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PubMed1986

[Cancer of the prostate: current status of chemotherapy].

Life expectancy of patients with prostatic cancer is varying from one case to another and, sometimes, these patients have a very long life expectancy. Less than a third of this patients are dying from their cancer. This notion implies to be very careful in the choice of aggressive treatments. Isolated or combined chemotherapy assays permitted to select cyclophosphamide, methotrexate, cis-platinum or estramustine phosphate as active drugs in the treatment of prostatic cancer. But the randomized studies, in Europe or in U.S.A., are not demonstrative enough to propose these drugs for a routine treatment. Cancer of the prostate is usually represented by cellular groups that are more or less sensitive to the different kind of available treatments. Perhaps in the future the best results of treatment will be the association of chemotherapy-radiotherapy and hormonotherapy.

Antineoplastic Agents↗

PubMed1987

[Studies on the anti-tumor effect of the E2 carrier drug and its mechanism].

In this study, the anti-tumor effect of E2 carrier drug on MM2 cells transplanted to C3H/He mice and its mechanism were observed. The results were as follows. The estrogen receptor on cytosol in MM2 cell and nuclei were positively confirmed, but the progesterone receptor was not. When the effect of this drug on MM2 cells was measured by the ratio of inhibition to the growth of the tumor, the effect on the group treated with a high dose of E2 carrier drug (100mg/kg) was found to be significantly higher than found with physiological saline (p less than 0.05). The main route of action is considered to be not related to the steroid receptor but to the retention of Estramustine (EM-2), Estromustine (EM-1), and Estradiol (E2) in tumor tissues. Histomorphological findings on the MM2 cells treated with E2 carrier drug revealed nuclear pyknosis and giant cell transformation. The strength of these effects seemed to depend on the size of the dose of E2 carrier drug.

Animals↗

PubMed1985

[Which endocrine treatment is preferred today for prostatic carcinoma?].

There is so far no evidence that the newest hormone compounds, such as progestational agents, antiandrogens or estramustine phosphate, yield better results than low dose estrogens or orchidectomy in previously untreated patients. Castration and the other modalities of androgen deprivation, although they can cause a measurable objective regression in less than half of cases, do often induce a marked, sometimes long-lasting subjective improvement and can delay progression. It has not yet been clearly established whether or not hormone therapy can bring about a prolongation in survival. The critical point still remains our poor understanding of the causes of acquired hormone resistance and our inability to prevent it. Further studies on hormone receptors and steroid metabolism in normal and neoplastic cells might lead to progress in this field. The unsolved problem, whether resistance is due to a selection of clones resistant to hormones ab initio or to acquired biochemical characteristics in cells that were initially responsive, might be of great practical significance. A reliable test, able to detect sensitivity or resistance towards hormone therapy before any treatment is given, would be extremely helpful. Unfortunately, neither the most sophisticated hormone balance studies nor receptor determinations have led to clinically useful implications.

Androgen Antagonists↗

PubMed1982

Response of the Dunning R3327H prostatic adenocarcinoma to radiation and various chemotherapeutic drugs.

Dunning R3327H prostatic adenocarcinoma was bilaterally transplanted in the flanks of animals at the Papanicolaou Institute in Miami, and the animals were received at the Cross Cancer Institute (Edmonton, Alberta, Canada) each month. The animal flanks were palpated weekly, and when tumor volumes reached a size of approximately 300 mm3 the animals were randomized into treatment groups for the assessment of various therapies. Tumor volumes were determined each week before and after various treatments, and tumor growth was compared to that in untreated controls. Ionizing radiation at relatively small single doses completely inhibits tumor growth for a period of up to 6 months. Some interesting characteristics of this radiation-induced growth arrest are that tumors do not die and shrink away as with some other tumor models but remain static in size and show histologic evidence of viable tumor cells. The hypoxic cell radiosensitizer misonidazole potentiates radiation response in this tumor model. Cisplatin, vincristine, etoposide, and estramustine phosphate administered in drug doses approaching their toxic limits have a partial effect on tumor growth.

Adenocarcinoma↗

PubMed1980

Hormone cytostatic agents.

Antitumour agents in which various steroids were used as carriers for different cytostatic groups have been synthesized at the Research Laboratories of AB Leo, Helsingborg, Sweden. The chemical and pharmacological properties of two of these agents, estramustine phosphate and prednimustine, are reported. These agents have been shown to have good effects in the treatment of advanced hormone-resistant cancer.

Animals↗

PubMed1981

Influence of sex hormones on prostatic secretion protein, a major protein in rat prostate.

Prostatic secretion protein (PSP) or estramustine-binding protein is a major protein in rat ventral prostate. The amount of PSP was measured per mg of cytosolic protein at different ages and after castration or administration of sex hormones. The amount of PSP is relatively low before puberty (25 microgram/mg of protein) but increases at about 28 days of age to about 670 microgram/mg of protein and then decreases to a constant level of about 300 to 400 microgram/mg of protein, which is stable until at least 9 months of age. Following castration, the amount of PSP decreased relatively slowly, but 6 days after castration less than 20% of the original amount of PSP was detected. Treatment with testosterone propionate (1 mg/day) for 2 weeks (starting 2 weeks after castration) restored precastration levels of PSP. It is concluded that PSP is an androgen-sensitive protein, and it is suggested that PSP should be considered as a probe for estimation of androgenic action on the prostate. PSP is similar to the so-called prostatic binding protein as well as to prostatein, and it is quite possible that the three proteins represent one and the same entity.

Aging↗

PubMed1995

[A case of huge prostate cancer].

An 89-year-old man with bilateral leg edema and a huge abdominal mass was admitted for further evaluation. CT scan showed a hugh prostatic mass which occupied the whole pelvis cavity accompanying multiple pelvic bone metastases. Suprapubic needle biopsy revealed that the mass was well differentiated adenocarcinoma of prostate origin. The treatment was initiated by 500 mg per day of estramustine phosphate combined with injectable LH-RH analogue 2 months later. The serum levels of tumor markers were markedly elevated at the first visit; PSA 210ng/ml, PAP 110ng/ml, gamma-Sm 800ng/ml. They became normalized 3 months after the initiation of the treatment, and the mass was reduced to 11.5% of the initial size, which lead to removal of indwelling urethral catheter. The patient and his family, however, refused further treatment and the patient died of disseminated disease 8 months later.

Adenocarcinoma↗

PubMed1994

[Hormone therapy before radical prostatectomy. Effects on surgical method and resection margins. Belgian Uro-Oncological Study Group (B.U.O.S.)].

127 patients with a clinical stage T2b and T3 prostate cancer were randomized in order to undergo either a radical prostatectomy alone or a radical prostatectomy after hormonal treatment (560 mg of estramustine phosphate daily for 6 weeks) in a prospective multi-center study. The clinical or radiological evaluation of an eventual downstaging being extremely difficult, the authors compared in the 2 groups the influence on the surgical act and the number of positive surgical margins at pathological examination of the resected specimen. There was no significant difference between the 2 groups concerning the surgery (duration of the procedure, blood transfusion, degree of difficulty). For clinical T2 prostate tumors the number of positive surgical margins was significantly lower in the group that had preoperative hormonal treatment. In the group with clinical T3 prostate cancer this difference was not found. The influence of positive margins on the later development of local or systemic recurrence and on survival still has to be awaited. At this moment one could conclude that only patients with a T2 prostate cancer benefit of a preoperative hormonal treatment.

Estramustine↗

PubMed1976

[Treatment of advanced carcinoma of the prostate with Estracyt (author's transl)].

40 patients with prostatic carcinoma were treated with parenteral and/or oral Estracyt (estramustine phosphate) until 55 months. Metastases were present in 37 patients (stage D). 35 of the 40 patients developed metastases in spite of estrogen therapy and/or orchidectomy. Diminution of metastasic bone pain as well as improvement of hydroureteronephrosis was frequently observed. Paraplegia secondary to metastatic disease improved in 1 case for 6 months. Side effects were relatively rare and were mainly gastrointestinal. A possible hepatotoxic action of the compound has been pointed out previously. On the basis of our studies Estracyt is recommended in the treatment of primary estrogen resistent prostatic carcinoma and in metastatic carcinoma of the prostate not responding to conventional antiandrogenic therapy anymore.

Administration, Oral↗

PubMedDate not supplied

Characterization of the Dunning R3327H prostatic adenocarcinoma: an appropriate animal model for prostatic cancer.

The Dunning R3327H rat prostatic adenocarcinoma appears to be an appropriate animal model for studying prostatic cancer. This report contains a detailed characterization of this tumor at the morphologic, biochemical, and therapeutic levels. Electron micrographic, histologic, and histochemical studies clearly establish the adenocarcinoma nature of this tumor. The histology of the R3327H tumor is similar to well-differentiated human prostatic cancer. The biochemical and enzymatic profile of the tumor indicates its origin from the rat dorsolateral prostate. The cell kinetics and growth rates of this tumor following a variety of hormonal manipulations (castration, estrogens, androgens, and antiandrogens) have established that 70%-90% of the cells in this tumor require androgens for their growth. However, 10%-30% of the cells are capable of growth in the absence of androgens. Both cell types are present in the initial tumor inoculum and these different cell types possess similar growth rates. The predominance of the androgen-sensitive cells accounts for the relatively greater size of the tumor achieved in the intact male animal at a given growth time. After the tumor is well established in an intact animal, subsequent estrogen therapy or castration resulted in a marked diminution in tumro volume. This was followed by a subsequent relapse. In addition, estramustine phosphate was also shown to cause shrinkage in the tumor volume.

Adenocarcinoma↗

PubMed1997

[Antimitotic agents].

Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport. Therefore, microtubules are considered one of the most important molecular targets for cancer chemotherapy. Tubulin is one of the major microtubular components, and its polymerization and depolymerization regulate microtubular dynamics. Other microtubular components such as microtubule-associated protein (MAPs), actin, and intermediate and microfilaments have also been demonstrated to be involved in microtubular dynamics. Recent studies provide evidence that the functions of MAPs and filaments in microtubule assembly are regulated by phosphorylation, which is catalyzed by mitogenactivated protein kinase (MAP kinase) and cdc2 kinase. Antimitotic agents that disrupt microtubules can be classified in two categories according to the mechanism of action, vinca alkaloids and taxanes. Vinca alkoloids, estramustine, rhizoxin, and E7010 inhibit microtubule polymerization. In contrast, taxanes such as paclitaxel and docetaxel promote polymerization of microtubules and enhance microtubule stability. We have demonstrated that paclitaxel inhibits the catalytic activity of MAP kinase and cdc2 kinase in lung cancer cell lines. This biological effect may be responsible for the increased affinity between MAP2 and tubulins, resulting in promotion of microtubule assembly. Factors that contribute to the resistance to antimitotic agents include intracellular accumulation of the drugs, genetic or functional alternations in tubulin, and alternations in MAP kinase cascade. Antimitotic agents showed a broad spectrum of preclinical antitumor activity. Clinical trials of taxanes revealed that they were effective for several cancers which were advanced or resistant against other anticancer drugs, especially for breast cancers, ovarian cancers and non-small cell lung cancers.

Animals↗

PubMed1997

Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer.

Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.

Anti-Inflammatory Agents↗

PubMed1996

Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients.

BACKGROUND: Hormonotherapy temporarily controls symptoms in 80% of patients with metastatic prostate carcinoma. Once progression occurs, no consensus exists on further therapy. Oral etoposide (VP-16) has shown clinical efficacy in advanced small cell lung carcinoma, breast cancer, germ cell tumors, and lymphomas, A synergistic effect between etoposide and alkylating agents such as estramustine was recently reported. We began a prospective Phase II study of an oral combination of cyclophosphamide (CPM) and VP-16 in patients with hormone-refractory [correction of refactory] prostate carcinoma (HRPC). METHODS: Patients were orally treated with CPM (100 mg/day) and VP-16 (50 mg/day) for 14 days every 28 days. Therapy continued until there was evidence of disease progression. RESULTS: From November, 1992, to February, 1995, 20 patients with HRPC were entered into the study. Patients were eligible if they had an ECOG performance status (PS) of 0 to 2. All of the patients presented with bone metastasis, and 70% presented with bone pain. Seventy-five percent had failed at least two hormonal manipulations. The mean duration of treatment was 5 months (range 2-12). Performance status improved in 26% of the patients, and bone pain was relieved in 71%. An objective response was defined as a decrease of 50% or more in the prostate-specific antigen (PSA) level. One patient demonstrated a complete response, and six patients had partial responses assessed by PSA plasma levels (objective response rate: 35%). The mean duration of response was 8 +/- 6 months (range: 2-24). Median survival was 11 months. Toxicities were minimal. CONCLUSIONS: The combination of oral CPM and VP-16 may be an active and well tolerated regimen for patients with HRPC.

Administration, Oral↗

PubMed1997

Coassembly of bovine and cod microtubule proteins: the ratio of the different tubulins within hybrid microtubules determines the ability to assemble at low temperatures, MAPs dependency and effects of Ca2+.

Cod and bovine microtubule proteins (MTP) differ from each other in many respects, e.g., tubulin isoforms and microtubule-associated proteins (MAPs) but only cod MTP are cold-adapted. We used these differences to determine how tubulin isoform composition affects microtubule properties. Mixtures of cod and bovine MTP coassembled at 30 degrees C as shown by light scattering and immunoelectron microscopy, with no apparent preference for one set of MAPs over the other. Bovine tubulin was, in contrast to cod tubulin, unable to assemble in the absence of MAPs, while 50%/50% mixtures of bovine and cod tubulin, respectively, coassembled readily without exclusion of cod or bovine tubulin isoforms in the hybrids, as shown by two-dimensional gel electrophoresis. Alteration in MAPs dependency was also confirmed by the use of the MAPs-binding microtubule inhibitor estramustine phosphate. Addition of 10 mM Ca2+ to microtubules induced formation of spirals or rings depending on the ratio of the cod and bovine MTP, respectively. Bovine MTP were unable to assemble at low temperatures, while cod MTP are cold-adapted and assembled efficiently at 14 degrees C in the presence of MAPs. Amounts of cod MTP as low as 33% were enough to induce assembly of bovine/cod MTP hybrids. The critical concentration for assembly of a 50%/50% mixture was similar to that of 100% cod MTP. Taken together, the results show that the divergent cod and bovine MTP can coassemble, and that alterations in tubulin isotype/isoform composition above certain thresholds significantly modulate microtubule properties such as MAPs dependency, effects of Ca2+, and ability to assemble at low temperatures.

Adaptation, Physiological↗

PubMed2000

Chemotherapy for patients with advanced prostate carcinoma: a new option for therapy.

BACKGROUND: Prostate carcinoma is the second leading cause of cancer-related death in men in the United States. In nearly all of these men, cancer progressed despite initial treatment with androgen ablation therapy. Managing hormone-refractory prostate carcinoma remains a difficult challenge for the clinician. In the past, cytotoxic chemotherapy was considered inactive, but recent advances have altered this view significantly. METHODS: A MEDLINE review of recent studies of chemotherapy in hormone-refractory prostate carcinoma was performed. RESULTS: Benefit of treatment may now be measured by prostate specific antigen as a marker of antitumor activity, quality of life and pain scores, and traditional objective measures of response. The antiandrogen withdrawal syndrome and secondary hormonal therapies are important treatment options that usually precede chemotherapy. New drug combinations are demonstrating promising levels of efficacy and proven palliative ability. Two large randomized trials have shown that mitoxantrone in combination with steroids is more effective in improving pain and quality of life than steroids alone. In several Phase II studies, estramustine combinations with vinblastine, etoposide, paclitaxel, or docetaxel produced significant responses in over 50% of patients. Future research will define optimal chemotherapy combinations and test new agents. In addition, systemic chemotherapy is being investigated in earlier stages of prostate carcinoma at high risk for progression. CONCLUSIONS: Cytotoxic chemotherapy has demonstrated clear activity and palliative benefit in patients with hormone-refractory prostate carcinoma. Its role in managing advanced prostate carcinoma patients is growing but remains an area of active investigation.

Clinical Trials as Topic↗

PubMed2002

Higher doses of mitoxantrone among men with hormone-refractory prostate carcinoma: a Cancer and Leukemia Group B study.

BACKGROUND: Mitoxantrone in combination with a low-dose glucocorticoid has been shown to produce more favorable outcomes among men with hormone-refractory prostate carcinoma than glucocorticoid alone. Therefore, the authors sought to determine the safety and activity of higher doses of mitoxantrone in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and a glucocorticoid in preparation for a possible Phase III trial comparing standard to dose-escalated mitoxantrone. METHODS: This Phase II trial enrolled 45 patients from October 1996 to March 1998. Twenty-one patients without pelvic irradiation (Arm I) received 21 mg/m(2) of mitoxantrone every 3 weeks, and 24 patients who had received pelvic irradiation (Arm II) were given 17 mg/m(2) on the same schedule. All patients received 40 mg of hydrocortisone in divided doses daily and GM-CSF at 500 microg/daily for a minimum of 10 days per cycle beginning on the third day of the cycle. RESULTS: In Arm I, 33% of assessable patients achieved a partial response, 50% had a > or = 50% decline in their PSA, and 35% had a > or = 75% decline in PSA values. The comparable numbers in Arm II were 24%, 48%, and 35%, respectively. The median survival times were 12 months in Arm I and 14 months in Arm II. Treatment had to be discontinued in 13% of patients because of thrombocytopenia. No other significant toxicities were encountered. CONCLUSIONS: Higher doses of mitoxantrone (17 and 21 mg/m(2)) were associated with activity comparable to many estramustine combinations and generally were well tolerated. However, because the degree and frequency of thrombocytopenia were greater than that observed with standard dose mitoxantrone (12-14 mg/m(2)), and because the median survival is apparently comparable to standard dose mitoxantrone, this approach to HRPC cannot be recommended for Phase III testing.

Aged↗

PubMed2003

Physician attitudes toward cytotoxic chemotherapy use in patients with advanced prostate carcinoma.

BACKGROUND: Attitudes toward the use of chemotherapy in patients with prostate carcinoma have changed as new therapeutics have demonstrated efficacy. This is important as randomized trials using chemotherapy are proposed. The authors used a questionnaire to investigate the attitudes of physicians in the New England area who care for patients with advanced prostate carcinoma. METHODS: A 15-question survey was developed and mailed in the year 2000. No monetary incentives were used to encourage return of surveys. Baseline demographic data were obtained, including type of practice and number of patients with prostate carcinoma seen. Urologists, radiation oncologists, and medical oncologists were asked whether they had recommended chemotherapy for patients with prostate carcinoma, what they perceived as the effectiveness of specific drugs, what concerns they had regarding chemotherapy, and the appropriateness of chemotherapy in three hypothetical patient scenarios. RESULTS: Of 1068 surveys that were delivered to practicing physicians, 232 surveys (22%) were returned and evaluable. Forty-six percent of respondents were urologists, 41% were medical oncologists, and 10% were radiation oncologists. Eighty-seven percent of respondents had recommended cytotoxic chemotherapy to their patients. Four agents were rated as moderately effective to very effective by 41-60% of respondents who rated effectiveness: estramustine, mitoxantrone, paclitaxel, and docetaxel. In three hypothetical patient scenarios of hormone-refractory prostate carcinoma, only one patient was judged as an appropriate candidate for chemotherapy. In a multivariate analysis, female physicians and physicians with practices comprised of > 25% patients with hormone-refractory prostate carcinoma were more likely to recommend chemotherapy. Concerns regarding severe toxicity and lack of benefit were among the most influential on respondent decisions to use chemotherapy. CONCLUSIONS: Most physicians who cared for patients with prostate carcinoma had recommended chemotherapy for patients with hormone-refractory disease. There were differences between specialties regarding the likelihood of recommending chemotherapy and clinical judgment regarding which patients were appropriate candidates for chemotherapy.

Adenocarcinoma↗

PubMed2004

Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates.

Despite the historical use of estrogens in the treatment of prostate cancer (PCa) little is known about their direct biological effects on the prostate, their role in carcinogenesis, and what mechanisms mediate their therapeutic effects on PCa. It is now known that estrogens alone, or in synergism with an androgen, are potent inducers of aberrant growth and neoplastic transformation in the prostate. The mechanisms of estrogen carcinogenicity could be mediated via induction of unscheduled cell proliferation or through metabolic activation of estrogens to genotoxic metabolites. Age-related changes and race-/ethnic-based differences in circulating or locally formed estrogens may explain differential PCa risk among different populations. Loss of expression of estrogen receptor (ER)-beta expression during prostate carcinogenesis and prevention of estrogen-mediated oxidative damage could be exploited in future PCa prevention strategies. Re-expression of ER-beta in metastatic PCa cells raises the possibility of using ER-beta-specific ligands in triggering cell death in these malignant cells. A variety of new estrogenic/anti-estrogenic/selective estrogen receptor modulator (SERM)-like compounds, including 2-methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. Increasing numbers of patients self-medicate with herbal formulations such as PC-SPES. Some of these compounds are selective ER-beta ligands, while most of them have minimal interaction with ER-alpha. Although many may inhibit testosterone production by blockade of the hypothalamal-pituitary-testis axis, the most effective agents also exhibit direct cytostatic, cytotoxic, or apoptotic action on PCa cells. Some of them are potent in interfering with tubulin polymerization, blocking angiogenesis and cell motility, suppressing DNA synthesis, and inhibiting specific kinase activities. Further discovery of other compounds with potent apoptotic activities but minimal estrogen action should promote development of a new generation of effective PCa preventive or treatment regimens with few or no side-effects due to estrogenicity. Further advancement of our knowledge of the role of estrogens in prostate carcinogenesis through metabolic activation of estrogens and/or ER-mediated pathways will certainly result in better preventive or therapeutic modalities for PCa.

Estrogen Receptor Modulators↗