Androgen Antagonistic Effect of Estramustine Phosphate (EMP) Metabolites on Wild-Type and Mutated Androgen Receptor

Wang, Long G.; Liu, Xiao M.; Kreis, Willi; Budman, Daniel R.

doi:10.1016/s0006-2952(97)00657-6

Cited by 16 publications

(6 citation statements)

References 19 publications

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“…PSA measurements do not, however, necessarily reflect clinical responses (25,32). One complicating factor is that PSA gene expression or release can be affected by various agents used for treatment, including estramustine (33). We nevertheless examined the association between increases in serum CK18 and decreases in PSA in a subgroup of 13 patients from which serum was available from treatment cycle 1 and/or 2 and from at least one additional cycle (Table 1).…”

Section: Different Patterns Of Increases Of Caspase-cleaved and Totalmentioning

confidence: 99%

Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18

et al. 2004

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Cytokeratins are released from carcinoma cells by unclear mechanisms and are commonly used serum tumor markers (TPA, TPS, and CYFRA 21-1). We here report that soluble cytokeratin-18 (CK18) is released from human carcinoma cells during cell death. During necrosis, the cytosolic pool of soluble CK18 was released, whereas apoptosis was associated with significant release of caspase-cleaved CK18 fragments. These results suggested that assessments of different forms of CK18 in patient sera could be used to examine cell death modes. Therefore, CK18 was measured in local venous blood collected during operation of patients with endometrial tumors. In most patient sera, caspase-cleaved fragments constituted a minor fraction of total CK18, suggesting that tumor apoptosis is not the main mechanism for generation of circulating CK18. Monitoring of different CK18 forms in peripheral blood during chemotherapy of prostate cancer patients showed individual differences in the patterns of release. Importantly, several examples were observed where the increase of apoptosis-specific caspase-cleaved CK18 fragments constituted only a minor fraction of the total increase. These results suggest that cell death of epithelially derived tumors can be assessed in patient serum and suggest that tumor apoptosis may not necessarily be the dominating death mode in many tumors in vivo.

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Section: Different Patterns Of Increases Of Caspase-cleaved and Totalmentioning

confidence: 99%

Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18

et al. 2004

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“…Our data suggest that the high incidence of mutations in the distal part of the NTD indicates that the clonal selection of tumor cells with AR NTD mutations is likely to provide CaP with a growth advantage and be associated with therapy relapse. The exact mechanisms by which mutations are driven are unknown, but a feasible hypothesis can be raised: In addition to the inhibition of the assembly of microtubules caused by the in vivo activated metabolites of EMP, EMP has been suggested to act as an androgen antagonist (Wang et al, 1998(Wang et al, , 1999. It is interesting that Wang et al (1998) observed binding of EMP and its metabolites to the AR and showed that EMP acts, analogous to bicalutamide, antagonistically.…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanisms by which mutations are driven are unknown, but a feasible hypothesis can be raised: In addition to the inhibition of the assembly of microtubules caused by the in vivo activated metabolites of EMP, EMP has been suggested to act as an androgen antagonist (Wang et al, 1998(Wang et al, , 1999. It is interesting that Wang et al (1998) observed binding of EMP and its metabolites to the AR and showed that EMP acts, analogous to bicalutamide, antagonistically. Furthermore, they demonstrated that exposure of LNCaP cells to EMP caused transcriptional inhibition of PSA.…”

Section: Discussionmentioning

confidence: 99%

Pattern of Somatic Androgen Receptor Gene Mutations in Patients with Hormone-Refractory Prostate Cancer

Hyytinen

Haapala

Thompson

et al. 2002

Laboratory Investigation

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SUMMARY:Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or ␤-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment. (Lab Invest 2002, 82:1591-1598. P rostate cancer (CaP) is the most common male malignancy in the Western world, and its prognosis greatly depends on at which stage the disease is diagnosed. Even in the era of prostate specific antigen (PSA) screening, advanced disease is diagnosed in 20 to 40% of patients with CaP when cure by radical prostatectomy or radiotherapy is not considered possible anymore. In addition, recurrence rates of CaP after radical surgery or radiotherapy approach 25 to 50% (Dennis and Griffiths, 2000;Määttänen et al, 1999;Scardino et al, 1994). For these patients, androgen deprivation therapy (ADT) remains the only effective palliative treatment. ADT is generally achieved by either surgical or chemical castration, but for patients with widespread, metastasized disease, the cytotoxic drug estramustine phosphate (EMP) is occasionally combined with ADT (Kuhn et al, 1994;Murphy et al, 1986). Although all ADTs are initially effective, in most patients, CaP progresses within months or a few years (Dennis and Griffiths, 2000;Scardino et al, 1994). Molecular mechanisms of ADT failure are not comprehensively known. Previous studies have suggested a link between androgen receptor (AR) gene and ADT failure (Culig et al, 1993;Elo et al, 1995;Koivisto et al, 1997;Schoenberg et al, 1994;Suzuki et al, 1993Suzuki et al, , 1996Taplin et al, 1995Taplin et al, , 1999Visakorpi et al, 1995;Wallen et al, 1999), and two main mechanisms by which CaP cells could adapt and sensitize AR signaling pathway for growth in low levels of androgens have been proposed. First, AR gene amplification has been shown to lead to increased expr...

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“…Studies in LNCaP cell lines also suggest that its metabolites bind to the mutated androgen receptor and block its phosphorylation [26,27]. Single-agent estramustine in hormone-refractory prostate cancer (at 560-840 mg/d) produces objective responses in 19% to 69% of patients and decreases in PSA level in only 14% [28].…”

Section: Estramustinementioning

confidence: 99%

Recent advances in chemotherapy for advanced prostate cancer

Olson

Pienta

2000

Curr Urol Rep

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Recently, several important studies have validated prostate-specific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormone-refractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.

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Androgen Antagonistic Effect of Estramustine Phosphate (EMP) Metabolites on Wild-Type and Mutated Androgen Receptor

Cited by 16 publications

References 19 publications

Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18

Differentiation between Cell Death Modes Using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18

Pattern of Somatic Androgen Receptor Gene Mutations in Patients with Hormone-Refractory Prostate Cancer

Recent advances in chemotherapy for advanced prostate cancer

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