Hormones

Hormones may alter the permeability of the cell wall and allow the entrance of cations in greater concentration.

Free Radicals And X-Rays

It is not possible to give a clear picture of how x-rays or free radicals influence the metallic components in the cell. The assumption must be made that normal and abnormal metals are affected differently by these forces. Tumors do become more radio-sensitive in animals treated with heavy metal salts. X-rays are reported to operate through free radical mechanisms, which may aid in the autoxidation of tissues. Autoxidation of dioxyphenylalanine (DOPA) is probably due to trace elements.

Free radicals are mediated through trace metals, and x-rays may change the oxidation state of the metals. X-rays may inactivate catalyase activity at the same time they liberate peroxide radicals. Hydrogen peroxide once formed may remain longer in cells, alter proteins and nucleic acid, and at the same time be mutagenic. Changed oxidation states of metals in the matrix may account for the lowering of viscosity of nucleic acids which have been exposed to x-rays.

Virus Theory

Literature is now appearing showing that metals may be associated with viruses. Copper is found in vaccinia and iron in mouse encephalomyelitis virus. Several metals, copper, calcium, and magnesium, but especially high iron, were reported present in tobacco mosaic virus. Viral chemo-therapeutic agents quite often are the same as those used for treating cancer. Especially noteworthy is the fact that many of the antiviral agents are sulfur compounds. Thus, thiourea is reported active against influenza, and phenylthiourea inhibits metastases of the Rous sarcoma; thiosemicarbazones, especially isatinthiosemicarbazone, have been reported active against vaccinia, and rabbit pox virus in ERK cells. The possibility of chelation of this compound has been recognized, and this suggested mode of action is more plausible than to consider the derivative as a tryptophan or adenine antagonist.

Carcinogenic viruses as carriers of metals may be acting as chelating agents. Penetrating the cell more efficiently, smaller quantities can be effective in transporting trace elements into the cell.

Anticancer Activity

In the field of anticancer drugs, the chelating agent, if sufficiently concentrated in cancer cells, will help diminish the concentration of abnormal metals by complexing them and thus disrupting the continuation of the biosynthesis of abnormal nucleic acid polymers. If the "deformed" poly unit is very sensitive to a chelating agent, this agent will act as a chemotherapeutic agent. For normal tissue with a high extracellular concentration of abnormal metals, the chemotherapeutic chelating agent may act as a carcinogen by the mechanism just discussed.

Chelating agents may have as one mechanism of action the chelation of normal metals that make up the matrix of the nucleic acid in the cancer cell. Thus, in this way, these agents can prevent cell multiplication. Also prevented from proliferating will be rapidly growing normal cells; therefore bone marrow depression, toxic liver injury, oral ulcerations, alopecia, and stomatitis would be expected. This is the case.