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[CANCER RESEARCH 37, 4408-4415, December 1977] Antitumor Effect of Two Oral Steroids, Mepitiostane and Fluoxymesterone, on a Pregnancy-dependent Mouse Mammary Tumor (TPDMT-4)1 Akio Matsuzawa and Tadashi Yamamoto Laboratory Animal Research Center ¡A.M.¡and Department of Oncology [T. Y.], Institute ot Medical Science, University of Tokyo, P. O. Takanawa, Tokyo 108, Japan SUMMARY (9). Pituitary glands released from hypothalamic control secreted primarily prolactin, with both luteotropic and Pregnancy-dependent TPDMT-4 mammary tumors, char mammotropic effects (17). Continuous tumor growth also acterized by requiring estrogen, progesterone, and pituitary occurred in virgins given implants of a pellet containing hormones for growth, grew continuously in female ODD 17/3-estradiol and progesterone (9). These experimental mice carrying pituitary isografts. The experimental model systems have provided useful models for studies on endo- was used to investigate the antitumor effects of two p.o. crinotherapy of hormone-dependent mammary tumors. In steroids, mepitiostane and fluoxymesterone. When tumors hosts with ectopie pituitary isografts, the tumors ceased to implanted with pituitary ¡sograftsinto the fat-pad reached grow and began to regress immediately after treatment palpable size, animals received 6 doses/week of 0.1, 0.3, with epitiostanol [2a,3«-epitho-5«-androstan-17/3-ol(10275-, 1.0, and 3.0 mg of either steroid intragastrically. Mepitio S)] (10). The steroid also suppressed mammary gland devel stane significantly suppressed tumor growth with regression opment in the hosts. The steroid has been used with some in 25 and 29% of animals at 1.0 and 3.0 mg, respectively, efficacy for treatment of advanced breast cancer (3). A but had no inhibitory effects at other doses. Fluoxymester derivative of the steroid that exerts an antiestrogenic effect one retarded tumor growth during the first week of treat after p.o. administration was synthesized (5); the derivative ment at 3.0 mg but finally had no inhibitory effects at any is mepitiostane [2a,3a-epitho-5a-androstan-170-yl 1-meth- doses. Under similar conditions ovariectomy caused tumor oxycyclopentyl ether (10364-S)]. Mepitiostane has been tried regression immediately, and epitiostanol, the parent steroid with some efficacy in advanced human breast carcinomas of mepitiostane, significantly suppressed tumor growth (6). Fluoxymesterone or 9a-fluoro-11/3, 17/3-dihydroxyan- when given in 3 injections/week of 0.5 mg s.c. Tumors had drost-4-en-3-one is another p.o. steroid that has been ex papillary structures and almost lacked secretory activity. A tensively used for treating human breast carcinomas (4, 7, comparison of these findings to those obtained with earlier 20). Both mepitiostane and fluoxymesterone antagonized generations suggests that TPDMT-4 tumors became less the uterine weight gain and vaginal cornification produced sensitive to the antitumor effect of epitiostanol and were by exogenous estrogen in immature or ovariectomized able to grow at lower hormone levels with succeeding mice, but only mepitiostane inhibited ductal growth of the generations. Morphologically, progression to more cancer mouse mammary gland and growth of hormone-dependent and less secretory activity was noticed. rat mammary tumors (15). This study was conducted to investigate the antitumor effects of mepitiostane and fluoxymesterone on TPDMT-4 INTRODUCTION mammary tumors in pituitary ¡sograft-bearing hosts. Treat ments with epitiostanol and ovariectomy were included to A very stable, transplantable pregnancy-dependent mam examine possible changes in TPDMT-4 tumors in response mary tumor line designated TPDMT-4 was first successfully to hormones during the course of serial transplantations. isolated in ODD mice, a strain of European origin (8). TPDMT-4 tumors are characterized by growth during preg nancy, rapid regression after parturition in breeders, and MATERIALS AND METHODS virtually no growth in virgins. These mammary tumors are very similar to the normal mammary gland in their response Animals. ODD mice, bred and maintained in the mouse to a variety of hormones. Estrogen and progesterone colony in the Laboratory Animal Research Center, were secreted from the ovary (9) and pituitary hormones includ used in all experiments. Female mice, 6 to 7 weeks old, ing prolactin (11) are essential for TPDMT-4 tumor growth. served as recipients. Pituitary isografts were obtained from The tumors have both cytoplasmic and nuclear estrogen syngeneic male and female mice 2 to 4 months old. The receptors. TPDMT-4 tumors grew without regression in origin and some characteristics of the strain have been syngeneic female mice carrying ectopie pituitary isografts described in detail elsewhere (12). ODD mice originated in Europe, carry a virulent strain of murine mammary tumor 1 Supported by a grant-in-aid for cancer research from the Ministry of virus (MTV-P), and are characterized by rare and late Education, Science, and Culture. Japan. Received May 3, 1977; accepted September 15, 1977. development of mammary tumors. Under the present exper- 4408 CANCER RESEARCH VOL. 37 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1977 American Association for Cancer Research. P.O. Steroids and Hormone-dependent Mammary Tumor ¡mentalconditions, spontaneous mammary tumors did not 80, 0.5% (w/v) carboxymethylcellulose, and 0.9% (v/v) ben affect the results. Fourteen, 15, and 7 animals were allo zyl alcohol and was injected s.c. into the neck region of cated to each group in Experiments 1, 2, and 3. respec the back 3 times weekly. Control and ovariectomized ani tively. Animals were given free access to F1 laboratory mals received s.c. injections of the vehicle alone at the chow (Funabashi Nojo Co. Ltd., Funabashi, Japan) and tap same frequency during the same period. In all experiments water throughout the experimental period. the first treatment day was designated as Day 0. At the Tumors. TPDMT-4 is a transplantable pregnancy-depend termination of treatments, all animals were killed to obtain ent mammary tumor line established from a spontaneous the weights of the body, ovaries, uterus, adrenal glands, mammary tumor of a ODD mouse. The response to hor and thymus. mones and other properties of this particular tumor line Morphology. In Experiments 1 and 2 the tumors and have been described in detail (8, 9, 11). A tumor at trans ovaries were fixed in 10% formalin, processed routinely, plant generation 23 or 24 was obtained from a female, and stained with hematoxylin and eosin for histological close to termination of her second pregnancy, and was cut study. The whole skins from all control and experimental into fragments measuring approximately 2x2x2 mm. A animals were fixed in 10% formalin, and whole mounts of tumor fragment and 3 pituitary isografts were implanted the third mammary glands were prepared as described into the right inguinal fat-pad of each recipient. These elsewhere (13, 14). The extent of lobuloalveolar develop animals were inspected, and the 2 diameters, bisecting ment was classified into 5 grades numbering 0 to 4, accord palpable tumors at a right angle to each other, were deter ing to the criteria described in 'Results." mined twice weekly. The arithmetic mean of the 2 diameters Statistics. The significance of difference in tumor diame was designated as the tumor diameter. Growth curves were ter and tumor, body, and organ weights between each obtained by charting the mean diameters versus time for treated group and the corresponding control was examined each group. by Student's t test. The differences were evaluated as Treatments. In Experiment 1 the antitumor effect of significant at p < 0.05. mepitiostane and fluoxymesterone was examined at daily doses of 0.1, 0.3, and 1.0 mg. The experiment was carried out at transplant generation 23. When tumor sizes had RESULTS reached 4x4 mm to 11 x 11 mm 27 to 30 days after implantation, the animals were randomly divided into 7 Experiment 1. Antitumor Effect of Mepitiostane and Fluox groups of 14 animals each; no significant difference in ymesterone at Small Doses tumor diameters, pretreatment periods (intervals between Each group included 14 animals with palpable tumors at tumor implantation and the start of treatments), and latent the commencement of treatment. However, 1 animal in periods (intervals between tumor implantation and the ap each group was discarded due to unsuccessful intubation pearance of palpable tumors) was noticeable among them. in all groups except for those treated with 0.1 and 0.3 mg Each test dose of steroids was dissolved or suspended in fluoxymesterone in which groups all animals were success 0.1 ml sesame oil and was p.o. administered with a stomach fully treated throughout the experimental period. As indi tube 6 times weekly over a treatment period of 36 days, cated in Table 1, mepitiostane at doses of 0.1 and 0.3 mg starting on the day of animal grouping. Control animals received i.g.2 doses of sesame oil alone. and fluoxymesterone at all doses had no influence on tumor weights and diameters. Although it is not illustrated Experiment 2 was carried out at transplant generation 24 in the charts, the growth curve of the tumor followed to examine antitumor effect of both steroids at a higher virtually the same course in these groups as in the control. daily dose of 3.0 mg. Treatment with 1.0 mg of either Mepitiostane significantly suppressed tumor growth as re steroid was included for reference because the growth of flected by weight and diameter at a dose of 1.0 mg (Table tumors varied to some degree with the tumors that served 1). Tumor regression occurred in 2 animals of this group as sources of tumor grafts (10). When tumor sizes reached (Chart 3). The degree of tumor growth retardation resulting 3x3 mm to 12 x 12 mm after 27 to 32 days, animals were from this dose was similar to that obtained at the same randomly divided into 5 groups of 15 animals each as dose in Experiment 2 and is presented in Chart 1.

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