Mammary carcinogenesis-enhancing effect of adrenalectomy in irradiated rats with pituitary tumor MtT-F4.

Mammary carcinomas were found at autopsy 98--100 days after irradiation in 12 of 14 (86%) multiparous Fischer female rats which had been adrenalectomized and given grafts of secretory pituitary tumor strain MtT-F4 soon after exposure to gamma-rays or fission neutrons. A single carcinoma was found in 1 of 10 unirradiated, MtT-bearing, adrenalectomized animals. When adrenalectomy was not done, no tumors were found in 8 unirradiated or in 13 irradiated MtT-bearing rats rats. In view of the well-established finding that Cortisol is essential for milk production, we suggested as a working hypothesis that, in the presence of high titers of mammotropic hormone and adrenal corticoids, differentiation of a given cell for milk secretion reduced that cell's proliferative potential. When such differentiation was precluded by adrenocorticoid deficiency, more irradiation-altered mammary epithelial cells retained their high proliferative potential and contributed to carcinoma formation.     

Permissive role of the pituitary in the induction and growth of estrogen-dependent renal tumors

Prolonged administration of estrogen to hamsters by implanted pellets induces not only renal adenocarcinomas but also enlarges pituitaries with hyperplastic and neoplastic changes, especially in the pars intermedia. The pituitaries of the diethylstilbestrol-implanted animals weigh 90 to 150 mg; those of control animals without diethylstilbestrol pellets weigh 7 to 12 mg. The enlarged pituitaries have 9.7 x 10(-10) M progesterone receptors compared to 0.75 x 10(-10) M in the controls. Castrated male hamsters were hypophysectomized, implanted with diethylstilbestrol pellets, fed laboratory chow ad libitum, and given 5% glucose in water to drink. New pellets were implanted every 3 months, and the animals survived for 12 to 15 months. At autopsy, none of the animals had a tumor. Sixty-two of 65 control castrated males with the same schedule of pellet implantation developed tumors. Hypophysectomized castrated males implanted with diethylstilbestrol pellets were given daily injections of 1 microgram each of follicle-stimulating hormone, luteinizing hormone, and prolactin; or with 0.9% NaCl solution. These animals survived for 12 to 15 months, but none developed kidney tumors. Other castrated males were hypophysectomized and implanted with diethylstilbestrol pellets, and 2 months later tumor tissues were transplanted under the kidney capsule. Eighty days later, no tumors were evident in the kidneys of these animals. Control castrated males were implanted with diethylstilbestrol pellets, and 2 months later tumor tissue was transplanted under the kidney capsule. Between 60 and 85 days later, 13 of the 15 controls had developed renal tumors. The concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin were measured by radioimmunoassays. The concentrations of circulating follicle-stimulating hormone and luteinizing hormone in animals with diethylstilbestrol implants decreased with time and, by 7 months, were similar to those in hypophysectomized animals. The concentration of prolactin in animals with diethylstilbestrol pellets increased with time and reached twice the value in the control animals without diethylstilbestrol pellets. These studies suggest that some factor secreted by the pituitary may be involved as a promoter or a cocarcinogen in the estrogen induction of kidney tumors.     

Flow cytometric analysis of the response of the r3327-g rat prostatic adenocarcinoma to endocrine manipulation

The technique of flow cytometric DNA histogram analysis (FCM) shows there to be two distinct cell populations (diploid vs aneuploid) in the poorly differentiated R3327-G rat prostatic adenocarcinoma. The following study compares tumor weight measurements with several FCM computer-based methods designed to determine rapidly the proliferative status of tumors. Hypophysectomy, bilateral adrenalectomy, orchiectomy, sham operations, or diethyl-stilbestrol treatments were initiated when the tumors were palpable (day 21) and continued until the tumors were excised (day 52). Hypophysectomy, orchiectomy, adrenalectomy, and diethylstilbestrol treatments all resulted in significant inhibition by tumor weight. Quantitation of the percentage of mid-S phase aneuploid cells by summation gave the best correlation with tumor weight. Tumors grown in hypophysectomized, orchiectomized, adrenalectomized, or diethylstilbestrol-treated animals showed a significant reduction in the proportion of mid-S phase cells as compared with controls. The calculation of the percentage of all aneuploid cells was significantly reduced in hypophysectomy, orchiectomy, and diethylstilbestrol-treated animals. However, tumors grown in adrenalectomized animals were not significantly different from controls by this method. Adrenalectomy was found to be the least effective form of therapy, and this was reflected in all of the parameters measured. These data show that FCM analysis may be useful in the quantitation of prostatic carcinoma response to therapy.     

Growth hormone and experimental cancer cachexia

Plasma levels of growth hormone (GH) and the effect of GH treatment have been evaluated in adult nongrowing sarcoma-bearing mice (C57BL/6J). Prepubertal tumor-bearing mice, tumor-bearing hypophysectomized Sprague-Dawley rats, and malnourished non-tumor-bearing animals served as additional groups of study and control animals. Adult sarcoma-bearing mice showed an increase in plasma levels of GH early following tumor implantation. GH levels increased further with tumor progression. The anorexia and the state of malnutrition in sarcoma-bearing mice were the major factors behind increased GH levels. Muscle wasting and body composition in the tumor-bearing host were not improved by GH treatment at doses that increased growth rate in normal growing mice with intact pituitaries or partially normalized growth rate in hypophysectomized rats. Exogenous GH supported tumor growth and host body growth to the same extent in hypophysectomized rats. Exogenous GH in excess of endogenous GH did not stimulate tumor growth further. It is suggested that increased GH production in a tumor-bearing host acts in concert with other hormones to stimulate endogenous substrate mobilization and in tumor-bearing animals to prevent substrate deficiency and hypoglycemia. On the basis of this conclusion, it is unlikely that GH supplementation to a freely eating tumor-bearing host will support replenishment of host tissues.     

Influence of prolactin and growth hormone on rat mammary tumors induced by N-nitrosomethylurea

The effects of hypophysectomy and prolactin-suppressing drugs on the growth of mammary tumors induced in Sprague-Dawley rats by N-nitrosomethylurea and dimethylbenz(a)anthracene were compared. The influence of ovine prolactin and growth hormone administration on N-nitrosomethylurea-induced tumors was also studied in hypophysectomized animals. After hypophysectomy, all 13 tumors induced in 13 rats by N-nitrosomethylurea underwent regression, as did ten of 12 induced by dimethylbenz(a)anthracene. There were no new tumors. Pergolide mesylate, a long-acting ergoline derivative, was given in a dose of 80 micrograms twice daily by s.c. injection for 28 days. Only three of 12 N-nitrosomethylurea-induced tumors regressed, while four became static. However, only two new tumors developed in the 12 pergolide-treated rats, compared to 11 in the 12 untreated controls. Bromocriptine mesylate, at ten times the pergolide dose, was even less effective; one of 16 tumors regressed, two became static, and eight new tumors appeared in the 16 rats. In contrast, eight of 12 dimethylbenz(a)anthracene-induced tumors regressed during pergolide therapy, two became static, and there was only one new tumor among the 12 rats. Prolactin, 1 mg twice daily for 7 days by s.c. injection, was given to another eight rats bearing 11 N-nitrosomethylurea-induced tumors, commencing 7 days after hypophysectomy. Regression of five tumors borne by four rats was reversed but resumed when treatment was stopped. Regression of five tumors in the other four animals was arrested without regrowth; the sixth became inpalpable. All of these six grew rapidly when growth hormone, 2 mg twice daily, was administered in addition to prolactin.     

Endocrine factors in the development of transplantable adrenal cortical tumors. I. Inhibition of the growth rate by corticotropin (ACTH)

The growth rate of transplantable adrenocortical tumors in male LAF 1 mice was found to be inhibited in hypophysectomized and in adrenalectomized animals. Castration and sex hormones did not affect the growth of these tumors. In intact mice a striking inhibition of the growth rate of adrenocortical tumors was brought about by the administration of ACTH. Evidence was obtained that ACTH inhibited growth by a direct action on the tumor cells. When expressed in terms of units of DNA, the biochemical and cytochemical effects on adrenocortical tumor cells appeared qualitatively similar to the effects of this hormone on the normal adrenal cortex. A single injection of ACTH stimulated the activity of glucose-6-phosphate dehydrogenase. Repeated administration of ACTH produced an increased oxygen uptake by sliced tissue and a moderate accumulation of RNA in the microsomal fraction. Water extracts of acetone powdered, ACTH-treated, adrenocortical tumors had lower dCMP-deaminase activity than extracts from untreated tumors. When expressed in terms of units of DNA, the homogenates of ACTH-treated adrenocortical tumors had a higher succinoxidase activity and the sliced tissue had a lower rate of anaerobic glycolysis than did corresponding samples of untreated adrenocortical tumors.     

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.     

Modification of immunogenic tumor growth by adrenalectomy in a syngeneic murine system

The immunosuppressive action of adrenal glucocorticosteroids is well-known, and depressed cell-mediated immunity and adrenal cortical hyperplasia have been described in tumor-bearing animals. This study was designed to evaluate the effect of removing the source of lympholytic steroids by adrenalectomy upon tumor growth rate, thymus weight, and thymocyte incorporation of iodine 125 (125I) deoxyuridine into DNA. Newly derived methylcholanthrene-induced immunogenic fibrosarcomas were used in male syngeneic mice. Log dosages of 10(4), 10(5), and 10(6) viable tumor cells as single cell suspension were injected subcutaneously into the popliteal space of adrenalectomized and control mice. Tumor size was followed serially with caliper measurements, and the animals were killed 4 weeks after inoculation. Adrenalectomized mice inoculated with 10(4) cells had smaller tumors (P less than 0.02), heavier thymi (P less than 0.01), and more thymic DNA synthesis (P less than 0.05) than their tumor-bearing controls. No differences were seen between populations receiving 10(5) or 10(6) tumor cell inoculations. A second experiment was carried out in which intact controls, adrenalectomized animals, and sham adrenalectomy animals were inoculated with 10(4) tumor cells and killed 28 days later. Tumor growth rate and volume were significantly decreased for the adrenalectomized mice, which had higher thymus weights and DNA synthesis. These findings suggest that pretreatment adrenalectomy slows the growth of antigenic tumor cells and prevents thymic involution after tumor growth in a syngeneic murine system.     

Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats.

It is well established that 85-90% of chemically induced mammary tumors in rats will disappear or diminish significantly in size after the ovaries are removed from the animal. However, it is less well established whether a high percentage of these mammary tumors will grow back with prolonged time after ovariectomy. It is also not known what changes in gene expression take place in the tumors as they develop an independence from hormones for growth. This study was carried out to investigate this. Virgin, 50-day-old female Sprague-Dawley rats were injected with N-methyl-N-nitrosourea (MNU) at the dose of 50 mg MNU/kg body wt. When at least one mammary tumor had grown to 1.0-1.5 cm in one dimension, the animal was bilaterally ovariectomized and reduction and then re-growth of the tumors monitored. Control animals were treated identically except they were not ovariectomized when tumors appeared. Re-growths and new tumors and tumors that developed in the control rats were removed when they reached 1.0-1.5 cm in diameter and all animals were killed 25 weeks after the MNU injection. All the animals in the study (100%) developed mammary tumors after MNU injection with an average latency of 56.5 days. After ovariectomy, 93% of the tumors showed 50% or more reduction in size and 76% of the tumors could not be detected by palpation. However, in 96% of the animals where tumor reduction or disappearance occurred, a re-growth or new mammary tumor development took place with an average latency period of 52.8 days from the day of ovariectomy. Of these post-ovariectomy tumors, 36% occurred at a location where tumors had developed prior to ovariectomy, but 64% appeared at new locations. The circulating levels of 17beta-estradiol (E2) was undetectable in the ovariectomized (OVX) rats and significant reduction was seen in the serum concentrations of progesterone (P4), prolactin (PRL), growth hormone (GH) and insulin-like growth factor-I (IGF-I). The tumors from the OVX rats showed indications of progression as evident from loss of differentiation and invasive characteristics. Comparison between tumors from OVX and intact rats revealed a significantly increased expression of P450 aromatase and elevated activation of extracellular signal-regulated kinase 1 and 2, but reduced levels of the progesterone receptor and cyclin D1 in OVX rats. However, the estrogen receptor (ER) content remained similar in tumors from both groups, at least at the protein level, and so did the expression of IGF-I, IGF-II, insulin receptor substrate-1 (IRS1), IRS-2 and epidermal growth factor receptor. IGF-I receptor (IGF-IR) and ErbB-2 were expressed, respectively, in 50 and 70% of the tumors from the OVX animals, whereas these genes were expressed in 100% of the tumors from the intact rats. It is concluded that chemically induced rat mammary tumors may still depend on the ER and local syntheses of E2 and growth factors for growth initially after ovariectomy. However, as these tumors progress, they develop a more aggressive phenotype and lose their dependency on the ER and possibly growth factors.     

High inhibitory activity of a new antiestrogen, RU 16117 (11alpha-methoxy ethinyl estradiol), on the development of dimethylbenz(a)anthracene-induced mammary tumors.

From the first day of dimethylbenzanthracene administration, daily treatment with 8 or 24 mug of the new antiestrogen 11alpha-methoxy ethinyl estradiol (RU 16117) completely prevented the appearance of mammary tumors in all animals up to the last time interval studied (130 days after dimethyl benzanthracene administration). At daily doses of 0.5 and 2.0 mug RU 16117, the tumor incidence was reduced to 78.6 and 40%, respectively. Not only was the number of animals developing tumors reduced after injection of low doses of RU 16117, but the number of tumors per rat and the size of tumors were also markedly reduced. The levels of receptors for estradiol, progesterone, and prolactin in tumor tissue were reduced after treatment with 2.0 mug RU 16117, while the binding of growth hormone and insulin was not affected. Whereas plasma luteinizing hormone levels decreased after treatment with 8 or 24 mug RU 16117, plasma prolactin levels slightly increased in animals receiving the highest dose of the antiestrogen. It is thus likely that the potent inhibitory effect of RU 16117 on the development of dimethylbenzanthracene-induced mammary tumors results from actions at both the hypothalamic-pituitary and the tumor (mammary gland) levels, the action at the peripheral level possibly being secondary to a reduced sensitivity of the tissue to circulating hormones through lowering of hormone receptor concentrations.     

Effects of the thiazolidinedione derivative CGP 19984 on growth and endocrine function of the MtT-W10 transplantable mammosomatotropic pituitary tumor in female rats

The thiazolidinedione derivative CGP 19984 has previously been shown to suppress the growth of hormone-dependent mammary and prostatic tumors, primarily by reducing gonadotropin and subsequently gonadal steroid secretion. The present study examines the effects of CGP 19984 on the growth and hormone secretion of the autonomous, but estrogen-responsive, MtT-W10 mammosomatotropic transplantable rat pituitary tumor. Intact tumor-bearing Wistar/Furth female rats were administered vehicle or 25, 100, or 250 mg/kg CGP 19984 p.o., 5 x week for 4 weeks. CGP 19984 was found to significantly reduce MtT-W10 tumor growth and weight and reduce prolactin and growth hormone (GH) secretion in a dose-responsive manner. A similar study in ovariectomized rats also showed that CGP 19984 treatment suppressed MtT-W10 pituitary tumor growth, weight and hormone secretion in a dose-responsive manner, suggesting a direct inhibitory action of this drug on the tumor. In a third study, bromocryptine (CB-154; 5 mg/kg) and CGP 19984 (50 mg/kg) were both found to be effective in suppressing growth of the MtT-W10 tumor in intact female rats. However, rats treated with CGP 19984 alone had reduced serum and tumor GH and prolactin concentrations, while rats treated with CB-154 alone had reduced serum and tumor prolactin, but no change in GH concentrations. These results suggest that CGP 19984 effectively inhibits growth and hormone secretion of the autonomous MtT-W10 pituitary tumor by apparently suppressing both somatotropic and lactotropic cell populations within the tumor. Furthermore, these findings indicate that CGP 19984 may be an effective alternative to CB-154 in the clinical treatment of prolactin-producing adenomas, as well as other types of pituitary adenomas.     

Antitumoral and endocrine effects of (+)-vorozole in rats bearing dimethylbenzanthracene-induced mammary tumors.

The antitumoral activity of vorozole, a potent and specific nonsteroidal aromatase inhibitor, against 7,12-dimethylbenz(a)anthracene-induced estrogen-dependent mammary adenocarcinoma was evaluated in 257 Sprague-Dawley rats. Twice daily p.o. administration of 1 and 5 mg/kg of the racemate R 76713 for 42 days induced almost complete regression of tumors, inhibited the appearance of new tumors, and reduced multiplicity of the remaining tumors. Antitumoral effects observed after ovariectomy or treatment with 5 mg/kg twice a day were not significantly different. R 76713, the racemate, (+)-vorozole (both at 2.5 mg/kg twice a day), and ovariectomy all similarly reduced tumor growth at 42 days by 90% or more, lowered the number of existing tumors, and prevented the appearance of new tumors. The less active levo-enantiomer (-)-vorozole at the same dose did not alter tumor growth. Vorozole reduced serum estradiol to the levels measured in ovariectomized animals. Serum progesterone levels were lowered, but to a much lesser extent than after ovariectomy, while serum luteinizing hormone and follicle-stimulating hormone concentrations increased, but also much less than after ovariectomy. On the other hand, the androgen levels, which remained undetectable or decreased after ovariectomy, markedly rose after vorozole treatment. These endocrine changes, observed in intact female rats, were not detected in ovariectomized animals demonstrating the ovarian origin of the endocrine changes induced by vorozole.     

Prolactin binding to 7,12-dimethylbenz(a)anthracene-induced mammary tumors and liver in diabetic rats.

Growth rates of 7,12-dimethylbenz(a)anthracene-induced mammary tumors and the specific 125I-labeled prolactin binding to membrane fractions prepared from livers and tumors were studied in rats made diabetic by streptozotocin injection. Growth was inhibited in a majority of tumors and prolactin binding was reduced in both tumors and livers from diabetic animals. Prolactin binding to individual tumors varied over a wide range in both intact and diabetic animals. Scatchard analysis of binding data revealed that the apparent affinity of prolactin binding to liver and tumor membranes was similar (Ka approximately 3.0 X 10(9) M-1) and was not affected by diabetes. We suggest that the reduction in prolactin binding to tumors may render these tissues less responsive to prolactin and thereby explain, at least in part, the observed inhibition of tumor growth in diabetic rats. However, some tumors in diabetic animals regressed despite relatively high levels of prolactin binding activity. Therefore, additional factors most certainly play important roles in the mechanism(s) by which the growth of 7,12-dimethylbenz(a)anthracene-induced tumors is impaired in the diabetic rat.     

Spontaneous and estrogen-produced tumors in Nb rats and their behavior after transplantation.

Tumors in rats of the Nb strain, arising either spontaneously or after prolonged treatment with s.c. pellets of estrogen, were transplanted to establish whether hormone conditioning was required for their growth. Whereas all spontaneous tumors arising in males and many of those in females were autonomous on transplant, most of those arising in estrogenized rats continued to require hormones for growth after transplantation. The latter included carcinomas of the adrenal cortex, breast, pituitary ectopic tissue, ovary (thecomas), Leydig cells of testis, thymus, pancreas,salivary glands, oribital gland (fibroadenoma), liposarcoma, and lymphoma. Many of the tissues of origin of the tumors have not been considered to be under theinfluence of estrogens. A type of hormone-responsive tumor that was inhibited by estrogen and that grew only in normal rats is described. Ali estrogens tested, including estriol , were interchangeable in action. The incidence of the more common tumors of the adrenal, breast, and pituitary was very low in normal rats, but higher in females. All tumors were more common after estrogenization in both sexes, particularyly in older animals. The secretion of steroids and pitiutary hormones by many tumors led to obvious biological effects. Pituitary secretion led to severe lesions frequently associated with diseases in humans, but the signs of such diseases in the rat apparently were hormone dependent and disappeared if the tumor was removed. The overall results raised the possiblity that estrogens were not carcinogenic per se but stimulated the growth of previously altered cells and that, following their transplantation, this hormone requirement was retained. Irrespective of the mechanism of carcinogenesis, hormone-dependent tumor growth was not irreversible but was controlled in an unexpectedly wide spectrum of organs by exogenous estrogen. Host factors may play a major role in controlling the growth of many tumors and the ultimate course of the disease.     

Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity

Melatonin inhibits the growth of breast cancer cells by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces aromatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. To investigate the in vivo aromatase-inhibitory properties of melatonin in our current study, this indoleamine was administered to rats bearing DMBA-induced mammary tumors, ovariectomized (ovx) and treated with testosterone. In these castrated animals, the growth of the estrogen-sensitive mammary tumors depends on the local aromatization of testosterone to estrogens. Ovariectomy significantly reduced the size of the tumors while the administration of testosterone to ovx animals stimulated tumor growth, an effect that was suppressed by administration of melatonin or the aromatase inhibitor aminoglutethimide. Uterine weight of ovx rats, which depends on the local synthesis of estrogens, was increased by testosterone, except in those animals that were also treated with melatonin or aminoglutethimide. The growth-stimulatory effects of testosterone on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in testosterone-treated rats. Tumors from animals treated with melatonin had lower microsomal aromatase activity than tumors of animals from other groups, and incubation with melatonin decreased the aromatase activity of microsomal fractions of tumors. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher survival probability than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by inhibiting the aromatase activity of the tumoral tissue.     

Influence of hormonal alteration of host on estrogen-binding capacity in 7,12-dimethylbenz(a)anthracene-induced mammary tumors.

The estrogen-binding capacity of mammary tumors induced by 7,12-dimethylbenz(a)anthracene was measured in lesions from animals after the ovariectomy, deprival of insulin (diabetes), or treatment with lergotrile mesylate to inhibit prolactin secretion. The average estrogen-binding capacity was 30 fmoles/mg cytosol protein in growing or static carcinomas from intact (control) animals. A significant reduction in estrogen-binding capacity was observed in regressing but not static mammary tumors from ovariectomized animals. In regressing and static tumors from diabetic rats, estrogen-binding capacity was significantly lower than in lesions from intact animals; this effect was not seen in growing tumors from diabetic rats. Tumors that were growing or static in lergotrile-treated animals showed reduced capacity to bind labeled estradiol. The effects of duration of hormone treatment or time of tissue storage on estrogen-binding capacity were examined and did not appear to be correlated with the decreased binding in tumors from treated animals. The results suggest that hormones capable of producing altered neoplastic growth may influence the level of estrogen receptors.     

Effect of aromatic retinoids on rat chondrosarcoma glycosaminoglycan biosynthesis.

Synthetic aromatic analogs of retinoic acid were administered i.p. and p.o. to Fischer F344 rats bearing a transplantable chondrosarcoma. 35CO4 incorporation into glycosaminoglycans were compared for neoplastic and normal cartilage explants after removal from animals given various analogs. There was a direct relationship between [35S]glycosaminoglycan synthesis by chondrosarcoma chondrocytes and inhibition of tumor growth. The degree of inhibition of [35S]glycosaminoglycan synthesis in the neoplastic cartilage was dependent on the dose of the retinoid administered. At 20-mg/kg/day doses of retinoid for 4 weeks, 35SO4 incorporated into glycosaminoglycan by treated tumor explants was reduced as much as 95%. There was no reduction of [35S] glycosaminoglycan produced in normal costal cartilage of the same animals. Retinoid treatment of 20-mg/kg/day doses for 4 weeks resulted in a 75% reduction in glycosaminoglycan per mg of chondrosarcoma; there was no reduction in costal cartilage glycosaminoglycan. Retinoid (10- to 20-mg/kg/day doses) elevated collagen levels per mg of chondrosarcoma but had no effect on costal cartilage collagen. Combined in vitro and in vivo studies showed that retinoid administration modified neoplastic chondrocyte function but had no measurable effect on normal chondrocyte function.     

Effect of hypophysectomy, hypophyseal explants and ACTH on the growth of human melanomas in diffusion chambers]

Under study was the hypophysis influence on the growth of human melanoma explants, cultivated in the abdominal cavity of mice and rats. The heterotransplants growth was compared in intact and hypophysectomized animals exposed to ACTH, and also the effect of the murine hypophysis explanted into the adjacent chamber compartments on the melanoma explants growth was investigated. The growth was assessed by a square area of the explants growth zones. ACTH and the hypophysis explanted were found to render a stimulating effect on the growth of tumor heterotransplants. Hypophysectomy in rats would suppress the growth of all melanoma explants under investigation. When injecting ACTH into hypophysectomized animals the growth of melanoma heterotransplants in the chambers does not differ from that in control series.     

Elevated Serum Growth Hormone Accelerates Gastric Tumorigenesis in F344 Rats after Treatment with N-Methyl-N-nitrosourea in Their Drinking Water

We examined the effects of growth hormone on tumorigenesis in F344 rats treated with N -methyl- N -nitrosourea (MNU). Four-week-old male F344 rats were exposed to 100 ppm MNU in their drinking water for 15 weeks. Thereafter Group II animals received 100 μCi/100 g body weight of ¹³¹I (radiothyroidectomy, Tx) injected i.p. and Group III rats were implanted with pituitary tumors (MtT) secreting growth hormone while Group I received no further treatment after MNU. Non-carcinogen control animals received MtT, Tx or no treatment. Animals were killed at 39 weeks after starting MNU administration. Gastric tumors were present in 13 of 31 (43%), 15 of 32 (47%) and 17 of 32 (53%) rats in Groups I to III, respectively. All tumors were of well-differentiated type. Spinal cord tumors appeared in 15 of 31 (47%) in Group I, 10 of 32 (32%) in Group II and 10 of 32 (32%) in Group III, most being malignant schwannomas. Thymic lymphornas also appeared in 10 of 31 (32%), 5 of 32 (16%) and 6 of 32 (19%) animals in Groups I to III, respectively. There were no significant differences among the groups. However, tumors in Group III developed significantly earlier than in Groups I or II. This was mainly due to gastric tumors, and cumulative incidence curves for spinal cord tumors or thymic lymphomas were similar in all groups. The results indicate that gastric tumors induced by MNU in F344 male rats are influenced by elevated levels of growth hormone.     

Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression

BACKGROUND: A sedentary lifestyle coupled with excessive energy intake is speculated to be a factor associated with increased incidence of prostate cancer. We have investigated the effects of energy intake on prostate tumor growth in experimental animals. METHODS: Two transplantable prostate tumor models, i.e., the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human carcinoma in severe combined immunodeficient mice, were studied. R3327-H tumor growth and relevant tumor biomarkers (proliferation index, apoptosis [programmed cell death], microvessel density, and vascular endothelial growth factor [VEGF] expression) were compared in ad libitum fed control rats, ad libitum fed castrated rats, and groups restricted in energy intake by 20% or 40%. A second set of experiments involving both tumor models examined tumor growth in ad libitum fed rats or in animals whose energy intake was restricted by 30% using three different methods, i.e., total diet restriction, carbohydrate restriction, or lipid restriction. All P values are two-sided. RESULTS: R3327-H tumors were smaller in energy-restricted or castrated rats than in control rats (P<.001). Tumors from energy-restricted rats exhibited changes in tumor architecture characterized by increased stroma and more homogeneous and smaller glands. In castrated rats, the tumor proliferation index was reduced (P<.0001), whereas apoptosis was increased in both energy-restricted (P<.001) and castrated (P<.001) rats. Tumor microvessel density and VEGF expression were reduced by energy restriction and castration (P<.003 versus control). Restriction of energy intake by reduction of carbohydrate intake, lipid intake, or total diet produced a similar inhibition of growth of R3327-H or LNCaP tumors. These effects were associated with reduced circulating insulin-like growth factor-I. CONCLUSIONS: Our observations are consistent with the hypothesis that energy restriction reduces prostate tumor growth by inhibiting tumor angiogenesis. Furthermore, dietary fat concentration does not influence prostate tumor growth when energy intake is reduced.