Relation Of Some Hormones To Carcinogens And Development Of Cancer From Inappropriate Hormonal Treatment

Some time ago it was recognized that certain well-known carcinogenic substances structurally resembled steroid hormones. These carcinogens had been shown to produce tumors in experimental animals. In this context, the structures of benzo[a]pyrene and 7,12-dimethylbenz[«]anthracene can be compared to the structure of estradiol (Figure 20-1). The structural similarities are even more apparent when the molecules are aligned and overlaid as shown in Figure 20-2. It thus is not surprising that steroid hormones can cause cancer if they are administered inappropriately or in high amounts.

A typical example of the carcinogenicity of hormones is tumor production in humans caused by treatment with diethylstilbestrol (DES), which is an artificial estrogen. The structure of DES is shown in Figure 20-3. In this figure, the chemical structure of DES is shown in the lower left-hand corner, and the three-dimensional models of its various forms are shown in the body of the figure. Notice that the A ring is superimposable with that of estradiol, and this may be, at least in part, the ring recognized by the estradiol receptor, so that DES is a strong artificial estrogen.

In the early 1970s it was noted in the medical literature that there was an increase in the occurrence of clear cell adenocarcinoma of the vagina, usually in teenaged women. It became apparent that this was due to DES treatment of the mothers of these young women where the drug had been administered for complications in pregnancy. DES provoked malignancies derived from usually absent Mtillerian tissue present in the vagina after birth, which appeared to be a direct consequence of the treatment of the mother with DES. Apparently, persistent congenital Miillerian epithelium may undergo further differentiation in the presence of hormones, and the occurrence of Miillerian epithelium is otherwise rare. Consequently, physicians

FIGURE 20-1 Top views looking down at the ring structures of estradiol and benzo[a]pyrene and dimethylbenz[«]anthracene. In both cases, the A, B, and C rings of the hormone seem to be superimposable over the analogous rings of the carcinogens. Reproduced with permission in part from Glusker J. P. (1979). Biochem. Act. Hormones, 6, 121-204.

benzo[a]pyrene 7,12-dimethyIbenz[a]anthracene

FIGURE 20-1 Top views looking down at the ring structures of estradiol and benzo[a]pyrene and dimethylbenz[«]anthracene. In both cases, the A, B, and C rings of the hormone seem to be superimposable over the analogous rings of the carcinogens. Reproduced with permission in part from Glusker J. P. (1979). Biochem. Act. Hormones, 6, 121-204.

FIGURE 20-2 Structure of estradiol (E, white bonds) overlaid on the structure of 3,9-dihydroxybenz[a]anthracene (BA, black bonds). Although the crystal structure of benzanthracene has not been determined, its structure is drawn from structural data on benzo[fl]pyrene and some phenols. The hydroxyl groups on 0-3 of both compounds have been aligned. The proximity of the other hydroxy groups in each compound is evident. Reproduced with permission from Glusker, J. P. (1987). Biochem. Act. Hormones, 6, 121-204.

FIGURE 20-2 Structure of estradiol (E, white bonds) overlaid on the structure of 3,9-dihydroxybenz[a]anthracene (BA, black bonds). Although the crystal structure of benzanthracene has not been determined, its structure is drawn from structural data on benzo[fl]pyrene and some phenols. The hydroxyl groups on 0-3 of both compounds have been aligned. The proximity of the other hydroxy groups in each compound is evident. Reproduced with permission from Glusker, J. P. (1987). Biochem. Act. Hormones, 6, 121-204.

believed that the generation of cancerous tissue could have been derived from the persistent Miillerian glandular tissue under the influence of DES from the maternal environment. As many as 2-4 million pregnant women may have been treated with DES, so that about 2 million daughters and 2 million sons were gestated in utero under conditions of DES treatment of the mother. Whereas there have been important incidences in cancer in the female offspring, there have been few effects in the male offspring.

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