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M Pollard

Publications and source records attributed to M Pollard.

At least 19 recordsLinked to original sources

Early manifestations of induced prostate tumors in Lobund-Wistar rats.

Lobund-Wistar (L-W) rats are susceptible to spontaneous and induced metastasizing prostate cancer. In the search for the initial site of tumor development in the induced disease, rats at risk were examined periodically to acquire this information. In the course of 12 months after the onset of the induction of prostate cancer in L-W rats, 14 of 40 rats (35%) developed visible tumors in the anterior and in the dorso-lateral lobes of the gland. The prostate tumors appeared at 7 months and thereafter. Two of the tumor-bearing rats had developed, in addition, a visible neoplasm in the seminal vesicle. None of the rats with small early tumors had developed visible metastatic tumors, which were manifested in rats with large tumors.

Animals

The Lobund-Wistar rat model of prostate cancer.

Two models of preventable metastasizing autochthonous prostate adenocarcinoma (PA) have been described in Lobund-Wistar (L-W) rats: spontaneous PAs that develop at a mean age of 26 months; and induced PAs that develop at a mean time of 10.5 months. Both are similar in many respects to the counterpart disease in man. PAs develop spontaneously, and by induction through a combination of N-methyl-N-nitrosourea (MNU)/testosterone treatments. Our investigations with L-W rats show that PA is manifested spontaneously in 26% of aged L-W rats, and by induction in approximately 90% of younger rats. It is characterized by metastatic adenocarcinoma initiated in, and expanding from, the dorso-lateral and anterior lobes, and occasionally in the seminal vesicles. It is regulated by genetic, hormonal, and age-related mechanisms. Spontaneous PAs are prevented by life-long moderate (25%) diet restriction and, in rats at risk of developing induced PA, by early treatments with estradiol, with dihydrotestosterone, with a retinoid, and by castration. While the "premalignant" stages of induced tumorigenesis are susceptible to intervention, the overtly malignant stage resists therapeutic trials with the same agents and procedures. The transition from dependency to autonomy has not yet been defined.

Adenocarcinoma

Prevention of primary prostate cancer in Lobund-Wistar rats by N-(4-hydroxyphenyl)retinamide.

We report for the first time that a synthetic retinoid, N-(4-hydroxyphenyl)retinamide, can prevent the development of both primary and metastatic tumors in an animal model of metastasizing primary prostate cancer. Prostatic adenocarcinomas were induced in high incidence in Lobund-Wistar rats by initiation with methylnitrosourea i.v. and promotion with testosterone. Feeding of N-(4-hydroxyphenyl)retinamide to these rats during the latency period markedly diminished the final incidence of both primary and metastatic prostate carcinomas.

Adenocarcinoma

The inhibitory effect of 4-hydroxyphenyl retinamide (4-HPR) on metastasis of prostate adenocarcinoma-III cells in Lobund-Wistar rats.

Tumor cells of transplanted prostate adenocarcinoma-III (PA-III) spread with very high frequency from the extravascular implant site through ipsilateral lymphatic channels to the lungs in which they produce visible focal tumors. The latter enlarge, coalesce and eventually kill the host. This system was used to demonstrate the effect of a retinoid on metastasis. Lobund-Wistar (L-W) rats were administered 1 mmol 4-HPR/kg diet L-485, and control rats received the same diet without 4-HPR. After an interval, all rats were inoculated subcutaneously with PA-III cells. When examined at autopsy, all rats had developed an anticipated tumor at the implant site. However, the numbers of focal PA-III tumors in the lungs were significantly reduced among the 4-HPR-treated rats compared to the control rats (P = 0.002).

Adenocarcinoma

Influence of aging, environmental antigens, and dietary restriction on expression of lymphocyte subsets in germ-free and conventional Lobund-Wistar rats.

Lymphocyte subsets from four groups of Lobund-Wistar (L-W) rats were quantitated to determine the influence of diet restriction (DR) and exposure to environmental antigens on the development of these cells. The following effects were found from 6 to 30 months of age: The number of Ts/c and Ts cells were higher in germ-free (GF) vs conventional (CV) rats, whereas B-cell numbers were lower. W3/13 T cells, Ts, and NK cell numbers were higher in DR vs full-fed rats, whereas B-cell numbers were lower. OX19 and W3/13 T cell numbers decreased from 6 months to 30 months in each group, whereas NK cell numbers increased. Also, OX6+ B cell numbers increased with age, and Ts/c numbers decreased. These data may reflect a relationship between enhanced T-cell function and the extended life span and lower tumor incidence observed in DR L-W rats.

Aging

Life span, morphology, and pathology of diet-restricted germ-free and conventional Lobund-Wistar rats.

The effect of germ-free life and dietary restriction (DR) on life span and pathology was investigated in isolator housed germ-free (GF) and conventional (CV) Lobund-Wistar rats fed either ad libitum or restricted to 12 grams per day (70% of adult ad libitum intake) of a natural ingredient diet from weaning. The median length of life of ad libitum CV and GF rats was 31.0 and 33.6 months respectively, while DR increased the median length of life of CV and GF rats to 38.6 and 37.8 months respectively. DR reduced the frequency or postponed the occurrence of diseases which eventually lead to death in the Lobund-Wistar rat. This was especially true of prostate adenocarcinoma, prostatitis, and mammary fibroma. The reduced early food intake and smaller body weight of adult GF rats may be the reason ad libitum fed GF rats live slightly longer than their CV counterparts, but GF life was without additional effect on life span when food intake was restricted.

Adrenal Gland Neoplasms

Prevention and treatment of primary intestinal tumors in rats by piroxicam.

Over 90% of methylazoxymethanol acetate-treated male Lobund Sprague-Dawley rats developed intestinal tumors within 20 weeks; the incidence and numbers of tumors remained basically the same at 40 weeks. However, at week 40 the numbers of large tumors (greater than 0.5 cm in diameter) were increased. At week 40, tumors in methylazoxymethanol acetate-inoculated rats that had been treated with piroxicam (approximately 2.3 mg/day) from week 1 or from week 20 (after tumors had developed) were significantly reduced in numbers, but many large tumors persisted. Rats treated with piroxicam up to 40 weeks carried 0.6 tumor/rat compared with 2.7 tumors/rat among untreated controls (P less than 0.0001). Rats at week 20 had developed 2.8 tumors/rat and rats treated with piroxicam from week 20 to week 40 carried 1.4 tumors/rat (P less than 0.007). Most of the tumors in the piroxicam-treated rats showed evidence of histological differentiation.

Animals

Prevention of prostate cancer and liver tumors in L-W rats by moderate dietary restriction.

Aging conventional (CV) and germfree Lobund-Wistar (L-W) rats developed spontaneous tumors, predominantly in the prostate, liver, and adrenal glands. In CV L-W rats a 30% reduction of daily intake (natural ingredient diet L-485) had the following effects: (1) reduction of the incidence of metastatic prostate adenocarcinomas (PA) from 25.7% to 6.3% and extension of the average latent periods from 26.6 to 36.7 months; and (2) reduction of the incidence of hepatomas from 59% to 26% and extension of the average latent periods from 31.3 to 34 months. Adrenal medullary tumors developed in approximately 60% of rats older than 19 months, regardless of dietary intake and microbial status. Stromal hyperplasia developed among 36 of 78 (46%) rats older than age 30 months. Rats with PA were free of stromal hyperplasia, and the reverse was also true. Germfree L-W rats developed all of the above tumors, but the diet-related differences were not as significant as those among the conventional counterpart rats. The incidence of prostatis was reduced from 22% to 6% among the diet-restricted rats, but this lesion did not develop among the germfree rats.

Adenocarcinoma

Prevention and treatment of experimental prostate cancer in Lobund-Wistar rats. I. Effects of estradiol, dihydrotestosterone, and castration.

The Lobund-Wistar (L-W) rat is unique in its susceptibility to spontaneous and induced metastasizing prostate adenocarcinomas (PAs). A single IV inoculation of methylnitrosourea (MNU) produced PAs in 20% of L-W rats in 12 months. The combination of MNU plus two to seven slow-release implants of testosterone propionate (TP) induced PAs in 50-90% of rats respectively in an average of 11.5 months. The induction of PAs was prevented by early treatments of rats at risk with estradiol and less so with dihydrotestosterone (DHT). However, on a technical basis, the results were not significant. Treatments of MNU-inoculated rats with estradiol, with DHT, or by castration, at intermediate points in the projected latency time of tumor development, reduced significantly the incidences of PA development. Rats in which overt PAs had already developed in response to 12 months of exposure to implants of TP did not respond to treatment by estradiol, DHT, or castration. Thus there are early stage(s) in induced prostate tumorigenesis in L-W rats that are sensitive to modulating agents.

Adenocarcinoma

The effect of intravenous nutrition on muscle mass and exercise capacity in perioperative patients.

This study was undertaken to compare the efficacy of four different types of perioperative intravenous nutritional support. Fifty-five patients undergoing routine major surgery were studied. They were prospectively assigned to one of four study groups. Group 1 received formal total parenteral nutrition (90 g amino acids, 3,000 calories as glucose, per day); Group 2, 100 g glucose per day; Group 3, 90 g amino acids per day; and Group 4, peripheral parenteral nutrition (90 g amino acids plus 1,600 calories, 60 percent as fat per day). Group 1 was maintained on therapy for 3 weeks and the other groups for 8 days. Nitrogen balance, maintenance of body cell mass, serum albumin levels, and maintenance of exercise capacity were measured. Patients receiving peripheral parenteral nutrition maintained their nutritional parameters, as did those receiving total parenteral nutrition. These infusions were both markedly superior to those receiving glucose alone or those receiving amino acids alone. Nitrogen balance was not correlated with maintenance of function, but maintenance of body cell mass was correlated with maintenance of exercise capacity (r = 0.66, p less than or equal to 0.01). We conclude that perioperative peripheral parenteral nutrition, in contradistinction to hypocaloric infusions of glucose or amino acids, is capable of maintaining postoperative muscle mass and function close to preoperative levels after major surgery, and in situations of relatively mild surgical stress, approaches the efficacy of total parenteral nutrition in this regard. A significant correlation exists between changes in body cell mass determined from isotope dilution and changes in the exercise capacity of large muscle masses.

Adult

The promotional effect of testosterone on induction of prostate-cancer in MNU-sensitized L-W rats.

Large metastasizing prostate adenocarcinomas (PAs) were induced in L-W rats by a single intravenous (i.v.) inoculation of methylnitrosourea (MNU) and then single subcutaneous implants of testosterone propionate (TP) at intervals of 2 months. This procedure induced PAs in approximately 90% of rats in an average of 11 months. PAs did not develop spontaneously in L-W rats under age 20 months. With this model system, it was demonstrated that within a 14-month observation period, significant numbers of PAs were elicited by TP implants in L-W rats after intervals of 1 week, 1 month and 2 months following the inoculation of MNU. A direct relationship was also demonstrated between amount of TP administered to L-W rats and the resulting incidence of PAs. TP is characterized as a prostate-directed promoter of PA, following a single inoculation of MNU which served as the tumor initiator.

Adenocarcinoma

A model system for the in vivo determination of the thrombolytic effect of plasminogen activators.

An in vivo model system for measuring the thrombolytic efficiency of plasminogen activators was used. The formation of radiolabelled microthrombi was induced by infusion with I-125 labelled fibrinogen and thrombin. Reactive fibrinolysis was inhibited by administration of suboptimal levels of e-aminocaproic acid. The thrombolytic and subsequent fibrinolytic events were followed in the capillary bed of the lungs of anesthetized rats by external monitoring of the I-125 activity over the lung field. The model was successfully employed to demonstrate the thrombolytic effect of plasminogen activator produced by a transplanted spontaneous rat prostate adenocarcinoma cell line (PA III). The system proved to be reproducible with detection limits of 6000 I.U. using the PA-III cell line derived activator.

Animals

Effects of diphosphonate and x-rays on bone lesions induced in rats by prostate cancer cells.

Prostate adenocarcinoma-III (PA-III) cells deposited over the scapula of Lobund-Wistar (L-W) rats induced osteolytic and osteoplastic changes in that bone. The osteolytic process was prevented and interrupted by administrations of dichloromethylene diphosphonate (Cl2MDP); but the osteoplastic process, once initiated, continued. The latter process was interrupted by ionizing radiation. Treatments of PA-III-affected bones with Cl2MDP and x-rays immobilized both osteolytic and osteoplastic processes.

Adenocarcinoma

Serum hormones in diet-restricted gnotobiotic and conventional Lobund-Wistar rats.

In order to clarify the reasons for life extension due to the germ-free state and mild dietary restriction, serum levels of thyroid stimulating hormone, thyroxine, triiodothyronine, prolactin, and testosterone were determined in conventional and gnotobiotic (single microbe contaminations) Lobund-Wistar rats fed either ad libitum or restricted to 12 grams (70% of ad libitum) of diet per day from weaning. Thyroid hormone levels were slightly higher in gnotobiotic rats, declined between 7 and 30 months of age in all rats, and were not affected by dietary restriction. Prolactin showed a significant rise with age within the ad libitum rats only. Testosterone levels declined significantly with age in all rats, but were significantly higher in restricted rats at all ages. These results indicate that mild dietary restriction extends life span without reducing circulating levels of thyroid stimulating hormone, thyroxine, triiodothyronine, or testosterone in mature Lobund-Wistar rats, and prevents the age-associated rise in serum prolactin. Life extension in germ-free rats is not related to differences in endocrine function.

Aging

Dihydrotestosterone does not induce prostate adenocarcinoma in L-W rats.

It has been postulated that dihydrotestosterone (DHT) is the active trophic androgen in initiating pathogenic changes in the prostate gland. Groups of prostate cancer-susceptible male L-W rats (age 3 months) were treated with subcutaneous depots of testosterone or of DHT. After 14 months, prostate adenocarcinomas had developed in 24% of the testosterone-treated rats but not in the DHT-treated rats. In the latter rats, the testes were significantly reduced in weight, there was no evidence of spermatogenesis, and serum testosterone levels were not detectable. It appears that DHT as administered to L-W rats had an antiandrogenic effect.

Adenocarcinoma

Autochthonous prostate adenocarcinomas in Lobund-Wistar rats: a model system.

An experimental model system for autochthonous prostate adenocarcinoma (PA) has been developed in Lobund-Wistar (L-W) rats. Large primary PAs were induced in 31 of 40 (77.5%) L-W rats within an average of 10.7 months after a single dose of methylnitrosourea (MNU) and subcutaneous implants of testosterone. Metastatic tumors had developed in over 60% of the tumor-bearing rats. In addition, localized in situ PAs had developed in 5 of the 40 test rats. At 14 months 50 untreated L-W rats were free of demonstrable PAs. Two of 20 (10%) L-W rats developed PA at 14 months after inoculation of MNU alone. Six of 42 (14%) L-W rats developed PAs within 14 months after s.c. administration of testosterone implants. Thus, testosterone acted as a tumor promoter of PA for cells that had been initiated by MNU. The manifestations of the PAs in the L-W rats resembled many aspects of the counterpart disease in man.

Adenocarcinoma