly, leukemia cell lines, melanoma cell lines, and ovarian cancer cell lines responded consistently showing a reduction of more than 50% in growth. According to the average graph as shown in Figure 2, most lines of leukemia and melanoma cells, cancer cell lines of the central nervous system SNB-75 and U251, prostate cancer cell line PC-3 , kidney cancer cell lines A498, CAKI-1, SN12C, and lung cancer cell line NCI-H522 were especially sensitive (relative to all cell lines tested) to treatment with arsenic trioxide. Table 2 Log Concentration 10 Average optical densities Panel / line Cell time Zero Ctrl. -8.9 -7.9 -6.9 -5.9 -4.9 Leukemia CCRF-CEM 0.047 3.511 3.601 3.592 3.051 0.320 0.048 K-562 0.041 3.011 3.042 2.992 3.360 2.931 0.096 MOLT-4 0.018 0.503 0.554 0.228 0.432 0.245 0.113 RPMI-8226 0.066 1.432 1.607 1.263 1.423 0.368 0.065 Lung cancer that does not affect small cells EKVX 0.030 0.682 0.573 0.601 0.628 0.414 0.014 HOP-62 0.061 1.026 1.076 0.997 1.019 0.451 0.014 HOP-92 0.115 1.292 1.455 1.834 1.319 1.229 0.079 NCI-H226 0.094 0.498 0.504 0.458 0.489 0.348 0.164 NCI-H23 0.075 1.624 1.818 1.814 1.872 1.303 0.086 NCI-H322M 0.035 0.702 0.680 0.620 0.674 0.552 0.054 NCI-H460 0.034 2.839 2.797 2.806 2.792 2.535 0.062 NCI-H522 0.175 1.224 1.269 0.535 1.191 0.128 0.028 Colon cancer COLÓ 205 0.022 2.351 2.308 2.026 2.283 1.404 0.024 HCT-116 0.046 3.420 3.395 3.289 3.381 3.284 1.931 HCT-15 0.033 3.838 3.965 3.921 4.227 3.432 0.404 HT29 0.017 3.060 3.189 2.988 2.706 1.476 0.027 KM12 0.012 0.808 0.487 0.533 0.507 0.036 0.017 SW-620 0.023 2.652 2.613 2.308 2.337 1.475 0.007 CNS cancer SF-268 0.054 0.798 0.990 0.381 0.356 0.387 -0.004 SF-295 0.031 1.324 1.284 1.279 1.244 0.659 0.010 SF-539 0.041 1.598 1.727 1.403 1.545 0.691 0.017 SNB-75 0.134 1.065 1.143 1.033 1.024 0.815 0.028 U251 0.105 2.324 2.129 2.018 1.908 0.088 -0.012 Melanoma LOX IMVI 0.013 2.153 2.000 1.666 0.053 0.002 -0.001 MALMI-3M 0.115 0.650 0.702 0.595 0.823 0.383 0.005 SK-MEL-2 0.213 0.500 0.491 0.462 0.426 0.128 SK-MEL-28 0.093 2.030 2.012 1.906 1.797 0.488 SK-MEL-5 0.181 1.907 1.935 1.864 1.929 1.846 0.013 UACC-257 0.053 0.883 0.872 0.857 0.832 0.504 0.039 UACC-62 0.030 1.537 1.546 1.460 1.409 0.539 0.001 Ovarian cancer IGROVI 0.335 3.115 3.541 3.056 3.204 2.877 0.216 OVCAR-3 0.081 1.153 1.047 1.128 1.124 0.482 0.001 OVCAR-5 0.038 1.404 1.433 1.460 1.478 1.287 0.028 OVCAR-8 0.016 2.090 2.272 1.848 2.242 1.437 -0.001 SK-OV-3 0.041 1.474 - 1.445 1.410 1.461 1.247 0.020 Kidney cancer 786-0 0.021 1.578 1.582 1.821 1.786 0.832 -0.003 A498 0.051 0.741 0.826 0.764 0.837 0.558 0.025 CAKI-1 0.032 1.352 1.254 1.725 1.573 0.491 0.004 RXF 393 0.198 1.515 1.327 1.301 1.727 0.909 0.017 S12C 0.024 0.956 0.882 1.141 1.113 0.829 0.013 TK-10 0.072 1.333 1.356 1.268 1.334 1.103 0.239 Prostate cancer DU-145 0.095 2.158 2.147 1.954 1.935 2.153 0.053 Breast cancer MCF7 0.028 2.650 2.647 2.611 2.603 1.683 0.008 NCI / ADR-RIS 0.050 2.304 2.075 2.253 1.951 1.319 0.072 MDA-MB- 231 / ATCC 0.158 0.761 0.759 0.764 0.771 0.563 -0.001 HS 578T 0.109 0.728 0.777 0.587 0.890 0.706 0.010 MDA-MB-435 0.054 1,500 1,276 1,470 0.865 0.631 0.021 MDA-N 0.028 2.652 2.468 2.616 2.606 1.738 0.026 BT-549 0.112 1.798 1.876 1.940 1.963 1.697 0.018 T-47D 0.098 0.824 0.883 0.336 0.539 0.398 0.027 Percent growth -8.9 -7.9 -6.9 -5.9 -4.9 GI50 Leukemia CCRF-CEM 103 102 87 8 0 3.68E-07 K-562 101 99 112 97 2 3.941-06 MOLT-4 111 43 85 47 20 RPMI-8226 113 88 99 22 -2 5,481-07 Lung cancer that does not affect small cells EKVX 83 88 92 59 -53 1.51E-06 HOP-62 105 97; 99 40 -77 8.66E-07 HOP-92 114 146 102 95 -31 2.85E-06 NCI-H226 101 90 98 63 17 2.40E-08 NCI-H23 113 112 116 79 1 2.97E-06 NCI-H322M 97 88 96 77 3 2.94E-06 NCI-H460 99 99 98 89 1 3.50E-06 NCI-H522 104 34 97 -27 -84 • Colon cancer COLÓ 205 98 86 97 59 0 1.81E-06 HCT-116 99 96 99 96 56 > 1.26E-05 HCT-15 103 102 110 89 10 3.93E-06 HT29 104 98 88 48 0 1.12E-06 KM12 80 87 83 4 1 3.29E-07 SW-620 99 87 88 55 -72 1.39E-06 Cancer SNC SF-268 126 44 41 45 -100 1.06E-08 SF-295 97 97 94 49 -69 1.17E-06 SF-539 108 87 97 42 -59 8.91E-07 SNB-75 108 97 96 73 -79 1.79E-06 U251 91 86 81 -17 -100 2.63E-07 Melanoma LOX IMVI 93 77 2 -88 -100 2.90E-08 MALMI-3M 110 90 132 50 -96 1.26E-06 SK-MEL-2 97 87 74 -40 -100 2.06E-07 SK-MEL-28 99 94 88 20 -100 4.60E-07 SK-MEL-5 102 97 1 * 01 96 -93 2.22E-06 UACC-257 99 97 94 54 -27 1.42E-06 UACC-62 101 95 92 34 -98 6.60E-07 Ovarian cancer IGROVI 115 98 103 91 -36 2.67E-06 OVCAR-3 90 98 97 37 -99 7.76E-07 OVCAR-5 102 104 105 91 -26 2.83E-06 OVCAR-8 109 88 107 68 -100 1.62E-06 SK-OV-3 98 96 99 84 -51 2.25E-06 Kidney cancer 786-0 100 116 113 52 -100 1.30E-06 A498 112 103 114 73 -52 1.94E-06 CAKI-1 93 128 117 35 -88 8.22E-07 RXF 393 86 84 116 54 -91 1.34E-06 S12C 92 120 117 86 -46 2.37E-06 TX-10 102 95 100 82 13 3.66E-06 Prostate cancer DU-145 99 90 89 100 -43 2.82E-06 Breast cancer MCF7 100 99 98 63 -73 1.57E-06 NCI / ADR-RIS 90 98 84 56 1 1.64E-06 MDA-MB-231 / ATCC 100 101 102 67 -100 1.59E-06 HS 578T 108 77 126 96 -91 2.23E-06 MDA-MB-435 85 98 56 40 -62 3.00E-07 MDA-N 93 99 98 65 -9 2.02E-06 BT-549 105 108 110 94 -84 2.22E-06 T-47D 108 33 61 41 -73 TGI LC50 Leukemia CCRF-CEM > 1.26E-05 > 1.261-05 K-562 > 1.26E-05 > 1.26E-05 MOLT-4 > 1.26E-05 > 1.26E-05 RPMI-8226 1.091-05 M.26E-05 Lung cancer that does not affect small cells EKVX 4.22E-06 1.18E-05 HOP-62 2.781-06 7.41E-06 HOP-92 7.111-06 > 1.26E-05 NCI-H226 > 1,261-05 > 1.26E-05 NCI-H23 > 1,261-05 > 1.26E-05 NCI-H322M > 1,261-05 > 1.26E-05 NCI-H460 > 1,261-05 > 1.26E-05 NCI-H522 7.641-07 3.19E-06 Colon cancer COLÓ 205 > 1.26E-05 > 1.26E-05 HCT-116 > 1.26? ^ Í) 5 > 1.26E-05 HCT-15 > 1.26E-05"> 1.26E-05 HT29 > 1.26E-05 > 1.26E-05 KM12 > 1.26E-05 > 1.26E-05 SW-620 3.43E-06 * 8.50E-06 Cancer SNC SF-268 2.57E-06 5.69E-06 SF-295 3.25E-06 8.64E-06 SF-539 3.29E-06 1.04E-05 SNB-75 3.80E-06 8.08E-06 U251 8.51E-07 3.16E-06 Melanoma LOX IMVI 1.32E-07 4.73E-07 MALMI-3M 2.78E-06 6.12E-06 SK-MEL-2 5.63E-07 1.85E-06 SK-MEL-28 1.86E-06 4.84E-06 SK-MEL-5 4.07E-06 7.46E-06 UACC-257 5.83E-06 > 1.26E-05 UACC-62 2.27E-06 5.43E-06 Ovarian cancer IGROVI 6.62E-06 > 1.26E-05 OVCAR-3 2.36E-06 5.49E-06 OVCAR-5 7.53E-06 > 1.26E-05 OVCAR-8 3.21E-06 6.36E-06 SK-OV-3 5.27E-06 1.23E-05 Kidney cancer 786-0 2.77E-06 5.91E-06 A498 4.85E-06 1.226E-05 CAKI-1 2.43E-06 6.226E-06 RXF 393 2.96E-06 6.546E-06 S12C 5.67E-06 > 1.26E-05 TK-10 > 1.26E-05 > 1.26E-05 Prostate cancer DU-145 6.32E-06 > 1.26E-05 Breast cancer MCF7 3.66E-06 8.51E-06 NCI / ADR-RIS > 1.26E-05 > 1.26E-05 MDA-MB-231 / ATCC 3.18E-06 6.33E-06 HS 578T 4.12E-06 7.62E-06 MDA-MB-435 3.10E-06 9.60E-06 MDA-N 9.55E-06 > 1.26E-05 BT-549 4.24E-06 8.08E-06 T-47D 2.90E-06 7.93E-06 In the second set of tests, in accordance with table 2, the dose-response curves, and the graph of means as illustrated in Figures 3A to 31, and Figure 4, arsenic trioxide was effective in reducing cell growth against all cell lines tested. The results were consistent with those obtained from the first set of tests. In particular, several melanoma cell lines appeared as especially sensitive in the various main response parameters. In conclusion, these results demonstrate that arsenic trioxide is effective in inhibiting the growth of leukemia cells and cancer cells in vitro, and that arsenic trioxide can be used in human patients to treat a wide range of leukemias, and cancers, including , not limited to, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer and breast cancer. The present invention is not limited in its scope to the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications fall within the scope of the appended claims.

Claims

CLAIMS. A method for the treatment of solid tumors in a mammal, comprising administering a therapeutically effective amount of one or more arsenic compounds to said mammal. A method for the treatment of metastatic neoplastic disease in a mammal, comprising administering a therapeutically effective amount of one or more arsenic compounds to a mammal in need of such therapy. A method for the treatment of melanoma, breast, colon, ovarian, renal, central nervous system, bladder, prostate or lung cancer in a human being, comprising the administration of a therapeutically effective amount of one or more arsenic compounds to said human being. The method according to claim 1 wherein said tumor is a tumor of epithelial tissue, lymphoid tissue, connective tissue, bone or central nervous system. The method according to claim 2 wherein said metastatic neoplastic disease is a disease of epithelial tissue, lymphoid tissue, connective tissue, bone or central nervous system. The method according to claim 4 wherein said epithelial tissue tumor is a tumor of epithelial glands, epithelial ducts, liver, biliary tract, gastrointestinal tract, respiratory tract, or urogenital tract. 7. The method according to claim 4 wherein said tumor is a squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, colorectal carcinoma, or gastric carcinoma. 8. The method according to claim 4 wherein said tumor of the lymphoid tissue is Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, diffuse lymphoma, lymphoblastic lymphoma, large cell lymphoma, or small lymphocytic lymphoma. 9. The method according to claim 4 wherein said tumor of the central nervous system is selected from the group consisting of neuroblastoma, retinoblastoma, glioblastoma, or oligodendroglioma. 10. The method according to claim 1, 2 or 3 wherein said arsenic compound is an aqueous ionic arsenic solution. The method according to claim 1, 2 or 3 wherein said arsenic compound is selected from the group consisting of arsenic trioxide and Fowler's solution. The method according to claim 1, 2 or 3 wherein the total daily amount administered is from about 10 μg to about 200 mg. . The method for the treatment of neoplastic diseases in a human being, comprising the administration to a human of an effective amount of an arsenic compound, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of at least one other agent therapeutic. . The method according to claim 12 wherein said other therapeutic agent is a chemotherapeutic or radiotherapeutic agent. . The method according to claim 1, 2, 3, or 12 wherein said administration is carried out parenterally, topically, dermally, directly in the tumor, or orally. . The method according to claim 12 wherein said other therapeutic agent is selected from the group consisting of etoposide, cisplatin, carboplatin, estramustine phosphate, vinblastine, methotrexate, hydroxyurea, cyclophosphamide, doxorubicin, 5-fluorouracil, taxol, diethylstilbestrol, VM-26 (vumon), BCNU, all transretinoic acid, procarbazine, cytokines, therapeutic vaccines, or other immunomodulators. The method according to claim 1, 2, 3 or 12 wherein said administration is carried out through an implanted device. 18. A method for the treatment of hematopoietic disorders in a mammal, comprising the administration of one or more arsenic compounds to said mammal, wherein said hematopoietic disorder is selected from the group consisting of acute lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, myeloid metaplasia, myeloid dysplastic syndrome, multiple myeloma and plasmacytoma. 19. An oral pharmaceutical composition useful for the treatment of neoplastic diseases in a human being, comprising an effective amount of an arsenic compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. A sterile unit dosage form adapted for parenteral administration, comprising a therapeutically effective non-lethal amount of arsenic trioxide in an aqueous vehicle, said dosage form being in a sealed sterile glass container. The invention relates to the arsenic compounds for treating various neoplastic diseases (see dose-response curve in the figure). In addition, arsenic compounds can be used to treat metastatic neoplastic diseases.