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ABSTRACT: The validity of the use of the monoclonal antibodies Ki-67 and anti-BrdUrd to evaluate proliferative activity of human prostate tumour models was studied. Growth of the transplantable PC-82 and PC-EW prostate tumours, as assessed by tumour volume measurements, was significantly correlated with the proliferative activity as reflected by BrdUrd incorporation into DNA (r = 0.64 and r = 0.78, respectively). The proliferative activity of PC-82 tumours detected by Ki-67 antigen expression paralleled the pattern observed with BrdUrd (r = 0.51) and a significant correlation (r = 0.60) between the results obtained with both markers was found. In growing PC-82 and PC-EW tumours only small variations in the Ki-67 and BrdUrd indices were observed. In contrast, Ki-67 expression in regressing PC-82 tumours varied considerably (2.7 +/- 2.2%). The BrdUrd index in regressing PC-82 tumours showed less variation (1.3 +/- 0.2%), but part of the BrdUrd-positive cells were found in the stromal (murine) part of the regressing tissue. It is concluded that the Ki-67 and BrdUrd proliferation markers are reliable parameters to monitor changes in growth of prostate tumour lines, but that in slow growing or regressing tumours Ki-67 and BrdUrd data should be interpreted with caution.
Cell Proliferation 02/1993; 26(1):67-75. · 2.52 Impact Factor
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ABSTRACT: The transplantable human prostate tumor lines PC-82 and PC-EW regress after androgen depletion. The castration-induced decline in tumor volume was faster in the PC-EW tumor (half-life 6 days) than in the PC-82 tumor (half-life 18 days), despite similar castrate androgen levels of less than 3 pmol/g tissue. Androgen ablation of the PC-82 tumor induced a wave of apoptosis, whereas in the PC-EW tumor, necrotic cell death was predominantly observed. The proliferative activity (BrdU index) of PC-82 and PC-EW tumor tissue declined from 3% to less than 1% after castration. After androgen depletion, some proliferative activity remained, the major part of which was localized in the (murine) stromal compartment of the tumors. In contrast to the PC-EW tumors, regrowth of androgen-ablated PC-82 tumors was rapidly induced by androgen resubstitution. The differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways. The role of the stroma in these processes is unclear.
The Prostate 02/1993; 23(2):149-64. · 3.48 Impact Factor
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ABSTRACT: The potential of the adrenal androgens androstenedione (A) and dehydroepiandrosterone (DHEA) to stimulate prostate tumor growth was investigated in the hormone-dependent human prostate tumor model PC-82, propagated in nude mice. Substitution of castrated mice bearing growth-arrested tumors with DHEA for 28 days, resulting in peripheral levels of 9.2 +/- 1.7 nmol/liter (mean +/- SEM), led to a decline of tumor burden comparable to that observed in castrated controls. Intratumor testosterone (T) and 5 alpha-dihydrotestosterone were similar to those detected in the castrated group. In contrast, high-dose A supplementation (peripheral level of 13.5 +/- 1.3 nmol/liter) in androgen ablated tumor-bearing mice resulted in tumor growth, although less pronounced than in T-resubstituted mice (T level of 18.8 +/- 1.5 nmol/l). Intraprostatic levels of androgens were not different between both groups. Substitution of castrated PC-82 tumor-bearing mice with low-dose A (2.5 +/- 0.4 nmol/l) neither stimulated growth of tumors nor did it lead to regression of PC-82 tumors. Proliferative activity as estimated by BrdU incorporation (S-phase cells) was not induced in these tumors. In conclusion, DHEA does not have a stimulatory effect on growth of PC-82 tumor tissue, but A is capable of inducing PC-82 tumor growth, most likely through peripheral conversion of A into T and 5 alpha-dihydrotestosterone.
Endocrinology 01/1993; 131(6):2909-13. · 4.46 Impact Factor
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ABSTRACT: The androgen dependent prostatic carcinoma of human origin, PC-82, was used as a model system to investigate the effect of various levels of androgen on the growth of prostatic tumor tissue. Plasma testosterone levels in mice were correlated to tumor growth and intratumor concentrations of testosterone and 5 alpha-dihydrotestosterone. PC-82 tumor burden remained stable at plasma testosterone levels of 0.8 nmol/l., whereas tumor growth occurred at higher levels and tumor regression was observed at lower plasma levels. This critical level of testosterone corresponded with intratumor testosterone and 5 alpha-dihydrotestosterone concentrations of six to 10 and three to four pmol/gm. tissue, respectively, which are significantly above the levels found in castrated non-supplemented animals (3.1 and 1.4 pmol/gm. respectively). This indicates that remaining concentrations of dihydrotestosterone, which amount to two to three times the castrate level, are not stimulatory for tumor growth in the model of the androgen dependent PC-82 tumor.
The Journal of Urology 04/1991; 145(3):631-4. · 3.75 Impact Factor
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ABSTRACT: The transplantable androgen-dependent human prostate tumor models PC-82 and PC-EW were used to study whether low levels of testosterone and androgens of adrenal origin were capable of stimulating the growth of prostatic carcinoma cells in these tumor models. At all circulating plasma testosterone levels applied in this study, much lower levels of dihydrotestosterone were found in PC-EW tumor tissue than in PC-82 tumor tissue. Nevertheless, both prostate tumor models had a similar threshold level of dihydrotestosterone for growth stimulation, i.e. 3-4 pmol/g tissue. This critical androgen level for tumor growth amounted to 2-3 times the tissue level found in castrated animals. At this threshold level approximately 2% of the cells showed proliferative activity, as assessed by bromodeoxyuridine incorporation into DNA. The adrenal androgen dehydroepiandrosterone did not stimulate PC-82 tumor growth, whereas androstenedione did induce a moderate increase in tumor volume. It is concluded that the adrenal androgen androstenedione exerts a stimulating effect on prostatic cancer cells when its conversion results in intra-tissue testosterone and dihydrotestosterone levels exceeding the threshold level for tumor growth.
Urological Research 02/1991; 19(1):1-5. · 1.23 Impact Factor
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ABSTRACT: Two transplantable, androgen dependent prostate tumor models of human origin, PC-82 and PC-EW, were used to study the effect of low androgen levels and adrenal androgens on prostate tumor cell proliferation. Tumor load of the PC-82 and PC-EW tumors could be maintained constant when plasma testosterone levels were 0.8 and 0.9 nmol/l, respectively, corresponding with an intratissue 5 alpha-dihydrotestosterone level of 3-4 pmol/g tissue. This critical androgen level for prostate tumor growth stimulation amounted to 2-3 times the castration level and proved to be similar for both tumor models. Relatively high levels of androstenedione resulted in physiological levels of plasma testosterone causing androgen concentrations in PC-82 tumor tissue exceeding the critical level for tumor growth. These results indicate that submaximal suppression of androgens can stop tumor growth in these prostate tumor models.
The Journal of Steroid Biochemistry and Molecular Biology 01/1991; 37(6):903-7. · 3.05 Impact Factor
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ABSTRACT: The transplantable human prostatic tumor model (PC-82) in nude mice was used to evaluate the indirect and possibly direct effects of estrogens on the growth of prostatic tumor tissue. High (pharmalogical) doses of plasma estradiol (E2) were achieved in tumor-bearing mice by using E2-containing Silastic implants of different lengths. In comparison with the situation in men, in mice much higher concentrations of circulating E2 (exceeding 3 nmol/liter) were necessary to attain (near)-castrate levels of plasma testosterone (T). Treatment of tumor-bearing mice with a high dose of E2 resulted in tumor growth arrest and a subsequent decline of the tumor volume, which equals the effects of castration. No evidence was found that either of the two doses of E2 applied had any additive inhibitory effect on tumor growth when compared to castration alone. It was inferred from these findings that in the PC-82 tumor model, estrogens, rather than having a direct effect on the tumor tissue, mainly act indirectly by their suppressive effect on T secretion in the host animal. A different and unexpected result was obtained in castrated tumor-bearing mice treated with a combination of E2 and T. With both doses of E2 this type of treatment led to a smaller increase of the tumor volume compared with mice receiving T only, the result of the high dose being statistically significant. This antagonistic effect of the two steroids on the PC-82 tissue was paradoxically associated with a sharp increase of nuclear androgen receptor levels and a higher concentration of dihydrotestosterone in the tumor tissue. Plasma and tissue concentrations of T appeared to be unaltered. The present study of the PC-82 prostate tumor shows that only by careful monitoring of plasma steroid levels in tumor-bearing mice can conclusions about the effectiveness of hormonal treatment regimens, such as estrogen therapy, be drawn.
The Prostate 02/1988; 12(2):157-71. · 3.48 Impact Factor
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ABSTRACT: Two transplantable, androgen dependent prostate tumor models of human origin, PC-82 and PC-EW, were used to study the effect of low androgen levels and adrenal androgens on prostate tumor cell proliferation. Tumor load of the PC-82 and PC-EW tumors could be maintained constant when plasma testosterone levels were 0.8 and 0.9 nmol/l, respectively, corresponding with an intratissue 5α-dihydrotestosterone level of 3–4 pmol/g tissue. This critical androgen level for prostate tumor growth stimulation amounted to 2–3 times the castration level and proved to be similar for both tumor models. Relatively high levels of androstenedione resulted in physiological levels of plasma testosterone causing androgen concentrations in PC-82 tumor tissue exceeding the critical level for tumor growth. These results indicate that submaximal suppression of androgens can stop tumor growth in these prostate tumor models.
The Journal of Steroid Biochemistry and Molecular Biology.
