Semicarbazide-cadmium therapy was an experimental cancer therapy that was tested in several clinical trials in the Soviet Union during the 1960s. Semicarbazide is an irreversible inhibitor of semicarbazide-sensitive amine oxidase (SSAO), an enzyme possibly involved in exacerbation of inflammation. Cadmium is a heavy metal and can also induce apoptosis.

The first study in humans was an open pilot trial conducted in Russia in 1957-1962.[1] It was also patented in Russia.[2] This method was successfully used for treatment of patients in later stages of lung, intestinal, and brest cancer, melanoma, and some other cancer types. The Experiments were accompanied by organizational problems (conflict between soviet authorities and scientists).[3]

Method

The method involved the use of the following preparations: semicarbazide hydrochloride, urea, and cadmium halides. Additionally, stable isotopes of gadolinium, as gadolinium oxides, can be used, in addition to other drugs.

Semicarbazide

Clinical use of semicarbazide (a SSAO-inhibitor) gives the evidence that an inflammatory reaction can be reduced by blocking the enzymatic activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO). SSAO activity was found significantly increased in blood and tissues in some pathological conditions. The enzyme activity has been reported to be elevated in diabetes and cancer. The mean specific activity of SSAO was significantly elevated in the group of patients having prostate cancer with skeletal metastases. Semicarbazide (and SSAO blockers) can reduce inflammatory response and can protect against the progressive vascular complications caused by oxidative stress. It also can reduce pain. The SSAO inhibitors also appears able to protect endothelial cells against toxic effects of free radicals.[4] Semicarbazide itself is a standard enzyme inhibitor and new SSAO inhibitors are in development. SSAO inhibitors significantly blocked the catalytic activity of VAP-1 in tumor, attenuated tumor progression, and reduced neo-angiogenesis.[5] Semicarbazide is a known inhibitor of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. GABA has emerged as a tumor signaling molecule in the periphery that controls the proliferation of tumor cells and perhaps tumor stem cells.[6]

Cadmium

Cadmium is a heavy metal and an environmental pollutant. Cadmium is a known carcinogen.[7] Cadmium exposure has been linked to lung, prostate and renal cancer.[8] It is not a strong mutagen, but acts as a promoter through mitogenic effects on gene expression. Cadmium (metallotherapeutic drug, metal-based drug) can induce apoptosis (programmed tumor cell death) in various cell types. It can also be anti-carcinogenic under certain conditions.[9][10][11] At low concentrations, cadmium is able to stimulate the immune system, while at higher concentrations inhibitory and suppressive reactions were observed.[12] Cadmium may inhibit angiogenesis.[13] As a stress agent, inducing apoptosis and blocking it, Cd can have both helpful and harmful effects.[14]

See also

References

  1. ↑ Volokhonskaya, M.L.; Voronko, N.D.; Vysheslavtsev, S.I.; Yaroshevskii, F.Yu (1963). "Results of the use of semicarbazide-cadmium therapy in patients with incurable malignant neoplasms". Vopr. Onkol. 18: 92–104., abstract in U.S. National Library of Medicine, and Volokhonskaya, M.L. et al. "Experience in the use of semicarbazide-cadmium therapy in patients suffering from malignant neoplasms in the incurable period", Voprosy Onkologii (U.S.S.R.); Vol: 9: No. 6, 1963 abstract in Energy Citations Database.
  2. ↑ Pat. №2071767, Russia. Method of treatment of oncological patients.
  3. ↑ Fedorov, B. S.; Fadeev, M. A.; Utenyshev, A. N.; Shilov, G. V.; Konovalova, N. P.; Tat'yanenko, L. V.; Sashenkova, T. E.; Blokhina, S. V.; Berseneva, E. N. (2011). "Synthesis, crystal structure, and antitumor activity of the cadmium dichloride complex with semicarbazide". Russian Chemical Bulletin. 60 (9): 1959–1962. doi:10.1007/s11172-011-0296-3. S2CID 96702197.
  4. ↑ Euromedica, Internationaler Medizinischer Kongress Hannover 2007, Germany.
  5. ↑ Li, Rui; Li, Hui; Luo, Hong-Jun; Lin, Zhe-Xuan; Jiang, Zhi-Wu; Luo, Wen-Hong (2013). "SSAO inhibitors suppress hepatocellular tumor growth in mice". Cellular Immunology. 283 (1–2): 61–69. doi:10.1016/j.cellimm.2013.06.005. PMID 23850964.
  6. ↑ Young, SZ; Bordey, A (2009). "GABA's control of stem and cancer cell proliferation in adult neural and peripheral niches". Physiology. 24 (3): 171–85. doi:10.1152/physiol.00002.2009. PMC 2931807. PMID 19509127.
  7. ↑ Huff J; Lunn RM; Waalkes MP; Tomatis L; Infante PF (2007). "Cadmium-induced cancers in animals and in humans". Int J Occup Environ Health. 13 (2): 202–12. doi:10.1179/oeh.2007.13.2.202. PMC 3399253. PMID 17718178.
  8. ↑ Waalkes MP (December 2003). "Cadmium carcinogenesis". Mutat. Res. 533 (1–2): 107–20. doi:10.1016/j.mrfmmm.2003.07.011. PMID 14643415.
  9. ↑ Cao, Xing-Jiang; Chen, Rui; Li, Ai-Ping; Zhou, Jian-Wei (2007). "JWAGene is Involved in Cadmium-induced Growth Inhibition and Apoptosis in HEK-293T Cells". Journal of Toxicology and Environmental Health. 70 (11): 931–937. doi:10.1080/15287390701290212. PMID 17479408. S2CID 26022100.
  10. ↑ Waalkes, Michael P.; Diwan, Bhalchandra A. (1999). "A". Carcinogenesis. 20 (1): 65–70. doi:10.1093/carcin/20.1.65. PMID 9934851.
  11. ↑ Shimoda R; Nagamine T; Takagi H; Mori M; Waalkes MP (December 2001). "Induction of apoptosis in cells by cadmium: quantitative negative correlation between basal or induced metallothionein concentration and apoptotic rate". Toxicol. Sci. 64 (2): 208–15. doi:10.1093/toxsci/64.2.208. PMID 11719703.
  12. ↑ Marth, E; Barth, S; Jelovcan, S (2000). "Influence of cadmium on the immune system. Description of stimulating reactions". Cent Eur J Public Health. 8 (1): 40–4. PMID 10761626.
  13. ↑ Woods, JM; Leone, M; Klosowska, K; Lamar, PC; Shaknovsky, TJ; Prozialeck, WC (Apr 2008). "Direct antiangiogenic actions of cadmium on human vascular endothelial cells". Toxicol in Vitro. 22 (3): 643–51. doi:10.1016/j.tiv.2007.12.009. PMC 2349099. PMID 18243643.
  14. ↑ Chandra, R; Dass, SK; Tomar, P; Tiwari, M (Jul 2001). "Cadmium, carcinogen, co-carcinogen and anti carcinogen". Indian J Clin Biochem. 16 (2): 145–52. doi:10.1007/BF02864853. PMC 3453642. PMID 23105310.
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