Progress in clinical and biological research最新文献

Although estrogens have been identified as key endocrine hormones in the control of early mitogenesis and development in the mammary gland, local control of cell proliferation during ductal morphogenesis may be regulated by polypeptides such as TGF-alpha or TGF-beta. Many breast tumors are estrogen dependent, and some breast tumor cell lines are known to produce TGF-alpha, suggesting that the mitogenic pathways controlling early normal mammary growth and the growth of some breast tumors may be similar. While progesterone does not appear to be important in the early program of ductal growth, progesterone and estrogen are necessary for the cyclic proliferation of mammary ductal cells that occurs during the menstrual cycle, and for lobuloalveolar growth during pregnancy. Since increased cell division enhances the chances for the formation of a malignant phenotype in the breast, exogenous hormones containing estrogen alone or estrogen and progesterone may increase breast cancer risk. While DES is no longer prescribed to prevent abortions, it demonstrates that high doses of an estrogen during a period of mammary proliferation can affect breast cancer risk. Whether the addition of progestogens to estrogen replacement therapy enhances breast cancer risk in postmenopausal women remains an unanswered question because of the lack of large, well-controlled prospective studies. There currently is no evidence to indicate that the progestogen-containing subdermal contraceptive Norplant increases breast cancer risk. However, it has not been determined if the elevation of serum estrogens reported in some Norplant users affects breast cancer risk. There is little evidence that combined OCAs enhance breast cancer risk in most women. More research is needed to substantiate the findings that OCA use in young women, especially before a first full-term pregnancy, may enhance breast cancer risk. Animal studies indicate that there are critical periods of susceptibility to chemical carcinogens, since the number and malignancy of tumors are increased when carcinogens are administered to young virgin animals during the proliferative period of ductal morphogenesis. Since the breast appears to be most susceptible to the carcinogenic effects of ionizing radiation during the first decade of life, exposure to other carcinogenic agents during the period of early breast development may be important in determining breast cancer risk. Therefore, more studies are needed to confirm the observation that heavy drinkers and heavy smokers are at higher risk for developing breast cancer when they start smoking or drinking at an early age. The observation that serum and urinary estrogen levels increase with alcohol consumption may provide a basis for the higher risk of developing breast cancer in heavy drinkers. While the restriction of methyxanthine intake may alleviate the symptoms associated with fibrocystic breast disease in some women, there is not enough evidence to suggest tha

The etiology of human testicular tumors is poorly defined. With the possible exception of prenatal estrogen exposure, no specific chemical exposures have been associated with testicular cancer risk in men. Prenatal as well as postnatal estrogen treatments induce testicular tumors in some mouse strains, but not in other mouse strains or in rats. Prenatal estrogen exposure also causes cryptorchid testes in mice and possibly rats. Cryptorchidism is a consistent risk factor for testicular cancer in men, and estrogen- or surgically-induced cryptorchidism is associated with Leydig cell tumorigenesis in mice. In rats, however, surgically induced cryptorchidism inhibits Leydig cell tumor formation. Overall, it appears that the mouse is the most appropriate species as animal model for testicular tumorigenesis in humans. Any of the following hormonal exposures can cause testicular tumor formation in rodents: 1) chronic exposure to estrogenic compounds of adult mice and hamsters; 2) prenatal exposure to estrogenic compounds of mice and possibly humans; and 3) any treatment or condition that induces cryptorchidism in mice and humans. The mechanisms whereby these treatments or conditions may cause testicular tumorigenesis are poorly understood. Undefined local testicular factors appear to be dominant in tumorigenesis in cryptorchid human and rodent testes. Pituitary factors, most likely LH and perhaps prolactin, play a critical but poorly defined role in estrogen-induced and spontaneous testicular tumorigenesis in rodents. In the mouse, estrogen receptor-mediated mechanisms seem to be involved in induction of testicular tumors by prenatal estrogen exposure, and a direct, perhaps estrogen receptor-mediated, inhibiting effect of estrogens on the action of müllerian inhibiting substance is probably central in the induction of cryptorchidism in this species.

Carcinogen-DNA adducts are generally regarded as relevant biomarkers of carcinogen exposure and their levels in target tissues have often been predictive of tumor incidence in experimental animals. Thus, human risk assessment procedures have utilized dose-response models that assume proportional relationships between carcinogen exposure and cancer susceptibility, even though wide inter-individual variations in human metabolic activating enzymes have now been clearly established. To evaluate these approaches, we have examined the relationship between carcinogen exposure, DNA adduct levels, metabolic activation phenotypes, and cancers of the larynx, urinary bladder, and colon. Cigarette smoking is a strong risk factor for cancers of the larynx and urinary bladder. In the larynx, the DNA adducts appear to be derived predominantly from polycyclic aromatic hydrocarbons (PAHs) and are evident only in tissue from smokers. However, adduct levels appear to be determined primarily by expression of cytochrome P450 (CYP) 2C9/10, which varies > 10-fold in different individuals. This CYP catalyzes the metabolic activation of benzo (alpha) pyrene (BP) to a 9-hydroxy-BP-DNA adduct that accounts for up to 25% of the putative PAH adducts formed in vivo. For the urinary bladder, putative aromatic amine (AA)-DNA adducts are predominant and are significantly elevated in current smokers. Rapid CYP1A2 and slow acetyltransferase (NAT2) phenotypes have been previously implicated in the activation (N-oxidation) and detoxification (N-acetylation) of AAs for human bladder carcinogenesis. Data now indicate that NAT1, which is expressed in human urothelium and catalyzes the O-acetylation of N-hydroxy arylamines, is significantly correlated with DNA adduct levels and is bimodally distributed in this tissue. Colo-rectal cancer risk, which has been associated with exposure to heterocyclic amines (HAs) in cooked foods, is strongly elevated in individuals with the combined rapid phenotypes for CYP1A2 and NAT2. These enzymes are uniquely responsible for HA N-oxidation and subsequent O-acetylation, forming DNA adducts that are found in human colon. These studies indicate that cancer risk assessment procedures should be redesigned to include biomarkers of susceptibility, especially those involved in carcinogen bioactivation.

There is no doubt that hormones have a role in the development of many, perhaps most, cancers. This is because they are vital in maintaining homeostasis in multicellular organisms in which cancer appears. The stage or stages at which hormones are important in the process are not known well, but experiments in animals indicate that hormonal intervention at initiation, promotion, or progression can be important, assuming that such neat division pertains to cancer development in humans (Schmähl, 1985). Hormones may affect initiation through control of the levels of activating and detoxifying enzymes in the liver and other organs, which affect the pharmacokinetics of carcinogens to which the animal is exposed. Hormones control the levels of structural or functional components of some organs, for example, the alpha-2 micro-globulin in the kidney of male rats, which affect the disposition of foreign chemicals. Hormones have enormous influence on growth and development of animals and must play a part in the well-known heightened susceptibility of young animals (including humans) to the effects of exposure to carcinogens. Animals exposed in utero to transplacental carcinogens, or those exposed to single doses as newborns or infants, frequently develop tumors that appear in animals treated as adults not at all or after exposure to much higher doses. Examples are nervous system tumors in rodents exposed transplacentally (Ivankovic, 1979) and liver tumors in rodents treated as infants (Vesselinovitch et al., 1979). It is probable that effects of hormones on cell proliferation are an important part of these effects. From the studies of hormonal effects on carcinogenesis in animals we can conclude that alterations in the function of hormones through inheritance, or through diet, habits, accidents, disease states, or sexual maturity could affect susceptibility of an individual to carcinogens, thereby increasing or decreasing the probability of developing cancer. Compounds with antithyroid properties (e.g., thiouracil or ethylene thiourea, a contaminant and by-product of many thiocarbamates widely used in agriculture and industry) or substances affecting adrenal or pituitary secretions might be implicated as modulators of tumor development, following the leads suggested by experiments in animals described above. Castration, aging, or hypersecretion of sex hormones would also modulate the effects of carcinogens, as they do in experimental animals. There have been few studies of the effects of other hormones such as insulin, gastrin, prolactin, and so forth (Griffin et al., 1955), although these vital hormones vary in distribution even within an individual at different times. An early study (Sugiura and Benedict, 1933) failed to show an effect of treatment with a variety of hormones on the growth of several transplanted tumors. One elusive mystery is why estrogens and diethylstilbestrol induce kidney tumors in Syrian hamsters but not mammary tumors, whereas