Germane Facts About Germanium Sesquioxide: I. Chemistry and Anticancer Properties
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THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 10, Number 2, 2004, pp. 337–344 ©Mary Ann Liebert, Inc. Germane Facts About Germanium Sesquioxide: I. Chemistry and Anticancer Properties BONNIEJ. KAPLAN, Ph.D., 1 W. WESLEYPARISH, Ph.D., 2 G. MERRILLANDRUS, Ph.D., 2 J. STEVENA. SIMPSON, Ph.D., M.D., 3 and CATHERINEJ. FIELD, Ph.D., R.D. 4 ABSTRACT This paper reviews the history, chemistry, safety, toxicity, and anticancer effects of the organogermanium compound bis (2-carboxyethylgermanium) sesquioxide (CEGS). A companion review follows, discussing the inaccuracies in the scientific record that have prematurely terminated research on clinical uses of CEGS. CEGS is a unique organogermanium compound first made by Mironov and coworkers in Russia and, shortly there- after, popularized by Asai and his colleagues in Japan. Low concentrations of germanium occur in nearly all soils, plants and animal life; natural occurrence of the CEGS form is postulated but not yet demonstrated. The literature demonstrating its anticancer effect is particularly strong: CEGS induces interferon- g (IFN-g), en- hances natural killer cell activity, and inhibits tumor and metastatic growth—effects often detectable after a single oral dose. In addition, oral consumption of CEGS is readily assimilated and rapidly cleared from the body without evidence of toxicity. Given these findings, the absence of human clinical trials of CEGS is un- expected. Possible explanations of why the convincing findings from animal research have not been used to support clinical trials are discussed. Clinical trials on CEGS are recommended. INTRODUCTION bispropionic acid; 3-oxygermylpropionic acid polymer; poly- trans-(2-carboxyethyl) germasesquioxane); proxigerma- n general, dietary supplements are an underinvestigated nium; repagermanium; and Serocion. The trade names Ge- Itherapeutic modality. One should not be surprised if it is 132 (Asai Germanium Research Institute, Tokyo, Japan) and shown that a disease or illness responds to dietary supple- SK-818 (Sanwa Kagaku Kenkyusho Co. Ltd. Mie, Japan) ap- ments: nutrition is the foundation of good health, and dietary pear in both the popular press and the scientific literature. supplements may prove to be some of the most powerful medicines ever discovered (Massey, 2002). For at least 35 years, both health claims and accusations of toxicity have ORGANIC CHEMISTRY OF THE METALLIC been attributed to bis (2-carboxyethylgermanium) sesquiox- ELEMENT GERMANIUM ide (CEGS), also widely referred to as organic germanium or germanium sesquioxide. Additional names for this com- The general chemistry, the organic chemistry, and the pound in The Merck Index (The Merck Index, 1996) include ubiquitous occurrence of the element germanium have been propagermanium; 3,3 9-(1,3-dioxo-1,3-digermanoxanediyl) known for years (Davydov, 1966; Glocking, 1969; Lesbre 1Departments of Paediatrics, and Community Health Sciences, Faculty of Medicine, University of Calgary, and Alberta Children’s Hospital, Calgary, Alberta, Canada. 2Parish Chemical Company, Vineyard, UT. 3Departments of Psychiatry and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. 4Department of Agricultural, Food and Nutritional Science, Faculty of Agriculture, Forestry and Home Economics, University of Al- berta, Edmonton, Alberta, Canada. 337 338 KAPLAN ET AL. et al., 1971). Germanium has many of the chemical charac- treating himself and other patients with this water-soluble or- teristics found in carbon, silicon, and tin, all in the same col- ganic germanium compound. The Asai Institute was organized umn (group IVA) of the periodic table. Research has iden- to promote this remedy for a variety of illnesses. Others ac- tified the unique features of the stable carbon–germanium cepted Asai’s report that he (and not Mironov) was the first to bond and the multiplicity of stable derivatives available from discover CEGS (Goodman, 1988; Kamen, 1987) and have con- this combination of elements. fused matters further (1) by not distinguishing among the var- Mironov of Russia explored various organogermanium ious germanium compounds promoted for different ailments compounds and their syntheses beginning in the 1950s. By and (2) by mislabeling organic and inorganic compounds (e.g., 1966, he and his colleagues had synthesized CEGS as well calling germanium citrate lactate* an organic germanium com- as three different intermediates that could be used for its pound, when its solution chemistry is actually inorganic). preparation (Mironov, 1989; Mironov et al., 1967). Three synthetic routes all begin with the formation of trichloroger- Polymorphism mane (HGeCl 3) from germanium dioxide by reduction and chlorination. This trihalogermane was then used to react with Some confusion has arisen because writers have not rec- various well-known acrylic compounds, acrylic acid, acrylic ognized the phenomenon of polymorphism that is charac- chloride, and acrylonitrile, in processes shown below: teristic of germanium compounds. The formula [(GeCH 2 CH2COOH)2O3]n and the term CEGS can be used to repre- HGeCl3 1 CH2 5 CH-COOH R Cl3GeCH2-CH2-COOH sent both Ge-132 and SK 818 (the trade names mentioned above), as well as other structures. Polymorphism presents HGeCl3 1 CH2 5 CH-COCl R Cl3GeCH2-CH2-COCl itself in the solid forms of this compound that manifest dif- ferent crystalline, molecular weight distribution, and parti- HGeCl3 1 CH2 5 CH-CN R Cl3GeCH2-CH2-CN cle size properties. Although there may be many polymor- phic solid forms, the aqueous solutions, once they are The products from trichlorogermane and each of these formed, are, for all practical purposes, identical. acrylic compounds, when treated with water under the proper Solid, dry CEGS belongs to a class of materials known as conditions, yield the same hydrolysis product, (GeCH 2 network oxide polymers, which are characterized by primary, CH2COOH)2O3, or perhaps (HO) 3GeCH2CH2COOH, which secondary, and tertiary structures. Each germanium center in becomes CEGS when induced to come out of solution. Mironov CEGS shares three oxygen atoms with other germanium cen- recognized the treatment with water and removal of chloride ters, hence the name sesquioxide. The primary structure is steps of the process that are necessary to produce O 1.5 the monomer subunit with the carboxyethyl germanium at- GeCH2CH2COOH, as he designated it. Mironov identified this tached to three shared oxygen atoms commonly represented compound as an intermediate in his conversion of Cl 3GeCH2- by the dimeric formula, (GeCH 2CH2COOH)2O3, which, in CH2-CN to Cl3GeCH2-CH2-COCl. In a later summary paper, fact, does not exist. A secondary structure shows how the Mironov stated that recognized that (O 1.5GeCH2CH2COOH)x monomeric units link up with each other. Eight- (8) (Sawai has “valuable biological activity” (Mironov, 1989). He ob- et al., 1993) and 12- (Tsutsui et al., 1976) membered ger- served that treatment of Cl 3GeCH2-CH2-COOH with water manium-oxygen rings have been reported. Models with 6- gives CEGS as the major hydrolysis product. membered rings indicate that this arrangement is also likely. Mironov first presented a summary of his work in 1967 A low-molecular-weight, three-dimensional adamantane at the Third International Symposium on Organometallic cage structure for which the formula [(GeCH 2CH2 Chemistry, held in Munich (Mironov and Gar, 1968). At the COOH)2O3]n, n 5 2 may well exist. Otherwise, “infinite” same time, Asai had been working on the extraction of ger- sheets of variable molecular weight are the rule. manium from coal ash in Japan. Asai and coworkers did Tertiary structure refers to how the secondary structures not acknowledge Mironov’s prior reported synthesis of fit into a crystal lattice. Different secondary structures will (GeCH2CH2COOH)2O3; hence, subsequent writers have erro- generally produce different crystal lattice types, referred to neously attributed the initial work to Asai, who lived in Ger- as polymorphs, each of which will display a characteristic many during World War II and must have known of Mironov’s crystal shape, density, packing order, melting point, or tran- work (Asai, 1977, 1980). In the 1970s, Asai wrote nonscien- sition temperature, and a characteristic x-ray diffraction pat- tific books for the lay public on what he referred to as a new, tern (Sawai et al., 1993; Tsutsui et al., 1976). The particu- miraculous germanium compound, which he named Ge-132 lar polymorph that is produced and the average molecular (Asai, 1977, 1980). In both of his books Asai told the same weight and distribution is a function of the process chem- story: In November 1967 (2 or 3 months after the Mironov re- istry and conditions. † Batch variations from a single sup- port in Munich), one of his workers told him about the prepa- ration of a substance described as an organogermanium com- *Germanium citrate lactate is the correct nomenclature for a pound that was soluble in water. Asai espoused a theory that compound that is often referred to as germanium lactate citrate, all diseases have a common cause (Asai, 1980), and he began germanium lactate-citrate, et cetera. GERMANIUM SESQUIOXIDE FACTS 339 plier are of the same order of magnitude as the variations ticularly well supported. As reviewed in Table 1, this effect between suppliers. Aqueous solutions of Ge-132, SK-818, has been shown in healthy mice and dogs as well as in an- and the products from other manufacturers are identical. imals which have been immunosuppressed by surgical pro- The oxygen-germanium bonds in CEGS can be somewhat cedures or other stressors, such as heat. The time course of transitory in aqueous solution. Hence, the basic formula the response, not shown in Table 1, has been reported to be (GeCH2CH2COOH)2O3 represents a member of a polymeric rather consistent: dose–response curves have often demon- chain best represented by [(GeCH 2CH2COOH)2O3]n where strated a peak response of IFN- g at approximately 24 hours the value of “n” depends on the way in which a solid prod- after oral administration (Aso et al., 1985; Nakada et al., uct separates out of a solution of the compound.