Nucleic acids and cancer.

Abstract It may be of some advantage to review, within the context of the problem of programing of information in the cell, some of the concepts which have been elaborated. An outline of the basic mechanisms of information transfer was indicated in the first section. It was emphasized that the information which resides in specific genes or DNA molecules must be coded by sequences of nucleotide pairs. This information must determine the sequence of amino acids in a specific protein synthesized under the direction of that particular gene or DNA molecule. An altered amino acid sequence in the protein may some day be shown to be due to an altered nucleotide sequence in the DNA molecule. The steps which allow the transfer of information from the DNA molecule to the protein involve the synthesis of specific RNA molecules present in the ribonucleoprotein granules of the endoplasmic reticulum (or microsome fraction). This is the major enzyme (or protein) forming system, and it is probably on a specific RNA, which acts in some manner as a template, that the amino acids are aligned in a sequence unique for the particular protein. Following peptide bond formation, the protein or enzyme molecule is released. This represents a gross outline of the transfer of information within the cell. The processes of differentiation and carcinogenesis may both be viewed as alterations of the information transferred. It was indicated that cell constituents can be divided roughly into machinery for specialized function and machinery for cell division. In general terms the units of machinery are the same, i.e., DNA, RNA, protein. It is the specific information which differs. In any line of cells undergoing differentiation, however, there is a changing emphasis between machinery for division and machinery for specialized function. In the extreme case of differentiation, as in the mature red blood cell, only machinery for specialized function is retained while all division machinery is lost. The opposite extreme is the anaplastic carcinoma cell in which division machinery is maintained with the loss of all obvious specialized function. At the present time it is possible to analyze nuclear and cytoplasmic differentiation in morphological, functional and chemical terms. It is apparent that there exist nuclear-cytoplasmic mechanisms which remain undescribed in chemical terms and which are responsible for maintenance of increased function of some genetic units in a cell and loss of function of others. The phenomenon of induction noted in embryonic development describes differentiation in one cell line due to the transfer of material from an adjacent cell line. What this material is and how it acts is at present unknown. Whether this phenomenon operates through any of the known control mechanisms, such as enzyme inhibition, enzyme repression or enzyme adaptation, also cannot be answered. The cancer cell possesses an hereditary defect in the normal mechanism of control of cell division. Since the nucleic acids form a chemical basis of heredity in the cell it is reasonable to suspect an alteration in nucleic acids in the process of carcinogenesis. This implies some sort of qualitative alteration in the information transfer system. (By qualitative is meant either a direct physicochemical effect which alters the structural configuration of a nucleic acid molecule, or a mechanism whereby foreign nucleic acid molecules are incorporated into the cell.) Evidence has been presented suggesting but not proving that some of the carcinogenic agents may affect the genetic material or DNA molecules. Included in this series are ultraviolet and x-radiation, chemicals such as the nitrogen mustards and possibly the polycyclic hydrocarbons, and the DNA-containing polyoma and papilloma viruses. Affecting information transfer at the RNA level are tumor viruses which contain RNA. The mechanism of their action is obscure, but it seems reasonable to place them in this category. Thus mechanistically there are several ways of producing the same biological phenomenon, the cancer cell. Assuming that this premise concerning altered information in the cancer cell is correct, the next problem involves the type of information which is altered. Here we can only describe the biological property of uncontrolled growth and state that the alteration leads to loss of some control mechanism. The question regarding the exact biochemical nature of the control mechanism remains unanswered. A number of the mechanisms described in the previous sections may be classified grossly as quantitative effects, possibly because of a lack of understanding of their true nature. The induction phenomenon may be considered as a quantitative alteration in the transfer of information from genes to enzyme-forming systems which involves the concept of functional genes, of morphological changes such as puffing and Balbiani rings, and chemical changes in chromosomal material. Enzyme adaptation and repression are control phenomena which occur either at the level of the functional genetic unit or at the level of the enzyme-forming system. Polyploidy and aneuploidy also may represent a quantitative change in the number of genetic units, although it is possible to envisage the complete loss of some units. Many of the changes noted in a cancer cell in terms of enzyme levels may be merely quantitative changes which occur as an adaptation to rapid cell division. Some of the changes in glycolysis, for example, noted during the process of promotion by chemical agents may represent steps of adaptation for rapid cell proliferation. Although this division of phenomena into qualitative and quantitative categories is an artificial and somewhat arbitrary way to consider all of these biological processes, it does serve temporarily at least to categorize them in relation to information transfer. Carcinogenesis, when envisaged as a twostage process of initiation and promotion, may involve both types of changes described here as qualitative and quantitative. The process of initiation may involve some irreversible alteration in the information transfer system which in itself does not result in a recognizable cancer cell. Promotion may then be a series of quantitative changes which occur in the cell during its ensuing divisions, resulting in loss of specialized machinery and gain in machinery for cell division. The end result of both of these processes is the cancer cell. The whole field of chemotherapy of cancer suffers from a lack of fundamental knowledge concerning the biochemical nature of the cancer cell. It is possible that with an increasing understanding of the chemical nature of differentiation and growth controlling mechanisms, it will be possible to develop an entirely new concept of chemotherapy, based not upon metabolic antagonists of relatively simple chemical structure, but either upon replacement of missing information or end products in the cell, or possibly upon mechanisms of diversion of synthetic machinery from one end product or series of end products to another.