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Flavin n-oxides: new anti-cancer agents and pathogen eradication agents

Flavin n-oxides: new anti-cancer agents and pathogen eradication agents description/claims

This application claims priority to U.S. Provisional Application Ser. No. 60/379,321 filed May 10, 2002, the entirety of which is incorporated herein by reference.

Solid tumors account for more than 90% of all human cancers. As the tumor grows, in order to sustain itself, it must develop its own blood supply. This blood supply, however, is much different from the blood supply to normal tissues. The blood vessels formed in tumors are typically highly irregular and tortuous. They may have arterio-venous shunts and blind ends, and lack smooth muscle or nerves and have incomplete endothelial linings and basement membranes. This leads to low overall levels of oxygen in most tumors. Many tumors have areas of extreme hypoxia. (Brown, J. M. “Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies.” Molecular Medicine Today April 2000 (Vol. 6)).

Unfortunately, there is considerable evidence that hypoxic tumors are refractory towards many of the currently available treatments for solid tumor cancers, including radiation therapy and chemotherapy. Accordingly, there exists a need for a method of treating solid tumor cancers having hypoxic regions.

A second problem existing in medicine today is the need for reliable methods for eradication of pathogens in blood products. In the United States almost 4 million individuals are transfused every year with over 28 million blood components derived from nearly 13 million units of blood donated by apparently healthy volunteers. The blood components are extensively tested for the presence of pathogens prior to administration. Testing has reduced the risk of transmission of enveloped virus to a small but finite value in the developed world. The NIH has estimated the risk during transfusion of a unit of screened blood is 1/1,000,000 for hepatitis A virus (HAV), 1/30,000-1/50,000 for HBV, and 1/2,000,000 for human T-cell lymphotropic viruses (HTLV). The odds of transmission for parvovirus B19 is much larger 1/10,000. Parvovirus and HCV lack a lipid membrane envelope and have relatively poor odds of transmission, relative to other pathogens.

The solvent detergent (SD) method is used to eradicate enveloped virus and bacterial pathogens present in units of plasma protein. The lipid envelope of the pathogen is dissolved by the solvent detergent. The SD method cannot be used to eradicate pathogens present in platelet and red cell concentrates because the cells also contain lipid envelopes and will be lysed by the pathogen inactivation treatment. The SD method does not inactivate HCV and parvovirus in units of plasma protein because they do not contain a lipid envelope. Thus, there is an urgent need to develop technology that may eradicate non-enveloped pathogens in units of blood components.

Provided herein are methods of treating solid tumors, non-solid tumor masses, leukemias, and non-small cell lung cancers in subjects in need of such treatment by administering an therapeutically effective amount of a flavin N-oxide, as shown in formula I:

wherein X1 is selected from H, monosaccharides, substituted monosaccharides, mono, di, and tri-ethylene glycol, alcohol, and alkyl ammonium ion; and X2, X3, and X4 can be the same or different and are selected from H, monosaccharides, substituted monosaccharides, glycol, alcohol, lower alkyl, and alkylene groups further substituted with monosaccharides, substitited monosaccharides, mono, di, and tri-ethylene glycol, alcohol, or alkyl ammonium ion.

It is preferred that the substituents are chosen such that the flavin N-oxide is water soluble. An example of a flavin N-oxide of formula I is riboflavin N-oxide, which is shown in formula II:

The method of treating a subject having solid tumors, non-solid tumor masses, leukemias, and non-small cell lung cancers comprises administering a therapeutically effective amount of a flavin N-oxide to a subject in need of such treatment. Once administered, the flavin N-oxide is exposed to an activator, which results in damage to the DNA of cancer cells without substantial damage to the DNA of normal cells in the subject. Riboflavin N-oxide is an example of a flavin N-oxide.

The activator may be a reducing enzyme or electromagnetic radiation. The activator is preferably a reducing enzyme. The reducing enzymes are preferably reducing enzymes that are in the cancer cells, though the reducing enzyme may be a reducing agent outside of the cell. When electromagnetic radiation is used as the activator in this method, it is preferably X-ray radiation. A combination of both electromagnetic radiation and reducing enzymes can serve as the activator.

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