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51.
Lampe JW Biggers CK Defauw JM Foglesong RJ Hall SE Heerding JM Hollinshead SP Hu H Hughes PF Jagdmann GE Johnson MG Lai YS Lowden CT Lynch MP Mendoza JS Murphy MM Wilson JW Ballas LM Carter K Darges JW Davis JE Hubbard FR Stamper ML 《Journal of medicinal chemistry》2002,45(12):2624-2643
A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA. 相似文献
52.
Baba T Touchi A Ito K Yamaguchi Y Yamazoe Y Ohno Y Sugiyama Y 《Drug metabolism and pharmacokinetics》2002,17(6):522-531
To investigate whether the free-drug theory is accurate in that only unbound drug is available for drug metabolism or enzyme inhibition. The effect of addition of rat liver cytosol to an in vitro system using human liver microsomes was examined by measuring the catalytic activities of CYP2C9 (tolbutamide and diclofenac) and CYP3A4 (terfenadine). And, the results were compared with those obtained when human serum albumin (HSA) was added to microsomes as far as unbound drug concentrations were concerned. After addition of rat liver cytosol, the unbound Km value (Km,u) for terfenadine metabolism by CYP3A4, and the unbound Ki value of miconazole (Ki,u) for CYP2C9 were smaller than for the controls. Addition of HSA resulted in smaller Km,u values for diclofenac and terfenadine metabolism by CYP2C9 and CYP3A4, respectively, and the Ki,u value for ketoconazole inhibition of CYP3A4 was also reduced. These results suggest protein-facilitated effects on drug metabolism and enzyme inhibition for both CYP2C9 and CYP3A4. However, no protein-facilitated drug metabolism was observed for tolbutamide in the presence of HSA or cytosol, or for diclofenac in the presence of cytosol. Protein-facilitated enzyme inhibition did not occur with miconazole in the presence of HSA or with ketoconazole in the presence of rat liver cytosol. Protein-facilitated metabolism and enzyme inhibition were observed for CYP2C9 and CYP3A4 in five cases but there was no obvious pattern of enzyme, substrate, or binding protein specificity. Further investigations are necessary to clarify the relevance of these results to in vivo observations. 相似文献
53.
Takei H Suemasu K Kurosumi M Uchida K Igarashi K Ninomiya J Naganuma R Kusawake T Sugamata N Matsumoto H Higashi Y 《Breast cancer (Tokyo, Japan)》2002,9(4):344-348
BACKGROUND: Sentinel lymph node biopsy (SLNB) is an important treatment option for breast cancer patients, as it can accurately predict axillary status. Our previous study using dye with or without radioisotope showed the accuracy and sensitivity of SLNB to be 97% and 94%, respectively. Based on these results, axillary lymph node dissection (ALND) was eliminated starting in January, 1999 in patients with intraoperatively negative SLNB at our institution. The present study shows the results and outcomes of SLNB as a sole procedure for patients with invasive breast cancer. PATIENTS AND METHODS: Three-hundred-fifty-four patients and 358 cases of invasive breast cancer (4 bilateral breast carcinoma) treated with SLNB alone after an intraoperative negative SLNB were studied prospectively from January 1999 to December 2001. RESULTS: The number of the identified SLNs per case ranged from 1 to 8 (mean, 2.5). Of a total of 358 cases, 297 (83%) were treated with hormone therapy and/or chemotherapy, and 281 (78%) were treated with radiotherapy to the conserved breast (50 Gy+/-10 Gy boost), the axilla (50 Gy), or the both sites. After a median follow-up of 21 (range 6-42) months, no patient developed an axillary relapse. Four cases initially recurred in distant organs and one case in the conserved breast. CONCLUSIONS: Our results indicate that an intraoperative negative SLNB without further ALND may be a safe procedure when strict SLNB is performed. To better assess the safety, however, may require longer follow-up. 相似文献
54.
Watanabe O Haga S Shimizu T Imamura H Kinoshita J Utada Y Okabe T Kimura K Hirano A Kajiwara T Aiba M 《International journal of clinical oncology / Japan Society of Clinical Oncology》2002,7(5):0322-0325
Intravenous digital subtraction angiography (IV-DSA) was performed before and after neoadjuvant chemotherapy (NACT) in five
patients with locally advanced breast cancer, and the efficacy of NACT was evaluated on the basis of the results of IV-DSA
and histopathological examination. Following NACT, the maximum density of tumor enhancement (MAX) in the IV-DSA image decreased
by 61.6% in case 1, 50% in case 2, 58.1% in case 3, 90.8% in case 4, and 97.2% in case 5. In all five patients, the efficacy
of chemotherapy was rated as a partial response in terms of tumor size, while histological efficacy was rated as slightly
effective in cases 1–4 and moderately effective in case 5. The pathological efficacy of NACT was highest in case 5, which
showed the greatest decrease in MAX. These results indicate that variations in MAX reflect clinical efficacy, and, to some
extent, also permit prediction of pathological efficacy.
Received: March 4, 2002 / Accepted: June 10, 2002
Correspondence to:O. Watanabe 相似文献
55.
Mild periodic acid-Schiff (mPAS) staining can discriminate non-O-acetylated(mPAS positive) from O-acetylated (mPAS negative) epithelial sialoglycoproteins in human colonic mucosa, giving three haplotypes of expression of a single polymorphic autosomal gene (oat). Increase in mPAS-positive crypts in heterozygotes is an indication of mutations, and wholly mPAS-positive (stem cell mutated) crypts and clusters of two or more mPAS-positive crypts in heterozygotes of ulcerative colitis (P < 0.0001) were found to be increased significantly, compared with controls. The observed correlation with ulcerative colitis duration (r = 0.892 and 0.853, respectively) supports a chronic inflammation-carcinoma sequence. 相似文献
56.
Tanaka S Nakaizumi A Ioka T Oshikawa O Uehara H Nakao M Yamamoto K Ishikawa O Ohigashi H Kitamra T 《Japanese journal of clinical oncology》2002,32(10):407-411
BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma remains very poor, but is better in patients with a small tumor without local infiltration. The identification of the sign of high risk for pancreatic cancer will lead to early detection and improvement of the prognosis of this disease. The purpose of this study was to evaluate the main pancreatic duct dilatation as a sign of high risk for pancreatic cancer. METHODS: The diameter of the main pancreatic duct was measured by ultrasonography. The proportion of cases with main pancreatic duct dilatation was retrospectively examined in a pre-cancer group (39 subjects in whom pancreatic cancer developed more than 1 year later and surgically resected) and in a control group (10 244 subjects). Then the proportions in both groups were compared using the odds ratio. RESULTS: The proportion of cases with a slight dilatation (>/=2 mm in diameter) of the main pancreatic duct was 65% in the pre-cancer group, more than 4 years before the resection of the pancreatic cancer. In contrast, it was 5.35% in the age-matched control subjects. The odds ratio of 32.5 (95% confidence interval: 10.9-107.3) shows a significant association between the main pancreatic duct dilatation and the pre-cancer condition. Moreover, the proportion and the mean diameter of the dilated duct in the pre-cancer group increased with time. CONCLUSION: Slight dilatation of the main pancreatic duct appears to be a sign of high risk for pancreatic cancer. The systematic examination of high-risk subjects is recommended for the early detection of pancreatic cancer. 相似文献
57.
Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. 总被引:39,自引:0,他引:39
Riichiroh Maruyama Shinichi Toyooka Kiyomi O Toyooka Arvind K Virmani Sabine Z?chbauer-Müller Alfredo J Farinas John D Minna John McConnell Eugene P Frenkel Adi F Gazdar 《Clinical cancer research》2002,8(2):514-519
PURPOSE: We investigated the aberrant methylation profile of prostate cancers and correlated the data with clinical findings. EXPERIMENTAL DESIGN: Gene promoter methylation was analyzed in 101 prostate cancer samples. In addition, we analyzed 32 nonmalignant prostate tissue samples, which included 25 with benign disease, benign prostatic hypertrophy, or prostatitis, and 7 normal tissues adjacent to cancer. The methylation status of 10 genes was determined. The methylation index (MI) was calculated as a reflection of the methylated fraction of the genes examined. RESULTS: Methylation percentages of the genes tested in prostate cancers were: RARbeta, 53%; RASSF1A, 53%; GSTP1, 36%; CDH13, 31%; APC, 27%; CDH1, 27%; FHIT, 15%; p16(INK4A), 3%; DAPK, 1%; and MGMT, 0%. Methylation percentages in nonmalignant tissues were much lower. For clinicopathological correlations, we divided the cancer cases into low (6 or less) or high (7 or more) Gleason score (GS) groups, and into low (8 ng/ml or less) or high (greater than 8 ng/ml) preoperative serum prostate-specific antigen (PSA) groups. Methylation of RASSF1A, GSTP1, RARbeta, and CDH13 genes was significantly more frequent in the high GS group than in the low GS group. Methylation of RASSF1A, CDH1, and GSTP1 genes was significantly more frequent in the high PSA group than in the low PSA group. The median MIs were significantly higher in the high GS and the high PSA groups. According to the Spearman rank-correlation test, there was significant correlation between MI and GS (coefficient = 0.43, P < 0.0001) and the preoperative serum PSA (coefficient = 0.37, P = 0.0003). CONCLUSIONS: Our results indicate that the methylation profile of prostate cancers correlates with clinicopathological features of poor prognosis. 相似文献
58.
Eiji Isozaki Toshio Shimizu Kiyomi Takamoto Satoshi Horiguchi Tetsuro Hayashida Masaya Oda Hitoshi Tanabe 《Journal of the neurological sciences》1995,130(2):197-202
Vocal cord abductor paralysis (VCAP) is rare in Parkinson's disease (PD), while it is frequent in multiple system atrophy (MSA). Although VCAP is a life-threatening complication it has not yet been clarified whether there is any difference in the mechanism of VCAP between PD and MSA. Examining 3 autopsy-proven PD patients who developed severe VCAP requiring tracheostomy, we found the following differences in the mechanism of VCAP between MSA and PD: (1) clinical and laryngofiberscopic examination showed that VCAP in PD was not exacerbated during sleep, unlike in MSA; (2) On histological examination of the intrinsic laryngeal muscles, the posterior cricoarytenoid muscle demonstrated no abnormalities in PD, while the muscle showed characteristic neurogenic atrophy in MSA. There seemed to be two types of VCAP, namely the nonparalytic type observed in PD, and the paralytic type observed in MSA. Severe dysphagia requiring tube-feeding was common among PD patients who presented with VCAP. Although the relationship between VCAP and dysphagia is unknown, one should be aware of the possibility of fatal VCAP in PD patients with severe dysphagia. 相似文献
59.
Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we studied their radiosensitivity by focusing attention on the dynamics of tumor clonogens. The movement of clonogens in the regrowing IA tumor after irradiation can be divided into three phases: first, the early and rapid survival recovery (PLD repair) phase; second, the delay phase involving a certain lag in survival change; and third, the repopulation phase consisting of two stages: the anoxic repopulation before angiogenesis and the hypoxic repopulation in the presence of a poorly developed vascular network. Clonogens in a regrowing tumor after irradiation were found to actively proliferate even in an anoxic environment before angiogenesis and under the hypoxic conditions prevailing after the formation of a tumor with a poorly developed vascular system. This re-grown tumor was found to be more radioresistant than a sham-treated control tumor. It is believed that these clonogens are genetically selected under hypoxic conditions throughout the process of tumor growth and regrowth, and may be primarily involved in tumor recurrence or accelerated repopulation in fractionated irradiation. 相似文献
60.
Ishikura S Tobinai K Ohtsu A Nakamura S Yoshino T Oda I Takagi T Mera K Kagami Y Itoh K Tamaki Y Suzumiya J Taniwaki M Yamamoto S 《Cancer science》2005,96(6):349-352
CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy is regarded as standard care for localized aggressive lymphoma; however, prospective confirmation of its applicability to localized primary gastric lymphoma is inadequate, and most patients in Japan have been initially treated with gastrectomy. We conducted a multicenter phase II study to evaluate the feasibility and efficacy of the non-surgical treatment. Eligibility criteria required primary gastric diffuse large B-cell lymphoma, stage I-II(1), age 20-75, performance status 0-1 and adequate organ function. Treatment consisted of three cycles of CHOP followed by radiotherapy 40.5 Gy. Fifty-five patients were enrolled between December 1999 and February 2003, and 52 eligible patients were analyzed. Patient characteristics were as follows: median age, 61 years; 28 men, 24 women; 36 with stage I, 16 with stage II(1); 47 with a low International Prognostic Index (IPI) and five with a low-intermediate IPI. All but one patient completed planned treatment. No serious complications including massive hemorrhage or perforation were observed. A complete response was achieved in 48 of the 52 patients (92%, 95% confidence interval: 82-98%) and progressive disease in three. Two patients underwent salvage gastrectomy due to disease persistence or recurrence. With a median follow-up period of 28 months, 2-year progression-free and overall survivals were 88 and 94%, respectively. CHOP followed by radiotherapy is safe and highly effective in localized gastric diffuse large B-cell lymphoma. This organ-preserving treatment should be considered as a very reasonable therapeutic option. 相似文献