Germane Facts About Germanium Sesquioxide: I. Chemistry and Anticancer Properties

Home , Germane, Organogermanium compound

THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 10, Number 2, 2004, pp. 337–344 ©Mary Ann Liebert, Inc.

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 different crystalline, molecular weight distribution, and parti- HGeCl3 1 CH2 5 CH-CN R Cl3GeCH2-CH2-CN cle size properties. Although there may be many polymorphic 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 support in Munich), one of his workers told him about the preparation 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. The solid 1993; Suzuki et al., 1985a, 1985b). polymers are most often cyclic and terminal hydration at the Several researchers have found that the optimum physi- ends of the chains in solution are often eliminated. Not only ologic response is produced at moderate and not at maxi- is the length of the polymer structure variable but also the mum doses. For instance, the longest survival in mice ex- orientation of this polymeric chain depends on the condi- posed to a lethal virus was in mice given 100 mg/kg, not 20 tions under which the solid comes out of solution. Particle or 500 mg/kg (Aso et al., 1989; Kumano et al., 1985). The size and bulk density of the dried solid in batch-to-batch dose, frequency of consumption, and length of treatment are comparisons are notoriously variable. † just three of many variables that require further research. Multiple polymorphs, therefore, are characteristic of this compound and efforts to show trivial distinctions are ill- Anticancer properties founded. Regardless of the polymorphic form or solution Feeding or supplementing with CEGS has beneficial configuration, CEGS is characterized by carbon–germanium effects on cancer in a variety of animal models: spontaneous bonds that are particularly stable, making it a truly organic leukemia, lung carcinoma, and chemically induced tumors germanium substance. of the gastrointestinal system (Table 2). Two other organic germanium compounds that have been studied in animal Organogermanium compounds in nature models are 1-phenyl-2-carbamoyle thylgermanium sesqui- The extent of germanium’s occurrence in plants and ani- sulfide (PCAGeS) and 1-phenyl-2-carbamoyl ethylgerma- mals has not been thoroughly investigated. The fact that nium sesquioxide (PCAGeO). The former, PCAGeS, was found to inhibit metastases from lung carcinoma in mouse organogermanium compounds do exist in nature was shown by Hara and coworkers who argued that germanium is an es- models, while PCAGeO exhibited a similar but smaller ef- sential trace element (Hara et al., 1990). Although many re- fect (Sato et al., 1988, et al., 1985). Both were reported to ports have alleged that there is no germanium in seawater, have low acute toxicity. In these few studies that have com- precise measurements of methylated germanium in seawater pared CEGS to other forms, such as germanium dioxide, the have demonstrated that organic germanium compounds do latter had no effect on cancer development (Jao et al., 1990). exist in the biologically active ocean (Lewis et al., 1985). Several studies have focused on the mechanism by which Furthermore, analytical methods for the determination of CEGS might exert its anticancer effect. Suzuki presented data in vitro germanium may be flawed because of the unique chemistry showing stimulation of sera with CEGS resulting in g of organogermanium compounds. The presence or absence the production of IFN- (Suzuki, 1985, 1987; Suzuki et al., g of many elements in low concentrations is often determined 1986). CEGS has been shown to induce IFN- and enhance by atomic absorption. Mino and associates (1980) have NK cell activity and these are logical mechanisms by which shown that the volatility of germanium compounds can of- the compound could inhibit cancer. Interferons have antipro- ten result in the loss of such materials during sample prepa- liferative actions and have been demonstrated to inhibit the g ration when the compounds are heated. Shinogi et al. (1989) growth of many tumor cells. IFN- is produced primarily by have refined the analytical methods by which germanium T lymphocytes, which are important in both modulating the can be detected in animal blood and tissue. immune system and inhibiting tumor growth. For example, a single dose of CEGS resulted in 50% survival from tumors that were 100% lethal in control animals (Suzuki et al., 1986). POTENTIAL CLINICAL EFFICACY Anti-IFN-g treatment completely reversed that effect, con- OF CEGS firming the importance of IFN- g in the CEGS anticancer effect (Suzuki et al., 1986). Subsequent in vivo and in vitro General enhancement of immunocompetence studies led a member of this group of researchers to propose a pathway by which CEGS results in T-cell production of The ability of CEGS to induce interferon- g (IFN-g) cytokines such as IFN- g (Suzuki, 1987). acutely and enhance natural killer (NK) cell activity is par- In support of the animal work, there is some published evidence of NK activity enhancement in humans with can- †Parish WW. Unpublished results from CEGS production runs, cer. Tanaka and colleagues (1984) gave CEGS to 18 patients 1990–2003. with cancer (1 g/d orally for 10 days). After 3 days, NK ac- 340 KAPLAN ET AL.

TABLE 1. GENERAL ENHANCEMENTOF IMMUNOCOMPETENCEBY CEGS

Model CEGS administration Outcome Reference

Mice 1 oral dose, 300 mg/kg IFN-g, NK cell activity Aso et al., 1985 Dogs 1 oral dose, 50 mg/ kg ¯ Surgically-induced immunosuppression; Nakada et al., maintained for 14 days 1993 Dogs Oral 50 mg/kg for 2 wks NK cell activity; especially in one Kuwabara et al., animal with cancer 2002 Mice 1 i.p. dose at 100 mg/kg Reversal of thermal-induced IFN- g Suzuki and Pollard, suppression 1984 Mice 20, 100, or 500 mg/kg survival time after exposure to lethal Aso et al., 1989 orally, 6 days virus; splenic NK cell activity Mice Various doses Survival time doubled following Fujita and Seto, exposure to lethal viruses 1990 Mice 1 oral dose, 100 mg/kg Splenic in cells producing IFN- g Ikemoto et al., 1996

CEGS, bis (2-carboxyethylgermanium) sesquioxide; IFN- g, interferon- g; NK, natural killer; i.p., intraperitoneally. tivity was significantly augmented; interestingly, an inter- at 5 and 7 months showed total disappearance of the tu- mittent schedule of administration was required to maintain mor. She continued to take CEGS but at a lower (un- the increase. specified) dose. More than 4 years later, the patient was More recently, a second report of CEGS therapy in hu- still cancer-free. mans came as a case study of a woman with a lethal form of lung cancer that was unresponsive to chemotherapy and Human clinical trials radiation therapy (Mainwaring et al., 2000). Symptom re- lief was said to occur within days of her taking CEGS (7.2 The possible use of germanium compounds for cancer g/d). A chest radiograph showed 60% clearing of the mass treatment is consistent with certain other metallic compounds

at 3 months, and thoracic computed tomograph y scans used or being studied as antineoplastic agents: cis-platin from

TABLE 2. ANTICANCER EFFECTS OF CEGS

Model CEGS administration Outcome Reference

Mice with Lewis 10, 100, or 500 mg/kg, Prevention of metastases; Kumano et al., lung carcinoma i.p., 7 days 50% ¯ at 100 mg/kg dose 1985 Mice with spontaneous 10 or 100 mg/kg orally, Weight of spleen, thymus, Fujita et al., 1990 leukemia twice/wk for 5 mos. lymph nodes ,50% that of controls Mice with Lewis Oral 100 mg/ kg/day Efficacy of antitumor Kobayashi et al., lung carcinoma treatments (e.g., bleomycin, 1986 5-FU) Rats with chemically 0.05% CEGS in diet Inhibition of neoplastic Jang et al., 1991 induced multiorgan for 36 wks lesions carcinogenesis model Mice with lethal tumors 1 dose, 100 mg/kg, orally 50% survival Suzuki, 1985, 1987 Rats with chemically 80 mg/kg daily for 20 wks Protective effect of CEGS Jao et al., 1990; induced intestinal Song, 1993 tumors Rats with chemically 600 mg/L of drinking ¯ Incidence of stomach cancer, Ming et al., 1996 induced stomach water for 5 wks &shallower infiltrating lesions depth of tumours Mice with ascites 1 oral dose of 100 IFN-g activity in plasma Suzuki et al., tumours mg/kg 1985a, 1985b 18 patients with cancer 1 g/day orally, for NK cell activity after 3 days Tanaka et al., 1984 10 days Patient with terminal 7.2 g/day initially; Disappearance of tumor Mainwaring et al., spindle cell carcinoma later reduced on CT scan at 5 mos.; 2000 of the lung maintained for 4 yrs

CEGS, bis (2-carboxyethylgermanium) sesquioxide; i.p., intraperitoneally; IFN- g, interferon- g; NK, natural killer; CT, computed to- mography. GERMANIUM SESQUIOXIDE FACTS 341 platinum, gallium nitrate, and even gold compounds (Jao et established many years ago (Heuper, 1931; Mueller, 1922; al., 1990). Based on the experimental data in animals and pre- Schroeder and Balassa, 1967). Reports by Nagata et al. liminary data from human studies, it would be logical to as- (1985), Okuda et al. (1987), Kobayashi et al. (1989), and sume that CEGS would have been tested in clinical trials. Al- others in the Japanese scientific literature reviewed by though clinical trials of a germanium compound have been Takeuchi et al. (1992), have explained that, during the 1980s conducted and published in the 1980s, CEGS was not the and early 1990s, there were very serious problems in Japan form studied. Instead, all the published clinical trials utilized resulting from many people taking very large doses (260 g/d Spirogermanium, which is a different organogermanium com- in one case) of germanium remedies. As discussed in the pound developed by Rice and colleagues (Rice et al., 1984) accompanying article (companion paper in this issue, pp. and manufactured by Unimed, Inc. (Marietta, GA). Spiroger- 345–348), most of those elixirs were contaminated by germanium, or 2-aza-8-germaniumspiro decane-2-propamine- manium dioxide. 8,8-diethyl-N,N-dimethyl dichloride, is an azaspirane-germa- Hess and colleagues (Hess et al., 1993) described two pa- nium compound. Spirogermanium was demonstrated earlier tients who took germanium citrate lactate for human im- to inhibit DNA, RNA, and protein synthesis (Gerber and munodeficiency virus (HIV) and developed renal damage Leonard, 1997; Saiers et al., 1987) and it also showed activ- (confirmed on biopsy). These authors made the interesting ity in vivo against several types of implanted cancer cell lines point that germanium citrate lactate is usually advertised as in laboratory animals (Slavik et al., 1983), providing the ra- “organic germanium” to suggest good tolerability, implying tionale for potential antineoplastic activity. However, it should its benign nature. The reality is that it is not an organoger- also be noted that many basic experiments produced no ef- manium compound because there are no germanium–carbon fect with Spirogermanium (Schwartz et al., 1983) or produced bonds and it probably is not safe. the effect only at “supralethal” doses (Mirabelli et al., 1989) A case study by Nagata et al. (1985) is often cited in while also revealing significant microscopic evidence of drug the literature as evidence of the toxicity of germanium toxicity, such as necrosis (Henry et al., 1980). dioxide. A patient who took 600 mg/d for 18 months died Phase II trials of Spirogermanium did not demonstrate from renal failure; evidence of tissue accumulation of the therapeutic benefit (Eisenhauer et al., 1985a, 1985b; Ettinger inorganic germanium preparation was documented. This et al., 1989; Falkson and Falkson, 1983; Goodwin et al., type of toxicity is often associated with nausea, vomiting, 1987; McMaster, Greco, Johnson, and Hainsworth, 1990; anorexia, and weight loss (Obara et al., 1991). There is a Saiers et al., 1987) and produced neurotoxicity in patients significant difference in clearance of germanium dioxide. (manifested by dizziness, drowsiness, paresthesias, ataxia, Unlike CEGS, which has been shown to be completely ex- disorientation, and nystagmus). These results might not be creted from the body within 72 hours (Miyao et al., 1980), so surprising: There was little support in the animal litera- some inorganic forms remain in the hair, nails, and kid- ture for the use of Spirogermanium to treat cancer (Mirabelli neys for years after ingestion is terminated (Obara et al., et al., 1989). 1991). Four-week-old mice were studied after a dose of In summary, although the preclinical studies of CEGS germanium dioxide given via oral gavage. Control mice suggest this compound may be useful for treating cancer, showed no detectable germanium in tissues but the treated clinical trials of CEGS have not been published. mice had accumulatio ns of germanium in the stomach, small intestine, kidney, and liver within 30 minutes of the gavage (Shinogi et al., 1989). Sanai and colleagues (1991b) determined the lowest observed adverse effect dose to be SAFETY AND TOXICITY OF CEGS 73.5 mg/ kg body weight per day. Translated to a 150- pound (68-kg) adult, this would be approximately 5 g of Micronutrients can exist in different forms which influ- germanium dioxide per day, an extremely high dose for a ence their biologic activity and potential safety. For instance, trace mineral. phosphorus in phosphoric acid is potentially toxic when ingested but entirely safe as an essential element of all nucleic acids. Similarly, sodium as sodium chloride (table salt) is CEGS appears to be safe even at large doses relatively safe but sodium hydroxide is toxic. Research on dietary germanium has not always taken these differences When ingested, CEGS or [(GeCH 2CH2COOH)2O3]n dis- into account and this has resulted in variable conclusions in solves to the polymer chain of which the basic unit may terms of potential efficacy and safety. be the monomer or dimer described above. The stable carbon–germanium bond ensures that potentially harmful inor- Inorganic germanium can be harmful ganic germanium compounds are not generated after ingestion. When absorbed into the blood either from the mouth at large doses in typical sublingual uptake or from the stomach and in- The nephrotoxicity of inorganic forms of germanium (such testines, this compound circulates and is excreted in urine as germanium dioxide or germanium citrate lactate) was well- unchanged in 72 hours (Miyao et al., 1980). 342 KAPLAN ET AL.

An important study of toxicity compared CEGS and ger- g/kg of body weight in mice and is greater than 10 g/kg of manium dioxide directly in Wistar rats (Sanai et al., 1991a). body weight in rats” for an oral dose. In mice and rats, the Renal function and histology were evaluated after 24 weeks Institute reported that the LD 50 value for i.v. administration of 75 mg/ kg daily of germanium dioxide, 120 mg/ kg of is higher than any physically relevant amount. When pure CEGS, or no germanium. The contrast between the two CEGS was “intravenously injected into dogs over a period of treatment groups was striking: the germanium-dioxide– six months in a dosage amount of 500 mg/kg of body weight treated group suffered weight loss, lowered hematocrit, el- per day, no toxicity was found.” Thus, neither acute nor evated blood urea nitrogen, elevated serum cholesterol, and chronic (6 months) toxicity has been associated with oral or signs of renal pathology. In contrast, these parameters in the intravenous doses. rats treated with CEGS did not differ from the controls. Chronic exposure was studied for a longer time (1 year) These studies support the low toxicity of CEGS. by Asano’s team, which gave large doses (750 mg/ kg) of Even large doses of CEGS appear to be safe. For in- CEGS or germanium dioxide to rats with chemically induced stance, Anger et al. (1992) gave rats 1 g/kg per day (equiv- (adriamycin or mercuric chloride) renal lesions (Asano et alent to 0.427 g/kg per day of elemental germanium) for 6 al., 1994). Germanium dioxide treatment resulted in renal months and found no discernible toxic symptoms or effects damage, in contrast to CEGS treatment, which resulted in on growth or behavior. They also recorded nearly total ex- no toxicity, even in rats with prior renal damage. As Ger- cretion of the CEGS in 24 hours. As Obara et al. (1991) ber and Leonard (1997) concluded, “[g]ermanium may thus stated after testing Spirogermanium and CEGS: “Whereas be considered an element of rather low risk to man.” [Spirogermanium] has neurotoxicity and pulmonary toxicity, [CEGS] has extremely low toxicity and both drugs have no nephrotoxicity.” CONCLUSION Miyao and colleagues (1980) reported that the median lethal dose (LD 50) for acute administration of CEGS was in CEGS has been shown to induce IFN- g, enhance NK cell the range of a few grams per kilogram of body weight, in- activity, and function as an anticancer agent in animal mod- dicating extremely low toxicity. In Wistar rats given oral els. Given the data in support of the possible clinical effi- doses from 30 to 3000 mg/kg, no evidence of toxicity was cacy of CEGS, it seems unfortunate that clinical testing has visible. Chronic toxicity was studied in dogs with intra- occurred only with Spirogermanium. This may be related venous doses from 125 to 500 mg/kg; again, there was no to industry support of the clinical trials in the 1980s. Com- evidence of toxicity in clinical or pathologic examinations. mercial, patenting, or licensing issues may have precluded Miyao et al. (1980) concluded that CEGS “[S]eems to have CEGS from being used as the test intervention. virtually no chronic toxicity.” Some additional facts re- A second reason may be the confusion between CEGS garding safety were summarized in this book chapter: Patho- and toxic forms of germanium that have contaminated some logic analyses revealed that CEGS does not seem to have of the over-the-counter preparations. The misinformation in any target organs— but distributes widely from the blood the scientific literature is discussed in detail in the compan- into all organs studied. ion paper in this issue (345–348). Miyao et al. (1980) also conducted four phase I studies Based on the literature demonstrating the safety of pure on the safety and toxicity of CEGS in 20 healthy volunteers. preparations of CEGS, as well as its proven anticancer prop- Routes of administration (oral, intravenous [IV] intraperi- erties in animal models, it appears to be prudent to encour- toneal) and doses (25, 50, and 75 mg/kg) varied. No unusual age phase I trials in healthy adults and phase II trials in pa- subjective reactions or blood or urine values were obtained. tients with cancer, using properly prepared CEGS. Interestingly, the researchers also observed an increase in IFN-g in the serum, particularly at the higher doses. The effect on IFN- g was not related to age or gender but there ACKNOWLEDGMENTS were individual differences that warranted further research. CEGS may have no demonstrated toxicity because it is This research was supported, in part, by the Alberta Chil- water-soluble, is rapidly removed from plasma, and does not dren’s Hospital Foundation. We thank Susan Crawford for accumulate in tissues (Gerber and Leonard, 1997). As sev- research and editorial assistance. eral authors have mentioned, inorganic forms of germanium often accumulate in body tissues but excess CEGS is easily excreted (Miyao et al., 1980; Tao and Bolger, 1997). REFERENCES Perhaps the strongest argument for safety rests on the LD 50 data. On the basis of IFN- g induction by “organogermanium,” Anger F, Anger JP, Guillou L, Papillon A. Subchronic oral toxic- the Asai Germanium Research Institute, Tokyo, Japan, ap- ity (six months) of carboxyethylgermanium sesquioxide in rats. plied for U.S. Patent #4,473581 on September 25, 1984, stat- Appl Organo Chem 1992;6:267–272. ing that CEGS has virtually no toxicity, in contrast to most Asai K. 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