Biomedical subjects
Publications and source records attributed to M Pollard.
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The prevailing hypothesis on the biosynthesis of erucic acid in developing seeds is that oleic acid, produced in the plastid, is activated to oleoyl-coenzyme A (CoA) for malonyl-CoA-dependent elongation to erucic acid in the cytosol. Several in vivo-labeling experiments designed to probe and extend this hypothesis are reported here. To examine whether newly synthesized oleic acid is directly elongated to erucic acid in developing seeds of Brassica rapa L., embryos were labeled with [14C]acetate, and the ratio of radioactivity of carbon atoms C-5 to C-22 (de novo fatty acid synthesis portion) to carbon atoms C-1 to C-4 (elongated portion) of erucic acid was monitored with time. If newly synthesized 18:1 (oleate) immediately becomes a substrate for elongation to erucic acid, this ratio would be expected to remain constant with incubation time. However, if erucic acid is produced from a pool of preexisting oleic acid, the ratio of 14C in the 4 elongation carbons to 14C in the methyl-terminal 18 carbons would be expected to decrease with time. This labeling ratio decreased with time and, therefore, suggests the existence of an intermediate pool of 18:1, which contributes at least part of the oleoyl precursor for the production of erucic acid. The addition of 2-[3-chloro-5-(trifluromethyl)-2-pyridinyloxyphenoxy] propanoic acid, which inhibits the homodimeric acetyl-CoA carboxylase, severely inhibited the synthesis of [14C]erucic acid, indicating that essentially all malonyl-CoA for elongation of 18:1 to erucate was produced by homodimeric acetyl-CoA carboxylase. Both light and 2-[3-chloro-5-(trifluromethyl)-2-pyridinyloxyphenoxy]-propanoic acid increased the accumulation of [14C]18:1 and the parallel accumulation of [14C]phosphatidylcholine. Taken together, these results show an additional level of complexity in the biosynthesis of erucic acid.
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The rate and extent of metastasis by prostate adenocarcinoma-III cells was enhanced in Lobund-Wistar rats by administration of immune-suppressive cyclosporine A. PA-III cells spread from the subcutaneous PA-III-derived tumor, through ipsilateral lymph nodes, to the lungs in which they developed secondary tumors. Swollen lymph nodes, compacted with PA-III cells, indicate that the 'normal' host-engendered level of intravascular non-specific restraints to metastasis were abrogated by CSA.
Lobund-Wistar (L-W) rats are inherently susceptible to spontaneous and induced metastasizing adenocarcinomas in the prostate-seminal vesicle (P-SV) complex. L-W rats were fed soy protein isolates containing high isoflavones (genistein and daidzein) or low isoflavones to determine their effects on development of induced P-SV tumors in two stages of the tumorigenic process. In rats fed the high-isoflavone-supplemented soy diet before initiation by methylnitrosourea (MNU), the incidence of induced prostate-related cancer was reduced and the disease-free period was prolonged by 27% compared with rats fed the same diet but low in isoflavones. Rats fed the same diets, started after MNU, manifested suggestive but less consistent results than those noted above. The incidence rates were of marginal significance, suggesting that the high intensity of the active induced disease may not represent the character of the slower-growing spontaneous (natural) disease. The delay of disease onset is of clinical significance.
An ion-sensitive field effect transistor (ISFET, Sentron, Sentron, Inc.) electrode was compared with a glass combination micro-electrode (MI-410, Micro-electrodes, Inc.) and a solid-state metal wire oxide pH sensor (Beetrode, World Precision Instruments, Inc.) with a liquid junction reference electrode (MERE1, World Precision Instruments, Inc.). The electrodes were assessed for linearity, reproducibility, accuracy, drift from the initial calibration between pH 4 and pH 7 and the time taken to record a stable reading. The ISFET was used to determine the pH in dental plaque samples (1 mg suspended in 20 microliters). The pH values correlated with the hydrogen ion concentration for all the electrodes (r = 0.98). The MI-410 fractured before this evaluation was completed. Coefficients of variation were 0.65% (pH 4) and 0.08% (pH 7) for the ISFET and 4.69% (pH 4) and 3.46% (pH 7) for the Beetrode. Both electrodes gave readings that differed significantly from the initial calibration, but the drift was greater for the Beetrode (F = 7.93; p = 0.0005) than the ISFET (F = 1.89; p = 0.1519). However, this drift was smaller than the change in pH as measured in dental plaque samples. The Beetrode gave a stable reading after 3.39 +/- 0.83 s and the ISFET after 2.2 +/- 0.76 s, while the MI-410 required at least 20 s. The ISFET type electrode is suitable for use in small volumes such as plaque suspensions, is easier to operate and yields results closer to the initial calibration than the Beetrode and is more robust than the MI-410 and the Beetrode.
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Two contradictory actions have been ascribed to thalidomide relative to tumor metastasis: immunosuppression and anti-angiogenesis. The latter effect was determined with basic fibroblast growth factor in a rabbit cornea micropocket assay system. The prostate adenocarcinoma (PA-III) transplanted tumor line in Lobund-Wistar (L-W) rats produces a tumor at the subcutaneous implant site from which tumor cells metastasize uniformly only through lymphatic channels through the heart to the lungs in which secondary tumors develop. L-W rats were implanted with PA-III cells and administered, by gavage, thalidomide (50 mg/kg body wt per day) in corn oil. Control rats with PA-III cells were administered corn oil. Autopsy examinations on day 30 revealed that the thalidomide-treated rats developed more metastatic tumor foci in the lungs than in the controls.
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PURPOSE: To study the mechanism of diminished arachidonic acid levels in malignant prostatic tissues. MATERIALS AND METHODS: Benign and malignant prostate tissues were obtained from human radical prostatectomy specimens and from rats using Pollard's Lobund/Wistar rat prostate cancer model. Fatty acid composition and a variety of enzyme activities involved in maintaining phospholipid fatty acid composition were compared in malignant and benign prostatic tissues. RESULTS: Decreased arachidonic acid levels, previously reported in human prostate cancer, were present in malignant rat as well as in human tissues. There were 21% and 26% decreases of arachidonic acid levels in the rat and human malignant tissues compared with benign tissues. Fatty acid desaturase activity was undetectable. Fatty acyl-CoA hydrolase and synthetase activities were not altered in the malignant tissues. However, there was a 2-fold increase in phospholipase A2 activity and a 4- to 12-fold increase in fatty acyl-CoA lysophosphatidylcholine acyltransferase activity in malignant rat and human prostatic tissues. CONCLUSIONS: These data indicate that, in malignant prostate tissues, the fatty acid remodeling mechanism is activated through the deacylation-reacylation cycle. This process may be a result of increased use of arachidonic acid for the formation of prostaglandins that may be crucial for the further development and growth of the malignant tissues.
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Aged Lobund-Wistar (L-W) rats develop: (i) spontaneous and induced metastasizing adenocarcinomas in the prostate and seminal vesicle (P-SV) complex; and (ii) spontaneous hepatomas and hepatocarcinomas. Within the time-frame of 14 months, similar adenocarcinomas were induced in the P-SV complex in 70-90% of younger L-W rats by a single i.v. inoculation of methylnitrosourea (MNU) which was followed by slow release s.c. implants of testosterone propionate (TP). Within the same time-frame, neither MNU nor TP alone induced significant incidences of P-SV tumors; and untreated control L-W rats were disease-free. Methylnitrosourea or TP and combinations thereof did not induce liver tumors. However, when MNU-inoculated L-W rats were fed phenobarbital (PB), they developed (i) metastasizing adenocarcinomas in the P-SV complex and (ii) altered cellular foci and nodules in the livers. Methylnitrosourea induced a high incidence of benign lung adenomas which progressed to lung cancers in numbers which were of marginal significance. Thus, dormant MNU-initiated cells in the P-SV complex were activated by phenobarbital, to produce adenocarcinomas in that complex.
Lobund-Wistar (L-W) rats are unique in their susceptibility to spontaneous and induced metastasizing adenocarcinomas in the prostate-seminal vesicle (P-SV) complex. Tumors were induced in 70-100% of rats by a combination of i.v. inoculated methylnitrosourea (MNU) followed by a series of subcutaneous slow-release implants of testosterone propionate (TP). Adenocarcinoma cells initiated by MNU in 3-month-old L-W rats were activated significantly by implants of the promoter, TP, after intervening periods of 3, 6 and 12 months following their exposures to MNU. The longer the time between MNU and TP, the shorter the subsequent latent period. Control rats inoculated with MNU (without TP) did not develop tumors during the observation period of 12 months, and their dormant tumor cells were activated by a single implant of TP, thereby eliciting P-SV tumors.
Using a one-stage kinetic chromogenic assay, we studied the procoagulant activity (PCA) of prostatic tissue in an experimental model of prostate cancer in the rat. PCA was present in homogenates of rat prostate glands containing either benign or malignant tumours. The procoagulant activated factor X directly and was provisionally characterised as a tissue factor-factor VIIa complex. There was no significant differences in PCA between control rats and rats exposed to carcinogens that did not develop tumour. Levels in rats that developed tumours were significantly higher (P < 0.01) than all other groups and there was a positive correlation between tumour weight and PCA (r = 0.85, P < 0.001). Furthermore, prostatic PCA levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this animals, the PCA of the primary tumour was compared with that of the corresponding secondary deposit and levels were higher in the metastasis (P < 0.02). We conclude that PCA reflects the malignant phenotype in this model of experimental prostate cancer and suggest that this parameter is worth evaluating as a potential tumour marker in the human disease.
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.
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.
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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.