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  The Mechanism of Induction of Cancer : A Model

There is a growing body of evidence that the enzyme ribonucleotide reductase (RNR) plays a pivotal role in the exquisite controls that regulate cell multiplication (1). This enzyme is responsible for the de novo conversion of ribonucleotides to deoxyribonucleotides, essential for the synthesis of DNA. In mammalian cells the active enzyme consists of two dissimilar subunits, proteins R1 and R2. Protein R1 is a dimer of molecular weight 170,000 and binds substrates as well as allosteric effectors (2). Protein R2 is also a dimer, has a molecular weight of 88,000, and contains binuclear ferric iron center and a stable tyrosyl free radical essential for activity (3).

   Fe(3+)  Fe(3+)
    Tyr-O•

Amongst the various enzymes involved in DNA synthesis, the activity of ribonucleotide reductase is most closely linked, by far, to neoplastic transformation and progression (4).

At the core of this model for the mechanism of induction of cancer is the proposition that the active site of the enzyme ribonucleotide reductase, consisting of a unique tyrosyl free radical and a non-heme iron center, is primary, and perhaps the only, target of all variety of carcinogenic agents. Various characteristics of tumor cells -- anchorage independence, dedifferentiation, metastasis, angiogenesis, genetic aberrations, chromosomal anomalies, etc. -- all result from the cascade of events that is initiated at the aforementioned active site by an adverse stimulus.

The synthesis of the limiting, active-site-containing subunit R2 is modulated at both transcription and post-transcription levels and is, in part, auto-stimulated (5,6). The presence of a self-regulating mechanism strongly implies that a minimum concentration of R2 is maintained even in quiescent cells -- making the radical-site an ever present potential-target for carcinogens. Since each tumor starts with a single cell (7), deviation initiated at a single, or a few, molecule(s) of the enzyme ribonucleotide reductase (RNR) may suffice for cellular growth to go awry.

Chemicals, thought to be culpable in a large number of cancer cases, fall in two broad categories of carcinogens: direct-acting and indirect-acting. The direct carcinogens, of which there are only a few, e.g., dimethyl sulfate, are reactive electrophiles, i.e., they seek out and react with negatively charged centers in other compounds. Indirect carcinogens such as highly inert polycyclic aromatic hydrocarbons, can attain even more reactive electrophilic centers by going through any of the various metabolic oxidative pathways in the body, involving powerful cytochrome P-450 enzymes (8).

In addition to being/becoming electrophilic, chemical carcinogens are, in general, hydrophobic in nature and, quite often, planar in shape.  Molecules with these characteristics are specially suited to access the active site of the enzyme RNR since: oxygen ligands around ferric ions constitute a negatively charged environment (9), iron-radical center is surrounded by hydrophobic residues (10), and the conformation of the polypeptide chain preferentially permits planar participants (11).

According to this model of the mechanism of induction of cancer, carcinogenic chemicals are attracted to the electro-magnetically charged active site of the enzyme ribonucleotide reductase, and once there, would disturb the finely tuned rhythmic controls in place. A chain of events is set in motion culminating in the production of outlaw tumor cells. Responding to the "nonself" antigens on the surface of these cells, immune system would eliminate them. However, over a period of time ("the latency period"), weakly antigenic cancer cells, capable of evading immune surveillance, may evolve. Alternatively, in the presence of preponderance of carcinogenic molecules, the number of tumor cells being formed may simply overwhelm body's ability to produce the immune cells needed to destroy them. Either way, cancerous growth gains a foothold.

Chemotherapeutic drugs, on the other hand, may overpower the entire machinery at the active-site causing it to shut down completely. It is noteworthy that quite often a chemotherapeutic drug would, under differing conditions, itself act as a carcinogen. (The very first cancer-drug, nitrogen mustard, is a good example.) Since these differing conditions invariably involve increased dilution, it may be inferred that a chemical which destroys the active site when injected in large quantities, merely disturbs it when present in minute amounts - this disturbance being enough for the precise mechanism to go astray.

Radiations from various sources and cancer of bone marrow & lymph system (leukemia) are closely inter-linked. Radicals & ions, found in the body in the wake of radiation exposure, are potential culprits. In blood, these reactive species will be attracted to the lymphocyte variety of white cells where, because of their above-average replicating requirements, there is enhanced production of ribonucleotide reductase. Violation by these radicals of the intricate mechanism at the active-site of the enzyme would ultimately result in the formation of deviant lymphocytes, which would, at the same time, impair body's immunocompetence. The unusual defection in the ranks of the immune defenses, may enable even a relatively small number of reactive molecules, over time -- corresponding to the latency period -- to cause permanent malignant transformation.

Radiation therapy is related to cancer-causing radiations just as chemotherapy is related to chemical carcinogens. Former destroy, later disturb.

Extremely fine asbestos fibers are known to cause malignant tumor growth after a latency period of 20 to 30 years. Since asbestos is an excellent insulator as well as extremely friable, its dust particles are prone to carry tiny charges (just like tiny water droplets in a cloud). After uptake by lung-cells, these charged fibrous-particles can produce oxygen free-radicals directly, or as a consequence of phagocytosis. Organic peroxides (RO2•) may soon be formed. It is rather well established that  reactive oxygen species are primary source of pathogenesis in asbestos-associated diseases (12). This model provides for these oxygen radicals a singularly sensitive target-site to initiate, albeit unwarranted, cell proliferation. Slow struggle with immune system would commence then on, which may be lost by the latter only after a few decades.

Electromagnetic fields generated by high-power transmission lines have been implicated in two Swedish studies as promoters of leukemia (13). There have also been reported cases where low-power, high frequency microwaves emitted by antennas of early models of cellular phones apparently contributed to the brain cancer (14). In both cases, the free- ribonucleotide reductase could be the target.radical at the active-site of

In the extremely rare instances where a virus causes cancer, there is often no latency period and the malignancy is tissue-sensitive. In accordance with these observed facts, this model proposes that the point of attack of a virus is not iron-tyrosyl-radical entity per se but its immediate environs where accessibility to the active site is controlled and modulated by various proteins during the G1 phase of cell division. A virus may substitute one or more of these proteins with its own. Previous harmony will be compromised, ultimately ending in improper proliferation of cells. The mechanisms of malfunction in case of retinoblastoma, a cancer of eye, as well as three types of cancer associated with the hereditary growth disorder Beckwith-Wiedemann Syndrome, may follow similar paths.

Thus a subtle agitation/alteration at the iron-tyrosyl-radical containing active-site of enzyme ribonucleotide reductase may be the jolt that sends the entire elegant machinery spinning out of control. Rapid elevations of ribonucleotide reductase activity have in fact been observed with cancer causing/promoting compounds such as phorbol ester (15), chlorambucil (16), okadaic acid and calyculin A (17). At the same time, an anti-tumor drug, 4-hydroxyanisole, seems to operate by quenching the tyrosine radical at the active site of the enzyme RNR (18).

Once the enzyme ribonucleotide reductase is under the spell of a carcinogen, it may not be able to maintain balanced nucleotide pools, thus compromising optimal fidelity of DNA replication. The resulting (aberrant) genes would contain point mutations. Chromosomal abnormalities may manifest thereupon. One such observation, that altered ribonucleotide reductase is a mutator locus, has been made in mammalian cells (19).

As suggested by Lance Liotta (20), various properties of an invasive tumor cell that causes metastasis, may not be unique. They are likely throwbacks to some normal function that is used occasionally, healing of a wound - for example, or only in the embryonic state -- something that is ordinarily under very tight regulation, and is now thrown out of kilter.

Evidence is continuously building that the vortex of the disease cancer is around the enzyme ribonucleotide reductase. The following disparate facts about cancer further point to the validity of the proposed model:

§  There are no cancers of the heart muscle, nor of the nerve  cells of the brain; cells of these tissues do not need and  thus may not possess basal level concentrations of the enzyme ribonucleotide reductase (20). Conversely, frequently dividing cells - of blood, intestine or hair-follicles - containing elevated concentrations of the enzyme RNR, are most sensitive to chemicals and radiations.

§  Tumor growth is stimulated by iron supplements (21).

§  Intake of certain foodstuffs containing antioxidants, such as vitamin C, vitamin E and beta carotene -- all of which are capable of gobbling up free radicals -- seems to provide protection against some types of cancer (22).

Genes, as a rule, control the synthesis of various proteins at the transcription level. However, there are exceptions and such seems to be the case, as forcefully pointed out recently (5) and alluded to before (6,23,24), in the regulation of the enzyme ribonucleotide reductase. The genes encoding the two subunits R1 and R2 of this enzyme are expressed, non coordinately, in conjunction with initiation of DNA synthesis, and DNA synthesis is cell cycle regulated. The regulatory region of the gene for R2 (the limiting subunit) seems to be inducible by transducers signaling the proliferation status of the cell. The (transcriptional) rate of synthesis of the mRNA is, therefore, cell-cycle dependent; so is the rate of translation of the mRNA into R2 subunit of the enzyme. Not surprisingly, in this highly regulated system, the half-life of R2-mRNA is 9 hr in G0/G1 phase vs 4 hr in S-phase with its steady-state level modulating throughout the cell cycle (6).

Thus the controls for the DNA replication reside with the specific activity of the enzyme RNR as well as the rate of synthesis/degradation of the mRNAs. A recent finding that R2-mRNA are copious in human colon carcinomas may be significant (25).

This model is able to encompass, and make comprehension possible of, various seemingly unrelated facets of the cancer mystery. It also explains the hitherto perplexing paradoxes in the behavior of chemicals and radiations: both groups are healers as well as annihilators.

And finally, since the activity of the enzyme ribonucleotide reductase in a cell shows a rather strange behavior of being inhibited by hydroxyurea at first, and then becoming resistant to it at higher concentrations, the following scenario spring-forths in my mind:

Imagine, if you would, a herd of elephants all to itself, with various members of the group knowing their role and there is a harmony. But then, slowly but surely, they start feeling pokes of arrows and gun-barrels from all sides. The situation only intensifies with time. A foreboding gloom starts hovering over the herd. They start reproducing at much shorter intervals but their communal cohesion is on wane. In the much-increased population, the behavior of various members is getting wilder. They start roaming maddingly in all directions. A few go on rampaging to distant localities, where even after a passage of time, their behavior pattern is still the samea.

Attempts are made to rein in the situation. The herd, with its explosive population, is surrounded - as much as is possible - and is slaughteredB. Those remaining and visible are shot down with accurate gunsC. Dense foliage may still hide some, and is showered with poisonous solutionsD.

This is the story of cancer.

ametastasis   bsurgery  cradiotherapy  dchemotherapy

ACKNOWLEDGEMENT: The author wishes to express gratitude for the 15-part series, Cancer - The Outlaw Cell, published in the journal Chemistry in 1977.

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References:

1.    Reichard, P. (1988) Annu. Rev. Biochem. 57, 349-374.

2.    Thelander, L., Eriksson, S., and Akerman, M. (1980) J. Biol. Chem.     255, 7426-7432.

3.    Thelander, M., Gräslund, A., and Thelander, L. (1985) J. Biol. Chem. 260, 2737-2741.

4.    Weber, G. (1983) Cancer Res. 43, 3466-3492.

5.    Sun, L., and Fuchs, J.A. (1992) Mol. Biol. Cell 3, 1095-1105.

6.    Carter, G.L., and Cory, J.G. (1992) Adv. Enzyme Regul. 32, 227-240.

7.    Laszlo, J., in Understanding Cancer, (Harper & Row, Publishers, NewYork, 1987), pp 69-70.

8.    Darnell, J., Lodish, H., and Baltimore, D., in Molecular Cell Biology (Scientific American Books, New York, 1990), pp 980-982.

9.    Gerez, C. and Fontecave, M. (1992) Biochemistry 31, 780-786.

10. Nordlund, P., Sjöberg, B-M., & Eklund, H. (1990) Nature 345, 593-598.

11. Kjøller Larsen, I., Sjöberg, B-M., and Thelander, L. (1982) Eur. J. Biochem. 125, 75-81.

12. Mossman, B.T., Marsh, J.P., Shatos, M.A., Doherty J., Gilbert, R., and Hill, S. in Asbestos Toxicity, G.L. Fisher and M.A. Gallo, Eds., (M Dekker, New York, 1988), pp 157-180.

13. Gorman, C. with Plon, U. (1992-2nd) Time 16, 70.

14. Lazzareschi, C. (1993) Los Angeles Times 30, D1.

15. Choy, B.K., McClarty, G.A., and Wright, J.A. (1989) Biochem. Biophys. Res. Commun. 162, 1417-1424.

16. Hurta, R.A.R., and Wright, J.A. (1992) J. Biol. Chem. 267, 7066-7071.

17. Hurta, R.A.R., and Wright, J.A. (1992) Biochem. Cell Biol. 70,    1081-1087.

18. Lassmann, G., Liermann, B., Arnold, W., and Schwabe, K.    (1991) J. Cancer Res. Clin. Oncol. 117, 91-95.

19. Weinberg, G., Ullman, B., and Martin, D.W., Jr. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 2447-2451.

20. Sylvester, E.J., in Target: Cancer, (Charles Scribner's Sons, New York, 1986), pp 245-249 and 046.

21. Silverstein, A., and Silverstein, V.B., in Cancer: Can It Be Stopped, (J.B. Lippincott, New York, 1987), p 123.

22. 'Close shaves, canaries, and cancer' (1993) University of California at Berkeley Wellness Letter 5, 1-3.

23. McClarty, G.A., Chan, A.K., Choy, B.K., Thelander, L., and Wright, J.A. (1988) Biochemistry, 27, 7524-7531.

24. Engström, Y., Eriksson, S., Jildevik, I., Skog, S., Thelander,L., and Tribukait, B. (1985) J. Biol. Chem. 255, 9114-9116.

25. Barker, K.T., Claysmith, A.P., Cioce, V., and Sobel, M.E.  (1992) FASEB, J. 6, A1933.

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