Effects of Egb 761 on bone mineral density,bone microstructure,and osteoblast function: Possible roles of quercetin and kaempferol

The effects of standardized and concentrated extract of Ginkgo biloba, Egb 761, were studied on estrogen deficiency-induced bone loss in ovariectomized (OVx) rats rendered osteopenic. Upon osteopenia development, Egb 761 was administered at a dose of 100 mg kg⁻¹ day⁻¹ by oral gavage to OVx rats whereas control group received vehicle. Following 5 weeks of treatment, the OVx + Egb 761 group (n = 12) of rats exhibited significantly higher whole body BMD and lower bone turnover markers (serum alkaline phosphatase and osteocalcin) than OVx rats that were given vehicle (n = 12). BMD levels in excised bones were also found to be higher in both trabecular (most robustly in lumbar vertebrae) and cortical bones of OVx + Egb 761 compared with OVx + vehicle group. Egb 761 did not exhibit estrogen agonistic activity at the uterine level. Microcomputed tomography demonstrated that OVx + Egb 761 group had better bone microarchitectural parameters compared with OVx + vehicle group. Moreover, OVx + Egb 761 group had higher femoral mRNA levels of osterix, type I collagen and osteocalcin compared with OVx + vehicle group. Determination of levels of three flavonoids of Egb 761, that are known to have bone conserving property, in serum and bone marrow suggests that kaempferol and quercetin, and not rutin, likely mediate the beneficial actions observed with Egb 761 treatment. These results show for the first time that oral administration of Egb 761 restores bone mass in aged OVx rats.     

Prospective evaluation of concomitant tumour bed boost with whole breast irradiation in patients with locally advanced breast cancer undergoing breast-conserving therapy

BACKGROUND AND PURPOSE: To evaluate prospectively the feasibility of concomitant weekly tumour bed electron boost along with whole breast radiotherapy (RT) following breast-conserving therapy (BCT) in patients with locally advanced breast cancer (LABC) with the aim of reducing overall treatment time. MATERIALS AND METHODS: Thirty patients with LABC suitable for BCT following neoadjuvant chemotherapy (CAF/CEF) were accrued in the study. Conventional RT (CRT) to the whole breast was delivered 5 days a week to a dose of 50Gy using 6-10MV photons. In addition, an electron boost to the tumour bed was delivered every Saturday, eventually delivering 5 such weekly fractions to a boost dose of 12.5Gy. Patients were evaluated for acute reactions during the treatment and cosmetic evaluation was done before, at the end of radiation therapy and at follow up by 2 independent observers blinded to each other. The study population (concomitant boost (CB) group) was compared with a similar cohort of 32 patients treated conventionally with tumour bed boost of 15Gy in 6 fractions delivered after the completion of whole breast irradiation (CRT group). RESULTS: All patients completed RT within the stipulated time with no grade IV skin toxicity in either group. At conclusion of RT, in the CB group, confluent moist desquamation (grade III) developed within the tumour bed region in 1 patient (3.3%) and outside tumour bed region in 3 patients (10%). In the CRT group, 3 and 4 patients (9.4% and 12%) developed moist desquamation within and outside the tumour bed regions, respectively. CB did not affect the global cosmesis as compared with CRT group (p=0.23) at the end of 3 years. CONCLUSION: Concomitant tumour bed boost along with whole breast RT appears to be safe and feasible in a select group of patients. As the treatment is completed earlier by 6-10 days than conventional practice, it has favourable time and resource implications, particularly attractive for patients travelling long distances for treatment. Based on these encouraging results, we are planning to confirm the results in an appropriately designed and powered randomised trial.     

Sarcoidosis mimicking metastatic breast cancer

The clinical and radiographic aspects of sarcoidosis and malignancy might mimic one another, making the distinction between the two difficult in some cases. Although there have been many theories on the link between sarcoidosis and malignancy, the association remains unproven. An unfortunate consequence of the presence of both entities in the same patient is the risk of misdiagnosis and incorrect treatment. We describe 3 patients who presented with locally advanced breast cancer and who were found to have pulmonary findings for metastatic disease that were proven upon biopsy to be consistent with sarcoidosis.     

p53 and p21 determine the sensitivity of noscapine-induced apoptosis in colon cancer cells

We have previously discovered the naturally occurring antitussive alkaloid noscapine as a tubulin-binding agent that attenuates microtubule dynamics and arrests mammalian cells at mitosis via activation of the c-Jun NH(2)-terminal kinase pathway. It is well established that the p53 protein plays a crucial role in the control of tumor cell response to chemotherapeutic agents and DNA-damaging agents; however, the relationship between p53-driven genes and drug sensitivity remains controversial. In this study, we compared chemosensitivity, cell cycle distribution, and apoptosis on noscapine treatment in four cell lines derived from the colorectal carcinoma HCT116 cells: p53(+/+) (p53-wt), p53(-/-) (p53-null), p21(-/-) (p21-null), and BAX(-/-) (BAX-null). Using these isogenic variants, we investigated the roles of p53, BAX, and p21 in the cellular response to treatment with noscapine. Our results show that noscapine treatment increases the expression of p53 over time in cells with wild-type p53 status. This increase in p53 is associated with an increased apoptotic BAX/Bcl-2 ratio consistent with increased sensitivity of these cells to apoptotic stimuli. Conversely, loss of p53 and p21 alleles had a counter effect on both BAX and Bcl-2 expression and the p53-null and p21-null cells were significantly resistant to the antiproliferative and apoptotic effects of noscapine. All but the p53-null cells displayed p53 protein accumulation in a time-dependent manner on noscapine treatment. Interestingly, despite increased levels of p53, p21-null cells were resistant to apoptosis, suggesting a proapoptotic role of p21 and implying that p53 is a necessary but not sufficient condition for noscapine-mediated apoptosis.     

Amplicon profiles in ovarian serous carcinomas

Ovarian serous carcinoma is the most common and lethal type of ovarian cancer and its molecular etiology remains poorly understood. As an ongoing effort to elucidate the pathogenesis of ovarian serous carcinomas, we assessed the DNA copy number changes in 33 high-grade serous carcinomas and 10 low-grade serous tumors by using a genome-wide technique, single nucleotide polymorphism array, performed on affinity-purified tumor cells from fresh surgical specimens. Compared to low-grade tumors, high-grade serous carcinomas showed widespread DNA copy number changes. The most frequent alterations were in loci harboring candidate oncogenes: cyclin E1 (CCNE1), AKT2, Notch3 and PIK3CA as well as in novel loci, including 12p13, 8q24, 12p13 and 12q15. Seven amplicons were selected for dual color fluorescence in situ hybridization analysis in approximately 90 high-grade serous carcinomas and 26 low-grade serous tumors, and a high level of DNA copy number gain (amplification) was found in CCNE1, Notch3, HBXAP/Rsf-1, AKT2, PIK3CA and chr12p13 occurring in 36.1%, 7.8%, 15.7%, 13.6%, 10.8% and 7.3% of high-grade serous carcinomas. In contrast, we did not observe high level of ERBB2 amplification in any of the samples. Low-grade tumors did not show DNA copy number gain in any of the loci, except in 2 (8%) of 24 low-grade tumors showing low copy number gain in the Notch3 locus. Taken together, our results provide the first comprehensive analysis of DNA copy number changes in highly pure ovarian serous carcinoma. These findings may have important biological and clinical implications.     

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.