I HORMONAL FACTORS 837 



Thus by hormonal manipulation mammary cancers presumably lacking the 

 milk-agent have been induced in agent-free mice. The role of the mammary tumor 

 agent in spontaneous mammary neoplasia may be acceleration of onset of the 

 disease; in the case of mammary cancer induced by pituitary isografts, cancer 

 occurred earlier in mice given the mammary tumor agent (Miihlbock, 1956). 

 Perhaps new methods may be devised, e.g. in tissue culture, for demonstrating 

 a mammary tumor agent, presently not revealed by bioassay. 



Cervical cancer has been induced in mice by estrogenic hormone administration 

 (Allen and Gardner, 1941). Since carcinogenic effects are obtained by local 

 application (Gardner and Frankenheuis, 1935), it appears that the tumor-inciting 

 action of the hormone is in this case "direct", unlike the "indirect" action of es- 

 trogenic hormone in testicular (Fig. 25) and mammary tumorigenesis, where the 

 pituitary gland is providing the more immediate tumor-inciting influence. 



[e) Neoplasms of ^'ton-targe f tissues induced by estrogen 



Leukemia is induced in certain inbred strains of mice by relatively large doses 

 of exogenous estrogen (Gardner et al., 1940, 1944); smaller doses augment the 

 leukemogenic action of X-rays (Kirschbaum et al., 1953). Estrogenic hormone 

 may overcome the protection against X-ray induced leukemogenesis afforded 

 by thigh-shielding (Toch et al., 1955). Simultaneous administration of androgen 

 may negate the leukemia-inciting action of estrogen (Gardner et al., 1940). 



In specific inbred strains of mice and their hybrids spontaneous leukemia occurs 

 earlier in females (Murphy, 1944; Liebelt, A.G., 1957) and the total incidence of 

 the disease is also higher than in males. Castration increases the incidence of 

 leukemia in males of certain high-leukemia strains (Murphy, 1944). In another 

 strain susceptibility to carcinogen-induced leukemia was increased by castration 

 (Kirschbaum et al. , 1 955) . The administration of androgen inhibited leukemogenesis 

 in castrates. Although the genesis of lymphocytic neoplastic disease is augmented 

 by estrogenic hormone, male mice are more sensitive than females to the induction 

 of granulocytic leukemia by X-rays (Upton and Furth, 1956). 



The lymphoid neoplasms induced by methylcholanthrene and the estrogenic 

 hormones are identical. If induction of leukemia is evidence of the carcinogenic 

 potency of the carcinogenic hydrocarbons, by the same token estrogenic hormone 

 is a carcinogen. The thymus appears to be the lymphoid organ primarily sensitive 

 to the induction of neoplasia by estrogenic hormone (Gardner et al., 1940), X-rays 

 (Kaplan, 1950a), or the carcinogenic hydrocarbons (Law and Miller, 1950a). 

 When methylcholanthrene is placed directly into the thymus, neoplasia results 

 more readily than if similar local treatment is applied to lymph node ; the action 

 of methylcholanthrene may be considered local or "direct" (Rask-Nielsen, 1950). 

 Thymic radiation/)^?- se is not leukemogenic (Kaplan, 1949); shielding of hemo- 

 poietic tissue is protective against the induction of leukemia (Kaplan and Brown, 

 1 951) and secondary effects of irradiation are important in leukemogenesis (Kaplan 

 et al., 1955, 1956). Similar data are not available for the leukemogenic activity of 

 estrogens. The possible mediation of viral activity by estrogens will be discussed 

 below. 



Renal tumors have been induced in guinea pigs and hamsters by estrogenic 



Literature p. 870 



