Isoflavone-deprived soy peptide suppresses mammary tumorigenesis by inducing apoptosis.

During carcinogenesis, NF-gammaB mediates processes associated with deregulation of the normal control of proliferation, angiogenesis, and metastasis. Thus, suppression of NF-gammaB has been linked with chemoprevention of cancer. Accumulating findings reveal that heat shock protein 90 (HSP90) is a molecular chaperone and a component of the IgammaB kinase (IKK) complex that plays a central role in NF-gammaB activation. HSP90 also stabilizes key proteins involved in cell cycle control and apoptosis signaling. We have determined whether the exogenous administration of isoflavone-deprived soy peptide prevents 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced rat mammary tumorigenesis and investigated the mechanism of action. Dietary administration of soy peptide (3.3 g/rat/day) significantly reduced the incidence of ductal carcinomas (50%), the number of tumors per multiple tumor-bearing rats (49%; P<0.05), and extended the latency period of tumor development (8.07+/-0.92 weeks) compared to control diet animals (10.80+/-1.30; P<0.05). Our results have further demonstrated that soy peptide (1) dramatically inhibits the expression of HSP90, thereby suppressing signaling pathway leading to NF-gammaB activation; (2) induces expression of p21, p53, and caspase-3 proteins; and (3) inhibits expression of VEGF. In agreement with our in vivo data, soy peptide treatment inhibited the growth of human breast MCF-7 tumor cells in a dose-dependent manner and induced apoptosis. Taken together, our in vivo and in vitro results suggest chemopreventive and tumor suppressive functions of isoflavone-deprived soy peptide by inducing growth arrest and apoptosis.

The prognostic significance of tumor volume regression during radiotherapy and concurrent chemoradiotherapy for cervical cancer using MRI.

OBJECTIVE: The purpose of this study was to determine the prognostic significance of tumor volume regression rate during radiotherapy (RT) measured by three serial magnetic resonance imaging (MRIs) studies performed in patients treated with RT alone and compare the results with patients treated with concurrent chemoradiotherapy (CCRT). METHODS: We evaluated 81 patients with uterine cervical cancer who underwent three serial MR examinations, i.e., at the start of RT, at 36-45 Gy of external RT and 1 month after the end of RT. Forty-three patients were treated with RT alone and 38 patients were treated with CCRT. Pre-RT tumor volume (V1), the tumor volume regression rate measured during the fourth week of RT and residual tumor volume at 1 month after the end of RT (V3) were determined for each patient. The cut-off value used for the three parameters studied was the one that made the largest outcome difference. These volume parameters were analyzed to determine a difference in the treatment outcome. RESULTS: In the patients treated with CCRT, the mean value of the V1 was larger and the mean value of the V3 was smaller than in patients treated with RT alone. The mean value of the mid-RT regression rate was somewhat higher in patients treated with CCRT than in patients treated with RT alone; however, this difference was not statistically significant (79% vs. 69%). In both the RT alone and the CCRT group, the patients with a mid-RT regression >/=75% had 100% 5-year local control rates and a better disease free survival than the patients with mid-RT regression <75%. The patients with V3=0 cm(3) also had a better 5-year local control rate than the patients with a V3>0 cm(3), but statistical significance was found only in the patients treated with CCRT. CONCLUSIONS: The mid-RT tumor volume regression rate, at 36-45 Gy of external RT, was a predictor of local control rate in both RT and CCRT patient groups. However, in the patients who were treated with CCRT, the local control rate difference was even larger by post-RT residual volume than by the mid-RT tumor regression rate. Further studies on appropriate evaluation timing for mid-RT response in patients receiving CCRT are needed.

Phase II study of consolidation chemotherapy after concurrent chemoradiation in cervical cancer: preliminary results.

PURPOSE: Our aim was to determine the efficacy of consolidation chemotherapy after concurrent chemoradiation (CCRT) using high-dose-rate brachytherapy in patients with locally advanced cervical carcinoma. METHODS AND MATERIALS: Patients with cervical carcinoma (FIGO stage IB2-IVA) were treated with external beam radiation therapy to the whole pelvis (50.4 Gy) and high-dose-rate brachytherapy (24 Gy to point A). Cisplatin 60 mg/m(2) (Day 1) and 5-fluorouracil 1000 mg/m(2) (Days 1-5) were given every 3 weeks starting concurrently with the radiation and followed by 3 more cycles of consolidation for a total of 6 cycles. RESULTS: Thirty patients (94%) received 3 more cycles of post-CCRT consolidation chemotherapy and were evaluable for the toxicity and efficacy of consolidation. The most common toxicities of Grade 2 or higher were nausea or vomiting (47%) and anemia (33%). Late complications of the rectum and bladder occurred in 13% and 6% of the patients, respectively. The clinical complete response rate was 87% (95% CI, 75%-99%). During a median follow-up of 27 months (range, 6-58 months), 5 patients (17%) had recurrence; the sites of failure were 3 (10%) inside the radiation field and 2 (7%) outside the radiation field. The estimated 3-year progression-free survival rate was 83% (95% CI, 67%-99%) and overall survival rate was 91% (95% CI, 79%-100%). CONCLUSIONS: Consolidation chemotherapy after CCRT is well tolerated and effective in patients with locally advanced cervical carcinoma. A prospective randomized trial to compare this treatment strategy with standard CCRT seems to be worthwhile.

TIMP-1 regulates cell proliferation by interacting with the ninth zinc finger domain of PLZF.

The tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that specifically inhibit matrix metalloproteinases (MMPs) and regulate extracellular matrix (ECM) turnover and tissue remodeling. This is directed by forming tightly bound inhibitory complexes with MMPs. Recent years have revealed important differences of various biological activities between TIMP families but molecular mechanisms are not clear. To define the molecular mechanisms of TIMP-1-dependent biological processes, we used TIMP-1 as bait in a yeast two-hybrid screen, along with a human ovary cDNA library. Further characterization revealed the ninth zinc finger domain as an interacting domain of the promyelocytic leukemia zinc finger protein (PLZF). Interaction of PLZF with TIMP-1 in mammalian cells was also confirmed by co-immunoprecipitation and with in vitro binding assays. We investigated whether TIMP-1-mediated anti-apoptotic activity could promote the growth of ovarian cancer in an experimental model system. TIMP-1 treatment was found to be more effective at increasing ovarian cancer growth when compared with PLZF in parallel experiments. Subsequently, the efficacy of a combined treatment with TIMP-1 and PLZF was investigated. In the presence of both of these proteins, TIMP-1 significantly reduced apoptosis induced by PLZF in cervical carcinoma cells. These combined results indicate that TIMP-1 functions as an anti-activator of the transcriptional repressive activity of PLZF.