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GENETIC CHEMISTRY AND CANCER CHEMOTHERAPY C. P. RHOADS, M.D.* From time to time in the course ofpragmatic scientific work a point is reached at which an important program is necessarily submitted to penetrating review. Sporadic feelings offrustration develop, increase, coalesce, and spread among the participants. Increasing numbers of investigators become convinced that their strategy may require modification if it is to be more effective. Sometimes such a review has an important result. Reorientation is found to be possible. Apparently unrelated facts drawn from a variety ofdisciplines are seen to converge, to have a common bearing, and to permit new arrangements, or useful extensions of the old, to be made. It is possible that such a point has now been reached in the present widespread and largely empiric, centrally co-ordinated search for chemotherapeutic agents effective in controlling cancer in man. Under an extremely substantial program—almost world-wide in scope —all kinds of chemicals and crude materials are collected and tested for their power to restrain early transplants ofthree different kinds ofmouse cancer. Advances have come from this program. It has yielded additional agents ofclasses already well known before the program began. These are effective in temporarily restraining a few types of neoplastic disease in human beings. No new groups ofagents ofproved activity have been discovered , however. And no substance is presently at hand or in sight that exerts a regular effect with a substantial chemotherapeutic index and either cures or permits regular long-term control ofany one type ofhuman cancer. Consequently, many well-informed scientists now ask, Is it possible that our national program is in some fashion incomplete? Must we modify * Sloan-Kettering Institute for Cancer Research, 410 East Sixty-eighth Street, New York 21, New York. 318 C. P. Rhoads · Chemistry and Cancer Perspectives in Biology and Medicine · Spring 1959 our basic concepts or just some detail, already correct but not yet fully and adequately exploited? There are some indications that classes of compounds other than those presently being tested should be included if more rapid progress is to be made. Many researchers, after careful review, are convinced that the weight of evidence indicates the correctness of converging on, or certainly of emphasizing further, the study ofnucleic acid and its antimetabolites in our search for better means of cancer control. Neoplastic disease is a disturbance of inherited cellular characteristics. A new line of cells resistant to normal controls appears and replicates. Clearly, the primary control of cellular characteristics, as recently summarized in Sinsheimer's brilliant review (i), resides in deoxyribose nucleic acid. It is the ever present principal component ofthe chromosome (2); its content is the same in the same types ofcells (3); its metabolism is comparatively stable (4, 5); and it divides equally at cell replication (6). These facts establish it beyond peradventure as the key to cellular heredity. Its partner, close relative, and, probably, functional arm—ribose nucleic acid —orders protein synthesis and, consequently, all cellular composition and biochemical activity (7). Only one conclusion is possible. Since neoplastic cells differ sharply from their normal analogues—in form, in physical characteristics, in function, and in growth capacities—the fundamental key to these differences and so to the control ofsuch cells by growth restraint or by destruction must be in the cellular nucleic acid. This may be the chromosomal DNA or, possibly , some RNA particle itself capable of replication. The latter would comply with our knowledge ofvirus infection, which has been shown to play some role in the cause ofcertain types ofcancer in birds and animals. In further support of this contention, nucleic acid, whether chromosomal or cytoplasmic, is the cellular constituent that is particularly sensitive to those agents which cause inherited changes: ionizing and ultraviolet radiation (8), the alkylating agents (9), and probably others. Neoplastic disease, regardless of its direct cause—physical, chemical, or viral—must be considered a persistent change in somatic cells capable ofbeing passed on indefinitely to their progeny. Nucleic acid, in addition to being circumstantially linked with the neoplastic process, has also been established pragmatically as the cellular component most sensitive to essentially all the agents that exert any substantial 319 degree ofcancer-restraining effect (io, n). These include ionizing radiation...

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