Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate
01 Jul 1972-CA: A Cancer Journal for Clinicians (American Cancer Society)-Vol. 22, Iss: 4, pp 232-240
TL;DR: Gutman et al. as mentioned in this paper showed that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens.
Abstract: Carcinoma of the prostate gland is peculiarly favorable for endocrine investigation since frequent serial observations of the activity of phosphatases in serum were found to provide objective indices of activity of the neo/~i~m when the enzymes were increased in amount above normal. In the present paper data are given for the values of serum phosphatases in carcinoma of the prostate and in normal men. We shall demonstrate that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens. We have been unable to find previous observations indicating any relationship of hormones to carcinoma of the prostate gland. An enzyme capable of hydrolyzing phosphoric esters was discovered by Grosser and Husler (4) in intestinal mucosa and kidney. Robison (16) found that this enzyme was particularly high in activity in growing bone and cartilage and that its activity was greatest at pH 9 to 9.5. This ~alkaline phosphatase," was found by Kay (9) to be increased in the serum in certain bone diseases including metastasis of neoplasms to bone and later work has shown that among these conditions is carcinoma of the prostate. Davies (3) and Bamann and Riedel (1) discovered that there occurs in the spleen and kidney of swine and cattle, in addition to the alkaline phosphatase, a phosphatase with an activity maximum at pH 4.8. An enzyme believed to be identical with this "acid phosphatase" was found by Kutscher and Wolbergs (11) to be present in very large amount in the human prostate gland. This finding of great activity of acid phosphatase in the prostate gland was confirmed and extended to include prostatic cancer by Gutman, Sproul, and Gutman (7). The serum of certain patients with disseminated prostatic carcinoma was found by Gutman and Gutman (6) and Barringer and Woodard (2) to exhibit increased acid phosphatase activity. Robinson, Gutman, and Gutman'~I5) summarized the acid phosphatase activity levels of 44 patients with carcinoma of the prostate. They concluded that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance. METttODS AND MATERIALS
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TL;DR: Treatment with le uprolide and flutamide is superior to treatment with leuprolide alone in patients with advanced prostate cancer, and Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade.
Abstract: To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.
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TL;DR: Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments.
Abstract: The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II-related programs, and the effects of drugs that evolved from them, that provided the impetus to establish in 1955 the national drug development effort known as the Cancer Chemotherapy National Service Center. The ability of combination chemotherapy to cure acute childhood leukemia and advanced Hodgkin's disease in the 1960s and early 1970s overcame the prevailing pessimism about the ability of drugs to cure advanced cancers, facilitated the study of adjuvant chemotherapy, and helped foster the national cancer program. Today, chemotherapy has changed as important molecular abnormalities are being used to screen for potential new drugs as well as for targeted treatments.
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TL;DR: Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
Abstract: Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
1,341 citations
TL;DR: GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease and the benefits of GnRH agonists should be weighed against these potential risks.
Abstract: Purpose Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease. Patients and Methods Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death. Results More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44...
1,298 citations
TL;DR: There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise.
Abstract: Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Prostate cancer may be asymptomatic at the early stage and often has an indolent course that may require only active surveillance. Based on GLOBOCAN 2018 estimates, 1,276,106 new cases of prostate cancer were reported worldwide in 2018, with higher prevalence in the developed countries. Differences in the incidence rates worldwide reflect differences in the use of diagnostic testing. Prostate cancer incidence and mortality rates are strongly related to the age with the highest incidence being seen in elderly men (> 65 years of age). African-American men have the highest incidence rates and more aggressive type of prostate cancer compared to White men. There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise. Screening is highly recommended at age 45 for men with familial history and African-American men. Up-to-date statistics on prostate cancer occurrence and outcomes along with a better understanding of the etiology and causative risk factors are essential for the primary prevention of this disease.
1,215 citations
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TL;DR: Robison was able to study for two years in Leipzig in the kdbordtories of Professor Hantz as mentioned in this paper, where he obtained a scholarship to attend the University of Nottingham.
Abstract: Robert Robison (Fig. 1) was born in 1883 in Newark-on-Trent. He attended the University College. Nottingham. He began his career in research before he obtained his initial degree. Having obtained a scholarship, Robison was able to study for two years in Leipzig in the kdbordtories of Professor Hantz
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TL;DR: Direct evidence in support of this assumption is afforded by the present investigation, which disclosed strikingly increased phosphatase activity of bone at the site of osteoplastic skeletal metastases in a patient with carcinoma of the prostate gland.
Abstract: Recent determinations of serum phosphatase activity in patients with cancer (1, 2, 3) suggest that values obtained in cases with widespread osteoplastic metastases are, in general, significantly higher than those found in association with osteolytic metastases. In the series reported by Gutman, Tyson and Gutman (1), for example, the serum phosphatase activity exceeded 10 Bodansky units per 100 c.c. in 6 of 10 cases with osteoplastic metastases but in only 3 of 19 patients with osteolytic metastases. In 2 patients with very extensive osteoplastic skeletal lesions, values exceeding 100 Bodansky units per 100 c.c. of serum were obtained, as contrasted with the normal maximum of 4.0 Bodansky units.
It has been assumed (1, 3) that the rise in phosphatase activity of the serum in such cases is the result of increased elaboration of phosphatase, which is subsequently released into the circulating fluids. Direct evidence in support of this assumption is afforded by the present investigation, which disclosed strikingly increased phosphatase activity of bone at the site of osteoplastic skeletal metastases in a patient with carcinoma of the prostate gland.
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