Knowledge, fatigue, and cognitive factors as predictors of lymphoedema risk-reduction behaviours in women with cancer.

OBJECTIVE: To identify social-cognitive factors predicting lymphoedema risk-reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. METHODS: A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self-care; (2) the Cancer Fatigue Scale; (3) social-cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). RESULTS: Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. CONCLUSIONS: Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors.

Identifying selection criteria for non-radical hysterectomy in FIGO stage IB cervical cancer.

AIM: This retrospective study sought to identify the selection criteria required for a non-radical hysterectomy with minimal parametrectomy in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB invasive cervical cancer. METHODS: Overall, 461 patients with FIGO stage IB cervical cancer who underwent a radical hysterectomy were reviewed clinicopathologically according to pathological tumor size (≤2 cm, >2 - ≤4 cm, and > 4 cm). RESULTS: The pathological parametrial involvement rate in the less than equal to 2 cm group (2%) was significantly lower than in greater than 2-less than equal to 4 cm (13%) or greater than 4 cm (29%) groups (both P < 0.001). The 5-year overall survival rate was significantly higher in the less than equal to 2 cm group (97%, 95% confidence interval [CI] 94-99%) compared with greater than 2-less than equal to 4 cm (90%, 95% CI 94-86%) and greater than 4 cm (70%, 95% CI 79-60%) groups (both P < 0.001). Cox model analysis identified tumor size to be an independent prognostic factor for survival (95% CI 1.33-5.78) and recurrence (95% CI 1.31-5.66) compared to other pathological factors. However, a significant difference between the three groups was not found in rates of Grade 3 or 4 adverse events following radical hysterectomy (P = 0.19). CONCLUSIONS: Tumor size is an independent prognostic factor for survival in patients with FIGO stage IB invasive cervical cancer. This retrospective study suggests that FIGO stage IB patients with a less than equal to 2 cm tumor size are optimal candidates for non-radical hysterectomy with minimal parametrectomy, and without resulting bladder dysfunction.

Methods for Measuring and Staging a Uterine Cervical Adenocarcinoma Showing Intracystic Papillary Growth: A Case Report.

Endocervical adenocarcinomas usually demonstrate infiltrative and/or destructive invasion, and the depth and horizontal extent of the invasion are known to have prognostic utility. Here, we report the unusual case of a patient with endocervical adenocarcinoma showing intracystic papillary growth and discuss our methods for measuring and staging this lesion. A 45-yr-old Japanese woman (gravida, 0; para, 0) underwent a cone biopsy for squamous cell carcinoma in situ and atypical glandular cells. Macroscopically, an intracystic tumor (∼7.5 mm in diameter) was detected in the cervix. Microscopically, we observed both squamous cell carcinoma in situ and adenocarcinoma involving the squamo-columnar junction. Adenocarcinoma cells lining the nabothian cyst showed papillary proliferation and expansile stromal invasion without desmoplastic reaction. We evaluated this macroscopically and found that the visible papillary growth and expansile invasion deviated from the adenocarcinoma in situ; hence, we concluded that this lesion was an International Federation of Gynecology and Obstetrics stage IB1 adenocarcinoma. The patient underwent an abdominal radical hysterectomy, followed by bilateral salpingo-oophorectomy and pelvic lymph node dissection. No residual cervical cancer, other gynecologic malignancies, or lymph node metastases were observed. Further studies using cases with the same growth pattern are needed to determine whether our evaluation method is optimal for this type of lesion.

Information-seeking, information sources and ongoing support needs after discharge to prevent cancer-related lymphoedema.

OBJECTIVES: To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. METHODS: We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. RESULTS: Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. CONCLUSIONS: Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Cox's univariate and multivariate analyses. For all patients, the 5-year recurrence-free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS.

Prognostic impact of the history of breast cancer and of hormone therapy in uterine carcinosarcoma.

OBJECTIVE: Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy. METHODS: Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses. RESULTS: Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors. CONCLUSIONS: Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations.

Serous adenocarcinoma of the uterine cervix: a clinicopathological study of 12 cases and a review of the literature.

BACKGROUND/AIMS: To determine the clinicopathological characteristics and potentially associated outcomes in patients diagnosed with serous adenocarcinoma of the uterine cervix. METHODS: The records of surgically-treated patients with pathological stage pT1b-2b serous adenocarcinoma were reviewed. RESULTS: Of 12 patients with serous adenocarcinoma who underwent radical hysterectomy, five had pT1b1N0 disease, two pT1b1N1, two pT1b2N0, and three pT2bN1. The 5-year overall survival rate for patients with or without parametrial involvement (pT2b vs. pT1b) was 0 and 89%, respectively. The 3-year recurrence-free survival rate for those with or without parametrial involvement was 33 and 89%, respectively. Four patients suffered recurrence, namely one of those who had pT1b (1/9, 11%) and 3 of those who had pT2b disease (100%). The sites of recurrence of pT2b disease were outside the pelvis in all 3 patients. Of these, 2 (67%) had peritoneal spread and 1 distant node metastasis. CONCLUSION: While patients with pathological stage pT1b disease may have a relatively favorable outcome after radical surgery, those with more advanced disease have a poor prognosis because of extra-pelvic recurrence.

Combination of squamous cell carcinoma-antigen, carcinoembryonic antigen, and carbohydrate antigen 19-9 predicts positive pelvic lymph nodes and parametrial involvement in early stage squamous cell carcinoma of the uterine cervix.

AIM: We examined the correlations between the pretreatment values of four tumor markers (squamous cell carcinoma [SCC]-antigen, carcinoembryonic antigen [CEA], carbohydrate antigen [CA]19-9, and CA125) and postsurgical high-risk factors (parametrial involvement and positive pelvic lymph nodes) in women with SCC of the uterine cervix who had International Federation of Gynecology and Obstetrics clinical stage IB and IIA disease and underwent radical hysterectomy. MATERIAL AND METHODS: In this retrospective study, we reviewed 291 patients between April 1989 and December 2008. The first 200 subjects, studied between 1989 and 2001, served as the training set, and another 91 subjects, studied between 2002 and 2008, comprised the test set. To evaluate the correlations between pretreatment tumor markers and postsurgical high-risk factors, the χ²-test and logistic regression analysis were used for univariate and multivariate analysis, respectively. RESULTS: Multivariate analysis with receiver-operator curves showed that the combination of SCC-antigen, CEA, and CA19-9 strongly predicted postsurgical high-risk factors. Analysis of the training set showed that 66.7% (95% confidence interval, 52.6-84.8%) of patients who tested positive for at least two of these three tumor markers had postsurgical high-risk factors. Similar results were obtained with the test set. CONCLUSIONS: Preoperative levels of SCC-antigen, CEA, and CA19-9 are useful for predicting the status of postsurgical high-risk factors in women with SCC of the uterine cervix who undergo radical hysterectomy.

Uterine Cervical Adenosarcoma Showing an Endophytic Growth Pattern.

Adenosarcomas are biphasic neoplasms that usually originate in the uterine corpus and comprise a benign epithelial component and a malignant stromal component. Uterine adenosarcomas typically present with abnormal genital bleeding, an enlarged uterus, and a tumor that protrudes into the endometrial cavity. These tumors rarely protrude through the cervical os and are often misdiagnosed as cervical polyps. We present the case of a patient with cervical adenosarcoma with characteristics different from those reported in previous cases. This tumor showed endophytic growth, which is rare in cervical adenosarcomas. No watery discharge or obvious genital bleeding was noted. Although the tumor measured 4 cm, vaginal bleeding was noted only once at 6 months before diagnosis and was in the form of faint brown discharge.

Novel virtual cytological analysis for the detection of endometrial cancer cells using autoscan fluoromicroscopy.

The current medical examinations for detecting endometrial cancer can sometimes be stressful and inconvenient for examinees and examiners. Therefore, we attempted to develop an autoscan-virtual cytology system for detecting endometrial cancer without relying on judgment by the human eye. Exfoliated cells from the uterus were retrieved using a tampon inserted for 3 h. More than 100 monoclonal antibodies (mAb) developed by us were screened in three steps of immunohistochemistry to find mAb sets that would enable the cancer and normal endometrium to be perfectly distinguished. The exfoliated cells provided by 30 endometrial cancer patients and a total of 37 samples of 14 non-malignant volunteers including the menstrual cycle were analyzed using imaging cytometry. All samples contained epithelial cells and dysplasia cells, but the pathologist could not definitively diagnose all of them as endometrial cancer cells because most cells had degenerated. Twenty-two of 28 endometrial cancer tissues (79%) were positive with four mAb sets, CRELD1, GRK5, SLC25A27 and STC2, and 22 of 22 normal endometriums (100%) were negative. Our newly developed autoscan-virtual cytology for exfoliated endometrial cells showed overall sensitivity for endometrial cancer patients and overall specificity for volunteers of 50% (15/30) and 95% (35/37), respectively. Our autoscan-virtual cytology combined with cancer-specific mAb and imaging cytometry could be useful for endometrial cancer detection. Autoscan-virtual cytology for endometrial cancer deserves further evaluation for future endometrial cancer screening.

A rare case of recurrent ovarian cancer presenting as a round ligament metastasis.

We report a rare case of recurrent ovarian cancer presenting as a round ligament metastasis. A 44-year-old woman presented with a lower abdominal mass. Computed tomography showed a pelvic mass. Primary surgery was performed. A histopathological examination showed an ovarian serous adenocarcinoma of Stage IIIb. The patient received 6 cycles of paclitaxel and carboplatin. Almost 2 years after the initial operation, the patient noticed a left inguinal mass. Computed tomography showed a left inguinal mass, 18 mm in size. An excisional biopsy was performed and the tumor was found to originate in the left round ligament. A histopathological examination showed serous adenocarcinoma and there was no evidence of lymph node tissue. Recurrence of ovarian cancer in the round ligament is extremely rare. This unique case suggests, however, that the round ligament in rare cases may be a recurrence site for ovarian cancer, and that accurate differentiation including confirmation by diagnostic imaging and excisional biopsy, is necessary for a definitive pathological diagnosis.

Renal Subcapsular Hematoma Formation Due to Hydronephrosis Caused by Recurrent Uterine Cervical Cancer.

Most non-traumatic renal subcapsular hematomas are found in the presence of primary or metastatic renal tumors, or in the presence of vascular disease of the renal blood vessels. We managed an asymptomatic renal subcapsular hematoma that formed due to uterine cervical cancer that metastasized to the left common iliac lymph nodes. A 48-year-old woman with stage IB1 cervical cancer underwent neoadjuvant chemotherapy and concurrent chemoradiation following a radical hysterectomy. Six months after the completion of her first treatment, she developed left-sided hydronephrosis, a left subcapsular hematoma and left common iliac lymph nodes enlargement as demonstrated with contrast-enhanced computed tomography. Although a renal subcapsular hematoma is rarely a symptom of cervical cancer recurrence, it should be considered if other neoplastic or vascular diseases are ruled out.

WAPL induces cervical intraepithelial neoplasia modulated with estrogen signaling without HPV E6/E7.

Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.

Villoglandular Papillary Adenocarcinoma With Cervical Intraepithelial Neoplasia 3 of the Cervix in a Woman With a Misdiagnosis of a Cervical Polyp.

We report a case in which a polypoid lesion with a diameter of 5 mm was diagnosed as a cervical polyp due to a negative Papanicolaou (Pap) smear in the cervix, and polypectomy revealed a diagnosis of villoglandular papillary adenocarcinoma (VGA) on histopathological examination. A 63-year-old woman with a cervical polyp, who had no abnormal symptoms and a negative Pap smear was referred to our hospital. We performed cervical polypectomy, and the pathological result was VGA with cervical intraepithelial neoplasia (CIN) 3. Even if an asymptomatic cervical polyp with a negative Pap smear is diagnosed, in some patients VGA of the uterine cervix may coexist with CIN. Therefore, asymptomatic cervical polyps with negative Pap smears should not be followed up without removal.

Vaginal Intraepithelial Neoplasia 3 in a Woman Without Simultaneous Cervical Intraepithelial Neoplasm.

In the presence of the uterus, it is rare that vaginal intraepithelial neoplasia (VAIN) alone exists. We described our experience with a case in which VAIN3 was found in the vaginal fornix without lesions in the uterine cervix. She had cervical intraepithelial neoplasm (CIN) 1 several years ago. After that, it disappeared. However, high-grade squamous intraepithelial lesion persisted cytologically. After hysterectomy was performed, VAIN3 was found in the vaginal fornix. CIN was not found in the cervix. We are apt to suspect endocervical lesions when Papanicolau (Pap) smear shows abnormalities and colposcopy fails to identify columnar epithelium. However, we need to keep in mind that the vaginal fornix may have a lesion. It may be difficult to assess the vaginal fornix in young women because of a large cervix. The presence of VAIN should also be considered when cytological abnormalities persist on Pap smears.

Biochemical properties of human full-length aryl hydrocarbon receptor (AhR).

The aryl hydrocarbon receptor (AhR) is a very unstable protein. AhR binds to the molecular chaperone complex (HSP90-p23-XAP2) to maintain a stable structure in the cytoplasm. After binding to ligands, such as dioxin, AhR translocates from the cytoplasm to the nucleus with a molecular chaperone complex. The protein forms a heterodimer with Arnt after nuclear transfer, functions as a transcription factor by binding to a xenobiotic responsive element (XRE), and induces the cytochrome P450 1A1 (CYP1A1). Because of the unstable protein, expression of the full-length AhR in the E. coli expression system is very difficult. Many studies investigated AhR using AhR domains in vitro. We expressed and purified the human full-length AhR in E. coli expression system. Furthermore, specific antibodies were prepared. Purified full-length AhR could bind to ligand. In the presence of ligand, α-helix and random coil of AhR increased and ß-sheet decreased on CD spectrum. Full-length AhR could bind to HSP90, XAP2 and p23 in the presence or absence of ligand. We now show the biochemical properties of full-length AhR.

Radical hysterectomy for FIGO stage IIB cervical cancer: clinicopathological characteristics and prognostic evaluation.

OBJECTIVE: To clarify the clinicopathological features and prognostic factors of patients with FIGO stage IIB cervical cancer who were treated with radical hysterectomy. METHODS: One hundred thirty-nine FIGO stage IIB patients with squamous or adenosquamous cell carcinoma (median age, 51 years) who were treated with primary radical hysterectomy were examined retrospectively. Sixty-six FIGO stage IIB patients who were treated with primary radiotherapy (median age, 70 years) were included for comparison of survival. RESULTS: Fifty percent (70/139) of the patients had pathological parametrial involvement. Among them, the positive rate of pelvic lymph nodes was 71% (50/70). Ninety-nine percent (138/139) of the tumors were completely removed, and the pelvic control rate was 88%. Major complications requiring surgery were found in 2.9% (4/139). Significant differences in survival were found among patients in subgroups according to pathological parametrial involvement, pelvic lymph node status, tumor size, lymph-vascular space invasion, and depth of myometrial invasion (log-rank test, P<0.05). Of these, the Cox proportional-hazard model revealed that parametrial involvement (P=0.001, 95% CI 1.992-6.297) and lymph node metastasis (P=0.042, 95% CI 1.023-3.298) were independent prognostic factors. The 5-year survival rate and relapse-free survival at 36 months were 69% and 72% among the radical hysterectomy group, and 69% and 75% among the radiotherapy group. The Cox model adjusted for age showed no significant differences in survival and relapse-free survival between these two groups. CONCLUSION: Pathological parametrial involvement and positive nodes were prognostic factors for surgically treated patients with FIGO stage IIB cervical cancer.

Prognostic significance of positive peritoneal cytology in adenocarcinoma of the uterine cervix.

OBJECTIVE: A retrospective analysis was carried out to evaluate the prognostic significance of peritoneal cytology in cervical adenocarcinoma. METHODS: The records of 107 patients with FIGO stage IB to IIB cervical adenocarcinoma who underwent hysterectomy were reviewed. RESULTS: Sixteen patients (15%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative cytology was 50% or 87%, respectively, showing a significant difference (log-rank, P<0.001). The recurrence-free survival (RFS) rate at 36 months in the cytology-positive or -negative group was 53% or 87%, respectively, the difference being significant (log-rank, P=<0.001). Cox model analysis revealed positive cytology [hazards ratio (HR) 6.27, 95% confidence interval (CI) 2.13-18.41], positive lymph node (HR 6.20, 95% CI 1.87-20.57), ovarian metastasis (HR 5.20, 95% CI 1.18-22.82), and histological grade (HR 5.97, 95% CI 2.00-17.78) to be independent adverse risk factors for survival among the factors analyzed (lymph node status, lymph-vascular space invasion, tumor size, depth in cervical wall, pathological parametrial involvement, infiltration to vagina, ovarian metastasis, and histological grade). Cox model analysis showed that positive cytology (HR 4.58, 95% CI 1.48-14.16), positive lymph node (HR 7.61, 95% CI 2.69-21.54), and histological grade (HR6.13, 95% CI 2.14-17.77) were independent adverse risk factors for RFS. The incidence of peritoneal spread at the first recurrence among the cytology-positive group (62.5%) was significantly higher than that among the cytology-negative group (12.5%) (Fisher's exact test, P=0.021). CONCLUSION: The presence of positive peritoneal cytology appears to be an independent prognostic risk factor in patients with cervical adenocarcinoma.

Affinity labeling of the proteasome by a belactosin A derived inhibitor.

Belactosin A is a potent proteasome inhibitor isolated from Streptomyces metabolites. Here we show that a hydrophobic belactosin A derivative, dansyl-KF33955, can covalently, and specifically, affinity label the catalytic subunits of the 26S proteasome, which consists of the 20S protein degrading core particle and the 19S regulatory particles. The labeling of catalytic subunits proceeds faster in intact proteasomes in vivo than in isolated 20S core particles. These data suggest that the 19S regulatory particle may facilitate entry of the inhibitor into the 20S core particle. This cell-permeable chemical probe is an excellent tool with which to study the interactions of this proteasome inhibitor with proteasomes in intact cells.

Conformational significance of EH21A1-A4, phenolic derivatives of geldanamycin, for Hsp90 inhibitory activity.

Hsp90 is an attractive chemotherapeutic target because it is essential to maturation of multiple oncogenes. We describe the conformational significance of EH21A1-A4, phenolic derivatives of geldanamycin isolated from Streptomyces sp. Their native free structures are similar to the active form of geldanamycin bound to Hsp90 protein. Their conformational character is a probable reason for their high-affinity binding. Lack of toxic benzoquinone in EH21A1-A4 also adds to their potential as lead compounds for anti-tumor drugs.