Cancer generally refers to one of a group of more than 100 diseases caused by the uncontrolled, abnormal growth of cells that can spread to adjoining tissues or other parts of the body. Cancer cells can form a solid tumor, in which the cancer cells are massed together, or exist, as dispersed cells, as in leukemia. Normal cells divide until maturation is attained and then only as necessary for replacement of damaged or dead cells. Cancer cells are often referred to as “malignant”, because they divide endlessly, eventually crowding out nearby tissues and spreading to other parts of the body. The tendency of cancer cells to invade and spread from one organ to another or from one part of the body to another distinguishes them from benign tumor cells, which overgrow but do not spread to other organs or parts of the body. Malignant cancer cells eventually metastasize and spread to other parts of the body via the bloodstream or lymphatic system, where they can multiply and form new tumors. This sort of tumor progression makes cancer a deadly disease.
Although there have been great improvements in the diagnosis and treatment of cancer, many people die from cancer each year, and their deaths are typically due to metastases and cancers that are resistant to conventional therapies.
Most drug-mediated cancer therapies rely on poisons, called cytotoxic agents, selective for dividing cells. These drugs are effective because cancer cells generally divide more frequently than normal cells. However, such drugs almost inevitably do not kill all of the cancer cells in the patient. One reason is that cancer cells can acquire mutations that confer drug resistance. Another is that not all cancer cells divide more frequently than normal cells, and slowly-dividing cancer cells can be as, or even more, insensitive to such cytotoxic agents as normal cells. Some cancer cells divide slowly, because they reside in a poorly vascularized, solid tumor and are unable to meet the needs required for cell division. For example, cytotoxic agents such as cyclophosphamide have been used to treat cancer.
Although cancer chemotherapy has advanced dramatically in recent years, treating cancers with a single agent has had limited success. Firstly, any single agent may only target a subset of the total population of malignant cells present, leaving a subpopulation of cancerous cells to continue growing. Secondly, cells develop resistance upon prolonged exposure to a drug. Combination therapies, which employ two or more agents with differing mechanisms of action and differing toxicities, have been useful for circumventing drug resistance and increasing the target cell population, but have not proven effective in the treatment of all cancers. In addition, certain combinations of agents may be synergistic: their combined effect is larger than that predicted based on their individual activities. Thus, combining different agents can be a powerful strategy for treating cancer.
The most striking difference between malignant and healthy cells is the capacity of cancer cells for unrestricted proliferation. This difference is exploited by many cytotoxic agents, which typically disrupt cell proliferation by interfering with the synthesis or integrity of DNA. Examples of classes of cytotoxic agents which function in this manner include alkylating agents, such as cyclophosphamide, antimetabolites (e.g. purine and pyrimidine analogues), and platinum coordination complexes.
One problem with cytotoxic agents which function by disrupting cell division is that they do not discriminate between normal and malignant cells: any dividing cell is a potential target for their action. Thus, cell populations which normally exhibit high levels of proliferation (such as bone marrow) are affected, leading to the toxic side effects commonly associated with cancer treatments.
As a tumor grows, it requires blood supply and, consequently, growth of new vasculature. Angiogenesis is a process of tissue vascularization that involves the growth of new developing blood vessels into a tissue, and is also referred to as neo-vascularization. Blood vessels are the means by which oxygen and nutrients are supplied to living cells.
Inhibitors of pro-angiogenic growth factors are agents used to inhibit the signaling of known pro-angiogenic factors like VEGF or FGF. Currently, these agents by themselves failed to demonstrate sufficient efficacy in the treatment of cancer.
With only a few exceptions, no single drug or drug combination is curative for most cancers. Thus, new drugs or combinations that can delay the growth of life-threatening tumors and/or improve quality of life by further reducing tumor load are needed.
Natori at al. (Biomedicine & Pharmacotherapy, 59: 56-60 (2005)) showed that Cimetidine, an H2-blocker, has anti-angiogenic properties and therefore anti-cancer properties. On the other hand, U.S. Patent Application 20030158118 (by Weidner, Morten and Sloth) showed that Cimetidine by itself did not inhibit tumor growth to any significant amount (Example 4 therein). Additionally, Saarloos M N et al. (Clin. Exp. Metastasis 11: 275-83 (1993)) performed immunotherapy tests on metastasis by administration of indomethacin plus interleukin-2 (IL-2), and showed that the addition of an H2-blocker did not improve the therapeutic efficacy. On the other hand, U.S. Patent Application 20030158118 suggested a cancer treatment composed of Cimetidine and a cysteine derivative.
Levamisole is a synthetic phenylimidothiazole which has been known in the art as an antihelmitic agent. While several studies failed to demonstrate any beneficial effect of Levamisole, by itself or in combination with 5-FU, others found some benefit for Levamisole when combined with 5-FU (DeVita et al. Cancer: Principles and Practice of Oncology, 5th Edition, pp 1171-5).
Quinones are known for their ability to induce oxidative stress through redox cycling, hereby referred to as “Redox quinones” (Powis G., Free Radic. Biol. Med. 6:63-101 (1989)). Pharmaceutically acceptable redox quinones such as Vitamin K3 have special therapeutic value since they are required for the bioactivation of proteins involved in hemostasis. Vitamin K3 is a redox quinone, known as a prothrombogenic agent, mainly in supplement of veterinary diet. Studies have shown that Vitamin K3 has failed to demonstrate beneficial anti-cancer properties (Tetef M. et al. J. Cancer Res. Clin. Oncol. 121:103-6 (1995)).
Retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth. A natural retinoid, all-trans retinoic acid (ATRA), regulates a variety of important cellular functions via the retinoic acid receptor (RAR). ATRA has therapeutically been used against various malignancies including acute promyelocytic leukemia. Anti-tumor effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. However, there is still some uncertainty with respect to ATRA role in angiogenesis. For example, Saito A. et al. (Endocrinology 148:1412-23 (2007)) claimed that ATRA has a pro-angiogenic effect.
U.S. patent application No. US2005/148521 relates to methods and compositions for treating cancer comprising administering a combination of an effective amount of cytotoxic agent, a non steroidal anti inflammatory drug (NSAID), an ester of benzoic acid and a pharmaceutically acceptable carrier.
WO 06/056889 relates to methods and pharmaceutical compositions for inhibiting angiogenesis, comprising administering a combination of at least one angiogenesis inhibitor, at least one agent that enhances accumulation of intracellular NADH+H+ and a pharmaceutically acceptable carrier.