Cancer cells differ with normal cells in that they grow very fast, uncontrolled and hardly die. They need a lot of enzymes in quantitative term than normal cells for their metabolic processes, of which there are two particularly important enzymes: Hexokinase and DNA polymerase. The enzymes are interesting due to the catalyst the energy metabolism and replicate the DNA. They possess the same magnesium metal ion cofactor. The use of beta-decay radioisotopes to replace stable metals in the cofactor enzymes to deactivate them is a new trend for cancer treatment research. In this work, ²⁸Mg is used to replace a stable Mg in the enzymes. Deactivated hexokinase may stop or disturb the supply of energy in tumor cells. Deactivated DNA polymerase may stop or disturb DNA replication. Disturbing these two important processes, tumors can stop development and even be destroyed. Besides, during deactivating radioactive isotopes will bombard tumor cells on the spot with a nearly 100% chance of hitting.

Keywords: ²⁸Mg, Deactivation, Hexokinase, DNA polymerase

For survive and expand, the cancer cells need more energy than the normal ones. The catalyst for energy supply is the Hexokinase enzyme, a metal cofactor enzyme. There is a divalent magnesium ion at the active site of this enzyme. The Mg ion can react with ATP molecular, an energy unit, through the mitochondrial membrane in the cell to convert to ADP molecular and release the energy [17-20]. This is the first stage of the cell's energy metabolism cycle. If this stage is interrupted, the energy cycle could be manipulated. Cells will starve and may die. Somehow, deactivation Hexokinase, we can disrupt the energy cycle.

DNA replication will make the cancer cells faster multiply and grow. This is the most complex cycle in nature, many substrates and enzymes involved in this cycle. For example, helicase to split DNA helix to double strands, then recombine each strand into a new DNA chain by DNA polymerase enzyme family, of which DNA polymerase III plays the most important role. Many studies on the role of DNA polymerase in the formation and development of cancer are carried out. They also anticipate the enzyme's restriction or deactivation in cancer treatment by chemotherapy [21-25].

DNA polymerase is also a cofactor enzyme, in which two metallic elements Magnesium and Zinc located at active site [26,27]. The process of DNA separation and cloning take place at a fork, where all involved elements in this process converge. This location is also the destination or target for the needed agents to inhibit or makes replication errors. Somehow deactivation the DNA polymerase can stop DNA replication. Cancer cells will not replicate or they will replicate errors. The tumor will not grow and gradually shrink by losing the older cells and the cancer mass is destroyed systematically. In the case of faulty DNA replication, the T cell will recognize and the body's immune system will destroy them.

The assumption that radioisotope ²⁸Mg, somehow, can replace stable magnesium ion in the Hexokinase and DNA polymerase enzyme, these enzymes will be deactivated due to the decays of ²⁸Mg at the active site changed to ²⁸Al and then ²⁸Si. Obviously, just only one radioactive isotope ²⁸Mg can stop or interrupt the two most important metabolic processes, which are the power supply and the DNA replicate of cancer cells. It is a combination of the two most successful traditional cancer treatments, chemotherapy and radiotherapy. The chemotherapy is deactivation the enzymes. Radiotherapy is irradiation the cancer cells on the spot with a probability of reaching nearly 100% by beta particles, X-rays, gamma rays and bremsstrahlung radiations.

MATERIALS AND METHODS

Magnesium is an essential element in human health [28-30]. It plays an important role in metabolism processes. It exists in cofactor enzymes [31-33] including Hexokinase and DNA polymerase. Magnesium can transport into the cell and the different cellular organelles [33]. Many works have carried out and published surrounding Mg problem, both of a deficiency and an excess of Mg nutrition [34-43]. Magnesium has three stable isotopes and some radioisotopes [44]. The organism accepts Mg isotopes in their compounds or substrates without differently seeing due to the similar valence of Mg. Among of radioisotopes of magnesium, only ²⁸Mg can have enough condition for replacing stable Mg in cofactor enzymes [45]. ²⁸Mg is a pure beta decay isotope (100% intensity) with a half time 20.9 h. It emits three electrons 0.211, 0.458 and 0.859 MeV in maximum energy accompanying with fours gamma rays and a lot of X-rays [44]. It has been produced by ⁶Li + ²⁶Mg alloy + thermal neutron or (27Al, α, 3p) nuclear reactions [46]. Its decayed product is a 28Al isotope. The 28Al is also pure beta decay isotope (100% intensity) with a half time 2.3 min. The isotope emits an electron with 2.87 MeV in maximum energy accompanying with a gamma-ray 1.779 MeV in energy. After decay, ²⁸Al changes to stable ²⁸Si isotope [44].

Hexokinase and DNA polymerase are two used enzymes in this propositional investigation.

Somehow, if the ²⁸Mg is transferred to the tumor cells, the enzymes with Mg cofactor will be deactivated and the tumor cells will be injured.

RESULTS AND DISCUSSION

The average energy of beta particles is used to in internal irradiation. The calculated average energies of beta particles for ²⁸Mg and ²⁸Al are 0.139 MeV and 1.114 MeV, respectively. According to Coderre [47], if the one MBq activity of ²⁸Mg is injected, the calculated absorbed dose rates of ²⁸Mg and ²⁸Al in tumor cells are 0.83 cGy/s and 1.78 cGy/s, respectively. These absorbed doses are below the limited dose for internal irradiation [48]. This activity is equivalent to 1.085E+11 ions or 5.016 E-12 g ²⁸Mg. These number of ions can target to hexokinase and DNA polymerase accordingly competition mechanism. The beta particles calculated maximum ranges of ²⁸Mg and ²⁸Al isotopes in body tissue are 62.19 mg/cm² and 143.91 mg/cm², respectively [49]. The results are equivalent to about 0.06 cm and 0.14 cm in an effective radius, respectively, if the average tissue density is considered as 0.96 kg/L. These results show that the radioisotopes can interaction with healthy cells with above interval in the case the isotopes located at the edge of the tumor body. It should take account that is a side effect of this method.

The assumption that somehow the one MBq of the ²⁸Mg pharma product can intravenously inject into the cancer cells. The Hexokinase and DNA polymerase enzymes can obtain ²⁸Mg as the cofactor. The situation is the same ¹³¹I competitive with the stable Iodine in the thyroid gland [15].

Bustamante and Pedersen [50] showed the high concentration of hexokinase in tumor cells of rats. The concentration of hexokinase in tumor cells is about 200 times higher than in healthy cells. Due to the tumor cells increasingly need divalent Mg. The supply of ²⁸Mg isotope can carry out to replace the stable Mg. There is no report to the high content of the DNA polymerase in the tumor cells. It should be taking into account that, the DNA replication of tumor cells is more rapidly than healthy cells, especially in metastasis phase. The tumor parasites onto the host organs but they increase in size very fast. By these, they need more substrate, energy, DNA replication and others to survival, development and growing up. They also need more enzymes, in which DNA polymerase is the most important one. Benzekry [51] showed the classical mathematical models for description and prediction of experimental tumor growth, in which the authors pointed out that the grown rate of tumor cell, is very fast. The tumor cells are highly avidity for Mg, seemly they are Mg traps and the intracellular Mg content is higher than extracellular Mg content [52]. By this reason, the supplying of ²⁸Mg could be targeting to DNA polymerase.

Studies using ²⁸Mg by human intravenous route Silver et al. [53] indicate that the absorption of Mg²⁺ in the gastrointestinal tract is very negligible. Isotope balance with magnesium in the body is slow about 10% to 25% of the whole after 40-60 h and up to 90 h to reach 30% [53]. Nevertheless, the rest of ²⁸Mg amount is about 25%, 12.5% and 6.25%, respectively, due to its decay for the above interval time. The true remained of ²⁸Mg amount of the total injected amount in the above balance periods are 2.5%, 3.12% and 1.87%, respectively. Thus, it noted that after 40 h the most of ²⁸Mg amount is excreted out of the body by urine. This should be considered when carrying out the clinical experiment.

As we have known, the cell needs energy to all its cycle. The energy unite of every organism is an ATP molecular. The ATP is created at mitochondria then is changed to ADP by hexokinase and these process products the energy [54]. The ATP will not be converted to ADP due to hexokinase was deactivation. The cell will be loose the functions due to lack of energy.

In the case of the cell duplication, after DNA is unzipped into two strands, the cell’s substrates and structured materials focus onto the fork. The DNA replication takes place by DNA polymerase helping. When the DNA polymerase is deactivation the old cell was dying due to the DNA was separated and cannot recover. The new one cannot generate because the DNA is not replication. Consequently, the tumor mass will be narrow.

Somehow, the ²⁸Mg isotope is transferred to the tumor cells it can compete to the stable Mg at the active site of the hexokinase and the DNA polymerase. Due to the ²⁸Mg decays to the ²⁸Al then to the ²⁸Si in situ. Both of the ²⁸Al and the ²⁸Si are not the cofactor of these enzymes anymore, the consequence is that two enzymes are deactivated.

Deactivation the hexokinase and DNA polymerase is very impacted to growing and duplicating of the tumor cells. It forbids the transferring of ATP to ADP, stops the replication of DNA. When both of process is inhibited the tumor cell would be harmful.

The irradiation due to the decayed ²⁸Mg and ²⁸Al will bombard the tumor cells in situ by beta particles, gamma-rays, X-rays and bremsstrahlung radiations. The probabilities of this bombardment are of about a hundred percent and do not cause significant side effects. This process causes the wounded to the tumor cells.

The free radicals created from radiation effect with intracellular fluid, in turn, will react with substrates and nucleotide molecules. Consequently, these materials will be damaged. The tumor cell will be injured.

Three above processes act into the tumor cells simultaneously. In the result, the tumor cells will dead (Figures 1 and 2).

CONCLUSION AND RECOMMENDATION

Many authors have studied hexokinase and DNA polymerase [17-32] but no one has used ²⁸Mg to investigate the kinetics, biochemical metabolism and the effect of Mg on the activity of these enzymes. There are studies on ²⁸Mg [53] but only stop at the level of marking and testing the metabolism and endurance of the body with Mg. There are many researches on biochemistry, metabolism and effects of Mg on cancer [34-43] and have revealed some ideas for curing cancer from these studies. Independent studies on hexokinase and DNA polymerase have shown how they work, the catalytic mechanism of these enzymes all recognize the important role of Mg cofactor in converting ATP into ADP and DNA replication.

The study of replacing stable Mg with ²⁸Mg radioactive isotopes in these enzymes for the purpose of deactivating them is a completely new study. It opens up a huge potential for disrupting and controlling important molecular and cellular metabolic processes. If these studies are successful it can be used to treat cancer. Enzymes will be the destination for cofactor radioisotopes [45]. In the ²⁸Mg case, this study will deactivate hexokinase and DNA polymerase and several other enzymes where Mg is the cofactor. This is a breakthrough in inhibiting energy supply for cells and a strong intervention in the process of DNA replication, two processes that determine the existence, development, and replication of cancer cells. Stopping or interrupting these processes in tumors we hope to eradicate this disease. In addition, the radioisotopes are introduced into the nucleus and mitochondria where the enzyme located, the radiation created by them will directly bombard cancer cells with a 100% probability of reaching the target. Free radicals generated by the interaction of radiation with the intracellular environment contribute to the disruption of the molecular level of substrates, proteins, polypeptides and others. All this effect will destroy tumor cells.

The processes of deactivation, irradiation, and reaction with free radicals all occur inside the cell so it can work on all types of cancerous tissue cells and in different stages of cancer. That is, it can destroy various types of cancers and intervene deeply into cancer stages. This is a distinct effect of this method compared to the existing cancer treatments.

Although, there are no evident experimental results we still hope that the proposal perspective is valuable to all of the people who are studying the cancer treatment.

1.       McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, et al. (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: The CHARM-Added trial. Lancet 362: 767-771.

2.       Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, et al. (1999) A chemical inhibitor of P53 that protects mice from the side effects of cancer therapy. Science 285: 1733-1737.

3.       Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, et al. (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6: 491-500.

4.       Folgueras AR, Pendás AM, Sánchez LM, López-Otín C (2004) Matrix metalloproteinases in cancer: From new functions to improved inhibition strategies. Int J Dev Biol 48: 411-424.

5.       Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161-174.

6.       Whittaker SR, Mallinger A, Workman P, Clarke PA (2017) inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther 173: 83-105.

7.       Chen S, Li J, Li Q, Wang Z (2016) Bispecific antibodies in cancer immunotherapy. Hum Vaccin Immunother 12: 2491-2500.

8.       Boik JC (2001) Natural compounds in cancer therapy. Oregon Medical Press, 1^st Edn.

9.       Dowlatshahi K, Alvarado R (2014) Interstitial laser therapy (ILT) of breast tumors. Breast Cancer 2014: 197-211.

10.    Turkington C, Edelson M (2005) The Encyclopedia of Women's Reproductive Cancer. Available at: http://www.books.google.com

11.    Khan FM, Gibbon JP (2014) Khan’s The Physics of Radiation therapy. 5^th Edn. Wolters Kluwer Health.

12.    Baskar R, Lee KA, Yeo R, Yeoh KW (2012) Cancer and radiation therapy: Current advances and future directions. Int J Med Sci 9:193-199.

13.    Seco J, Verhaegen F (2016) Monte Carlo techniques in radiation therapy. CRC Press, p: 342.

14.    Sharp PF, Gemmell HG, Murray AD (2005) Practical nuclear medicine. Springer London.

15.    Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, et al. (2008) Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 35:1941-1959.

16.    Tubiana M (2009) Prevention of cancer and the dose-effect relationship: The carcinogenic effects of ionizing radiations. Cancer Radiother 13: 238-258.

17.    Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase. Proc Natl Acad Sci U S A 74: 3735-3739.

18.    Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: Cancer’s double-edged sword acting as both facilitator and gate-keeper of malignancy when bound to mitochondria. Oncogene 25: 4777-4786.

19.    Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, et al. (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24: 213-228.

20.    Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 1787: 553-560.

21.    Lange SS, Takata K, Wood RD (2011) DNA polymerases and cancer. Nat Rev Cancer 11: 96-110.

22.    Albertella MR, Lau A, O'Connor MJ (2005) The overexpression of specialized DNA polymerases in cancer. DNA Repair (Amst) 4: 583-593.

23.    Hoeijmakers JH (2009) DNA damage, aging and cancer. N Engl J Med 361: 1475-1485.

24.    Jachimowicz RD, Goergens J, Reinhardt HC (2019) DNA double-strand break repair pathway choice - From basic biology to clinical exploitation. Cell Cycle 18: 1423-1434.

25.    Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319: 1352-1355.

26.    Slater JP, Mildvan AS, Loeb LA (1971) Zinc in DNA polymerases. Biochem Biophys Res Commun 44: 37-43.

27.    Hartwig A (2001) Role of magnesium in genomic stability. Mutat Res 475: 113-121.

28.    Fair Hall AW (1961) The radiochemistry of magnesium. NAS-NS 3024.

29.    Ebel H, Günther T (1980) Magnesium metabolism: A review. J Clin Chem Clin Biochem 18: 257-270.

30.    Wolf FI, Trapani V (2008) Cell (patho)physiology of magnesium. Clin Sci 114: 27-35.

31.    Gunther T (2008) Comment on the number of magnesium activated enzymes. Magnes Res 21: 185-187.

32.    Adhikari S, Toretsky JA, Yuan L, Roy R (2006) Magnesium, essential for base excision repair enzymes, inhibits substrate binding of N-methylpurine- DNA glycosylase. J Biol Chem 281: 29525-29532.

33.    Yuan BF, Xue Y, Luo M, Hao YH, Tan Z (2007) Two DNAzymes targeting the telomerase mRNA with large difference in Mg²⁺ concentration for maximal catalytic activity. Int J Biochem Cell Biol 39: 1119-1129.

34.    Castiglioni S, Maier JA (2011) Magnesium and cancer: A dangerous liason. Magnes Res 24: S92-S100.

35.    Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, et al. (2011) Second messenger role for Mg²⁺ revealed by human T-cell immunodeficiency. Nature 475: 471-476.

36.    Wolf FI, Cittadini AR, Maier JA (2009) Magnesium and tumors: Ally or foe? Cancer Treat Rev 35: 378-382.

37.    Wolf FI, Maier JA, Nasulewicz A, Feillet-Coudray C, Mazur A, et al (2007) Magnesium and neoplasia: From carcinogenesis to tumor growth and progression or treatment. Arch Biochem Biophys 458: 24-32.

38.    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70.

39.    Hanahan D, Weinberg RA (2011) The hallmarks of cancer: The next generation. Cell 144: 646-674.

40.    Bernardini D, Nasulewicz A, Mazur A, Maier JA (2005) Magnesium and microvascular endothelial cells: A role in inflammation and angiogenesis. Frontiers Biosci 10: 1177-1182.

41.    Maier JA, Nasulewicz-Goldeman A, Simonacci M, Boninsegna A, Mazur A, et al. (2007) Insights into the mechanisms involved in magnesium-dependent inhibition of primary tumor growth. Nutr Cancer 59: 192-198

42.    Nasulewicz A, Wietrzyk J, Wolf FI, Dzimira S, Madej J, et al. (2004) Magnesium deficiency inhibits primary tumor growth but favors metastasis in mice. Biochim Biophys Acta Mol Basis Dise 1739: 26-32.

43.    Cohen L, Kitzes R (1985) Early radiation induced proctosigmoiditis responds to magnesium therapy. Magnesium 4: 16-19.

44.    http://nucleardata.nuclear.lu.se/toi/nuclide.asp?iZA=120028

45.    Tran L (2019) A proposition for a cancer treatment study using radioactive metal co-factor enzymes. Biomed Res Ther 6: 2983-2985. 

46.    Weinreich R, Qaim SM, Michael H, Stocklin G (1976) Production of ¹²³I and ²⁸Mg by high-energy nuclear reactions for applications in life sciences. J Radioanal Chem 30: 53-66.

47.    Coderre J (2004) Principles of Radiation Interactions. Fall Massachusetts Institute of Technology: MIT OpenCourseWare; License: Creative Commons BY-NC-SA. Available at: https://ocw.mit.edu

48.    (1987) NCRP Report No. 87, Use of Bioassay Procedures for Assessment of Internal Radionuclide Deposition.

49.    https://courses.ecampus.oregonstate.edu/ne581/three/index3.htm

50.    Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase. Proc Natl Acad Sci U S A 74: 3735-3739.

51.    Benzekry S, Lamont C, Beheshti A, Tracz A, Ebos John ML, et al. (2014) Classical mathematical models for description and prediction of experimental tumour growth. PLos Comput Biol 10: e1003800.

52.    Leidi M, Wolf F, Maier JAM (2011) Magnesium and cancer: More questions than answers. Magnesium in the central nervous system [Internet]. Vink R, Nechifor M editors Adelaide AU: University of Adelaide Press.

53.    Silver L, Heine M, Tassinari L (1960) Magnesium turnover in the human studied with ²⁸Mg. J Clin Invest 39: 420-425.

54.    https://www.adefenceofthebible.com/2018/09/27/gods-amazing-creation/

55.    https://pediaa.com/what-is-the-difference-between-replication-and-duplication-of-dna/