Proposed: A link between cancer and cell replication
in the very young and the very old
To protect the very young and the very old from the ravages of cancer requires an understanding of the process of cancer development during these two periods of life. By what is observed regarding the biological impact of radiation and certain viruses and chemicals on a young, growing, biological system -- and especially from the known radiation risk factors that radiation-caused cancer, radiocancer , can more readily strike when the body is very young -- the high cell division rate (replication rate) during early years becomes suspect as involved in the cause . Also, this known relationship between high cell replication rate in the young, and cancer, can apply similarly to the older, aging, body , probably from 50 years old and beyond. It is proposed here that during the body's later years its cell division rate increases in a moderate rate from age 50 to a high rate in the very old. The increasing cell division rate in the aging body between 50 and 90 (and possibly above) and its link to cancer has not been considered heretofore by scientists. During the two periods of life, the very young and the very old, the reason for greater cancer susceptibility is, as proposed here, their high rates of cell replication.
It is thus proposed here that the Law of Bergonie and Tribondeau continues to apply throughout the lifetime of the body and that the Law relates not only to increased numbers of cancers in childhood, but also to increased numbers of cancers in the elderly. To indicate the presence of the Law in the elderly, the number of cancers and their recorded incidence rates can be observed moving slowly upward as the body ages. The incidence rates for colon cancer , for example, rise from 10 per 100,000 between the ages 40 and 45 to 300 per 100,000 between ages 75 and 80. And so, it is suggested here that this dramatic increase of the colon cancer incidence rate is related to increasing replication of cells in the colon to make up for increasing cell death in the aging process of that organ. In another example, it can be reported that ninety percent of colorectal cancer cases in the United States occur after age 50. Once again, the cause is here depicted as a result of an increased rate of cell replication after age 50. The incidence of lung cancer rises rapidly above the age of fifty. Breast cancer becomes more common in the fifties and beyond. Cancer of the lining of the womb occurs in women of middle age and older, with a peak in the late fifties and early sixties. Bowel cancer has a peak incidence in the early sixties. Bladder cancer occurs predominantly in late adulthood, in the fifties, sixties, and older. Ninety percent of the cases of chronic lymphocytic leukemia occur after the age of fifty. Acute myeloid leukemia becomes steadily more common into adulthood around age fifty and into ages above seventy. Lymphoma cancer occurs more commonly with advancing age, and a certain type of lymphoma in the elderly has had a disproportionate increase in the last few decades over all lymphomas. Oral cancers are predominantly conditions that develop in the fifties and sixties. Myeloma is a cancer of one particular white cell in the bone marrow, and its incidence rises from the fifties onward. Breast cancer becomes more common in the fifties and beyond, as well as glial cell brain tumors . Renal cell carcinoma, cancer of the kidney, has a peak incidence in the fifties. In the United Kingdom , over one third of all cancers are diagnosed in people over 75. A few general reasons are given by the research community as the basis of such cancer development in the aged, such as: reduced musculoskeletal function, aerobic capacity, cognitive and integrative neurological function, and nutritional state, all of which might render the elderly vulnerable to small environmental challenges, but missing in these reasons is increasing cell replication in the aging organs of the body.
Thus, it precludes that because of their particular rates of cell replication, the young and the old are at special risk for developing cancer. Why is this so? How can this assumption be made? How do cell replication rates relate to cancer risk? What is the depicted technical basis for this proposed relationship? Why, when body cells are replicating more rapidly than normal, the body is then more prone to developing cancer?
To help explain this particular cancer phenomenon, which applies no matter when cancer strikes during a lifetime, it is important to begin with the Law of Bergonie and Tribondeau . This law has been well known and followed closely over the years by radiation specialists. The Law of Bergonie and Tribondeau, published in 1906 (Bergonie, J. and Tribondeau, L.C.R., Acad. Sci., Paris, Vol. 143 , p. 983, 1906), states that a tissue is more radiosensitive the more undifferentiated its cells are morphologically and physiologically, the more active they are mitotically, and the longer they remain in an active stage of proliferation , that is, the more divisions they undergo between the youngest precursor cell and the mature functional cell. Thus, by referring to this Law, radiation specialists suggest a highly cautious use of radiation on the young, and they note that an association truly exists between radiation, at certain wavelengths and energies, and cancer in the young. However, the author here is confident to propose that the Law of Bergonie applies to cell replication rates in the human biological system not just during childhood but throughout the lifetime of the living body. The author emphasizes that this Law is not repealed after childhood.
Does the Law of Bergonie and Tribondeau imply that the regulatory system of DNA is somehow involved in radiosensitivity? It is well known that cell proliferation begins with replication of the DNA. The model used to support involvement of the regulatory system in DNA indicates that radiation energy can be absorbed in DNA through a critical energy-absorption window that opens momentarily but frequently in rapidly dividing cells. The model indicates that each time this regulatory-based window opens, it allows into the DNA a selective but critical amount of energy that can produce a lesion in this particular radiosensitive site in DNA. The model indicates that the radiation energy entering the DNA through this window can produce a lesion in the regulatory nucleotides of DNA and that this lesion can produce cancer. When this window opens more frequently during more frequent replication, it gives the radiation a better chance to enter into the DNA and cause a serious lesion. A slower replication rate and a less frequent opening of the window protect the DNA by making it more difficult for the energy to enter the window and strike this lesion-producing site.
What and where are this window and the lesion-producing site? The description of this window and the lesion-producing site and the energy-absorption in the lesion-producing site has been identified in detail by molecular modeling (refer to The Concept and The Model in this website). But first, it is important to know something about the TATA box in DNA and a description by Dr. Goldberg who first discovered and identified the box. He explained in his doctoral thesis that it is an 8-nucleotide, T hymine/Adenine; A denine/Thymine; T hymine/Adenine; A denine/Thymine helical structure in DNA and that “The TATA boxes are transcriptional control sequences along the DNA strand and are located beyond the gene proper, i.e., upstream from the gene's transcriptional start site.” (Michael Lewis Goldberg, doctoral thesis, Stanford University, 1979). He described the TATA box as a key regulatory unit in DNA.
(1) The model developed by the author called the Symmetry Analytical Model (SAM) and the author's new physicochemical concept called Periodic Symmetry identifies the TATA box as the most likely nucleotide sequence in the DNA double strand to contain the primary carcinogenic chemical bond lesion ; it also identifies three unaligned double bonds -- located in the thymine nucleoside of the TATA box -- that if aligned could then absorb energy imposed on the double bonds by a critical wavelength of radiation, or by means of a chemical, or a virus, to produce a carcinogenic lesion.
(2) During DNA transcription or replication, it is known that the regulatory TATA box is bent dramatically (100 degrees), but only momentarily, by a protein called the TATA Box Protein (TBP); thus, it is predicted that by means of the bending, the three thymine nucleoside double bonds become aligned, momentarily, which allows them to absorb energy and be converted into a single-bonded structure. This momentary alignment of double bonds by TBP bending is identified as the OPEN WINDOW to energy absorption inside a TATA box in DNA. Whenever these double bonds are aligned, the window is open. The more frequently it is opened, the greater the opportunity for energy absorption and production of a lesion inside the TATA box.
(3) Because there are three oxygen atoms in the thymine nucleoside, two of which have double bonds, and also two carbon atoms linked by a double bond, this lesion can readily be energy- produced, like the thymine dimer lesion, by this closely assembled arrangement of double bonds. The lesion resulting from energy impact on these elements and on these double bonds is produced via a well known process called ozonolysis. The lesion produced via ozonolysis is an ozonide. The ozonide is thus constituted of the thymine nucleoside’s three oxygen and two carbon atoms bonded together by single bonds. This is considered by the author as the primary carcinogenic chemical bond lesion and its site in DNA.
(4) This particular thymine nucleoside lesion, the ozonide, according to the model, changes the structure of the nucleoside and the normal operation of the TATA box by locking the box in its ON, or active, mode, thus causing cessation of normal DNA regulation and so initiating uncontrolled replication.
(5) Once formed, the ozonide can be readily and continuously reproduced -- due to the close proximity of the various thymine nucleosides in the TATA box -- by a well known reaction called autoxidation. Autoxidation can quickly and readily transmit the ozonide from one thymine nucleoside on one side of the TATA box to another adjacent thymine nucleoside on the other side of the box. Thus, the ozonide in the thymine nucleoside in the mother strand of the TATA box can readily be reproduced in the thymine nucleoside in the opposite daughter strand of the box. In his manner, the ozonide can reproduce itself via cell division from one cell to another.
(6) It should be noted that over the lifetime of the body, radiation can accumulate mutations in DNA. Some of these mutations either those accumulated, or alone, can increase DNA replication and, if another energy impact occurs following the created mutation and the energy enters DNA through the open window, the cell can be converted by the ozonide into a full blown cancer. This cancer-causing process can be viewed as being initiated by the increased replication caused by the mutation. A few of the well known mutations that have been associated with carcinogenesis, but in a manner not completely understood, are N-Ras, Rb, p53, p16, K-Ras, BrCA1, COX-2, and Ber-Abl. It is known that these mutations actually serve to increase the rate of replication, thus increasing the open window rate and thus increasing the likelihood that impacting energy will enter the window and produce an ozonide.
The ozonide is known to be a strong dehydrogenation catalyst and by this means can cause select mutations throughout the genome, causing many of the various well known mutations associated with the particular needs of the cancer cell. It is observed that something dramatic is occurring within the cells of a tumor. Dr. William C. Hahn of the Dana-Farber Cancer Institute said that “If you look at most solid tumors in adults, it looks like someone set off a bomb in the nucleus.” The known dramatic properties of the ozonide and its explosively reproductive and catalytic expression would readily make it look like someone set off a bomb in the nucleus causing a massive and well known genomic instability called aneuploidy.
There are many TATA boxes in the genome, but the TATA box affected in the manner described herein is viewed necessarily as residing in that part of the genome called the replication origin . TATA boxes are known to reside particularly in the replication origin and, because their structural conformational compatibility can be easily relieved by unwinding the DNA helix, the TATA box would serve most capably in the initiation of replication. The replication origin is the location in the genome where replication of the genome begins; and, this apparently locked-ON operation of the TATA box causing a disorderly and uncontrolled replicating system in DNA -- as the locked-on replicating cell duplicates itself throughout an entire organ in the body and then possibly metastasizes, or moves, to some other organ or organs in the body and finally dominates and overwhelms its bodily environment to the point of destruction -- is observed here as, and is called, cancer .
Age and incidence data are from “What You Really Need to Know about Cancer” by Dr. Robert Buckman, in collaboration with the specialists at M.D. Anderson Cancer Center, Houston, Texas, The Johns Hopkins University Press, 1997; and, from the Intercultural Cancer Council, “Elderly & Cancer,” 2/8/05, and from EurActiv, EU News, Health & Pharma, 2/7/05.
A provocative study, suggesting that Vitamin D helps in cancer survival , was reported in 2005 at an American Association for Cancer Research conference in Anaheim , CA , and by Dr. Edward Giovannucci, Professor of Nutrition and Epidemiology at the Harvard School of Public Health, who helped conduct this study to look at vitamin D and lung cancer survival . It was noted that Vitamin D has many features that could explain its possible benefit against cancer, such as stifling cell growth.
Also, in 2005, Dr. Scott Christensen, associate clinical professor of oncology at the University of California, Davis Medical Center, said that during a woman’s menstrual cycle, hormones cause cells to grow and divide, making their DNA more susceptible to cancer-causing damage.
All Rights Reserved 2006
