Abstract
Extensive world-wide studies in cancer epidemiology throughout most of this century have led to a generally accepted view that as much as 80-90% of all human cancer has its origins in environmental factors in our diet and lifestyle. Although in most cases several factors are likely to combine to produce a particular disease, the real significance of the above conclusion is its corrollary, that identification and elimination of these environmental factors should reduce the incidence of the disease. During this time period the incidence of most forms of cancer has remained essentially constant with one notable exception, lung cancer. Mortality from this disease has risen inexorably to its present epidemic proportions during the last seventy years and now accounts for the death of some 26000 men and 15 000 women each year in England and Wales alone. There is now no doubt that this is a direct result of cigarette smoking, and it is reliably predicted that abandonment of the habit would reduce this death rate ten-fold. The causes of other major forms of cancer, such as breast cancer in women and colon cancer in both sexes, have proved to be much more elusive. Their origins are probably complex and they are more difficult to study because there are no natural 'controls' as there are with lung cancer, where direct comparisons may be made between smokers and non-smokers. All possibilities for their causation are now under active consideration, and among them the influence of endogenous carcinogens generated by aberrant metabolism within the host is unknown, but cannot be discounted. It is now established that carcinogens of varied types are elaborated by both plants and microorganisms, and there seems to be no a priori reason why animals should not be similarly afflicted. Since most cancers are primarily diseases of old age it would seem unlikely that there would be strong evolutionary pressure against this happening. The idea that carcinogens, arising from steroids by incorrect metabolism, might be important in the induction of human cancer was a view commonly held in the past, but which has been neglected in recent times. Over fifty years ago, at the very outset of research into chemical carcinogenesis, the potent poly cyclic aromatic hydrocarbon carcinogen 3-methylcholanthrene was prepared by simple chemical transformations from a bile acid derivative. The correct structures for the bile acids and sterols were themselves established at about the same time, and the synthesis of this carcinogen took on an exaggerated importance in the minds of scientists. The enduring idea that methylcholanthrene formed by incorrect bile acid or sterol metabolism in the body might prove to be a cause of human cancer led to numerous attempts to identify this carcinogen in tumours and other tissues, but without success. The reason for this failure now seems obvious because experience has shown that cyclization of the sterol side chain does not occur to provide a fifth fused ring. Instead this side-chain tends to be lost with migration of the angular methyl groups, leading to compounds of the simpler four-ring cyclo-penta[a]phenanthrene series. These compounds thus possess the same basic carbon ring system as the steroids, but lack the angular methyl groups which characterize the latter. They are therefore capable of complete dehydrogenation to fully aromatic phenanthrene derivatives, and compounds of this type do in fact occur widely in petroleum and in oil-bearing shales as well as in river and lake sediments; they are also found in cooking oils that have been overheated. Advances in our understanding of oestrogen biosynthesis and metabolism have moreover suggested a plausible route by which cyclopenta[a]phenanthrenes might be formed in the body, but so far no attempts have been made to test this possibility. The need for further investigations in this area using modern techniques is now apparent, because numerous cyclopenta[a]phenan-threnes have since been synthesized and some have been shown to be strong carcinogens, similar in potency to the classical poly cyclic hydrocarbon carcinogen benzo[a]pyrene. This book is concerned with the occurrence, chemical synthesis, physical and chemical properties, and biological attributes of cyclo-penta[a]phenanthrenes. These are discussed in detail, as is their history which is intimately connected with the establishment of the correct structure of steroids. Interesting structure /carcinogenicity relationships, similar to those found among related polycyclic aromatic systems such as the chrysenes and benzo[a]anthracenes, are examined in relation to the metabolism of these compounds and the interactions of their metabolites with biological macromolecules. The book also lists physical data for nearly 350 cyclopenta[a]phenanthrene derivatives and contains exhaus- tive references to the original literature. It is hoped that it will provide a useful point of departure for those concerned with the possibility of the involvement of cyclopenta[a]phenanthrenes in the aetiology of human disease.