Biomedical subjects

K Chi

Publications and source records attributed to K Chi.

9 recordsLinked to original sources

PubMed2006

Development and assessment of conventional and targeted drug combinations for use in the treatment of aggressive breast cancers.

Combination chemotherapy has been at the forefront of cancer treatment for over 40 years. However, the rationale for selecting drug combinations and the process used to demonstrate clinical effectiveness has primarily followed trial and error methodology. Typically, the selection and assessment of combined drug therapies has been based on the effectiveness of each agent as monotherapy in treating the neoplasm and avoiding overlapping toxicities, followed by clinical trials to establish dose scheduling, toxicity, and efficacy. Unfortunately, this scheme is inefficient in terms of the time required to complete and revise these clinical trials based on the outcome to optimize the drug combination. A more rational approach for the development of combination oncology products should consider (i) in vitro assays for assessing therapeutic effects of drug combinations (antagonistic, additive or synergistic interactions) when added simultaneously; (ii) methods for measuring these interactions in vivo; (iii) the importance of understanding pharmacokinetic and biodistribution parameters when using drug combinations; (iv) the need to assess pathways known to contribute to cancer cell survival as well as metastasis; and (iv) the need to assess the fate of different cell populations (cancer and stroma) contributing to the development of cancer. Therefore, the goal of this article is to provide a road map for the preclinical development of drug combination products that will have improved therapeutic activity and a high likelihood of providing beneficial therapeutic outcomes in patients with aggressive cancers with a specific focus on patients with breast cancer.

Animals↗

PubMed2003

Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain.

PURPOSE: To compare the incidence of palliative response in patients with hormone-resistant prostate cancer (HRPC) treated with mitoxantrone and prednisone (MP) plus clodronate with that of patients treated with MP plus placebo. MATERIALS AND METHODS: Men with HRPC, bone metastases, and bone pain were randomly assigned to receive clodronate 1,500 mg administered intravenously (IV) or placebo every 3 weeks, in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid. Patients completed the present pain intensity (PPI) index and Prostate Cancer-Specific Quality-of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis. The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50% in analgesic intake, without increase in either. RESULTS: The study accrued 209 eligible patients over 44 months. One hundred sixty patients (77%) had mild PPI scores (1 or 2), and 49 (24%) had moderate PPI scores (3 or 4). The primary end point of palliative response was achieved in 46 (46%) of 104 patients on the clodronate arm and in 41 (39%) of 105 patients on the placebo arm (P =.54). The median duration of response, symptomatic disease progression-free survival, overall survival, and overall quality of life were similar between the arms. Subgroup analysis suggested possible benefit in patients with more severe pain. CONCLUSION: MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.

Aged↗

PubMed2003

Phase II study of troxacitabine (BCH-4556) in patients with advanced and/or metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

Aged↗

PubMed2003

Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumour model.

OBJECTIVE: To evaluate the effect of clusterin overexpression on radiation-induced tumour growth rates and apoptosis in human prostate LNCaP cells, as prostate cancer cells are relatively resistant to radiation-induced apoptosis and local recurrences are common, but overexpression of the anti-apoptotic protein clusterin can accelerate progression to androgen-independence and to confer a chemoresistant phenotype in various prostate cancer models. MATERIALS AND METHODS: Western blot analysis and immunohistochemistry were used to compare clusterin expression levels in parental (P) and clusterin-transfected (T) LNCaP cells in vitro and in vivo. The effects of radiation on clusterin-expression in both parental LNCaP/P and clusterin-transfected LNCaP/T tumours were analysed by Northern blot analysis. The cellular response to radiation was determined up to 3 weeks after irradiation using tetrazolium and re-growth assays, and cell-cycle analysis by flow cytometry. RESULTS: Clusterin mRNA expression increased from undetectable to low levels in LNCaP/P tumours after radiation and more than three-fold in LNCaP/T tumours. Clusterin overexpression decreased the radiosensitivity in a time-dependent manner, reducing the extent of growth arrest and apoptosis by up to 54%. Re-growth assays showed that the improved survival rates of LNCaP/T cells after radiation did not change after 3 days, remaining constant over 3 weeks. CONCLUSIONS: These results identify clusterin as a promoter of cell survival that may help mediate resistance to radiation-induced apoptosis. Furthermore, clusterin overexpression seems to provide an extended protection against radiation-induced cell cycle arrest and apoptosis.

Apoptosis↗

PubMed2001

Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer.

BACKGROUND: Androgen resistance develops, in part, from upregulation of antiapoptotic genes after androgen withdrawal. Identification and targeting of genes mediating androgen-independent (AI) progression may lead to development of novel therapies that delay hormone-refractory prostate cancer. Clusterin is a cell survival gene, that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the ability of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer xenograft models. RESULTS: Immunostaining of radical prostatectomy specimens confirm that clusterin is highly expressed in 80% prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Clusterin levels increase >10 fold in regressing Shionogi tumors after castration. Pretreatment of mice bearing androgen-dependent Shionogi tumors with calcium antagonists inhibited castration-induced apoptosis, tumor regression, and clusterin gene upregulation, illustrating that clusterin is an apoptosis-associated gene and not an androgen-repressed gene. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels by 70% and resulted in earlier onset and more rapid apoptotic tumor regression, with significant delay in recurrence of AI tumors. Species-specific clusterin ASOs also increased the cytotoxic effects of paclitaxel, reducing the 50% inhibitory concentration (IC(50)) of PC-3 and Shionogi cells by 75% to 90%. Although clusterin ASOs had no effect on the growth of established AI Shionogi or PC-3 tumors, clusterin ASOs synergistically enhanced paclitaxel-induced tumor regression in both Shionogi and PC-3 models. CONCLUSIONS: Collectively, these data identify clusterin as an antiapoptosis protein, upregulated in an adaptive cell-survival manner by androgen ablation and chemotherapy, which confers resistance to various cell-death triggers. Inhibition of clusterin upregulation using clusterin ASOs can enhance cell death after treatment with androgen ablation and chemotherapy.

Androgen Antagonists↗

PubMed2001

Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2'-O-(2-methoxy)ethyl chemistry.

Phosphorothioate (P=S) antisense oligonucleotides (ASO) targeting the cell survival gene clusterin synergistically enhance castration- and chemotherapy-induced apoptosis in prostate cancer xenografts. This study compares efficacy, tissue half-lives, and toxicity of P=S clusterin ASO to third-generation backbone 2'-O-(2-methoxy)ethyl (2'MOE) ribose-modified clusterin ASO. Northern analysis quantified changes in clusterin mRNA levels in human PC-3 cells and tumors. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay measured effects of combined clusterin ASO plus paclitaxel on PC-3 cell growth. Athymic mice bearing PC-3 tumors were treated with paclitaxel plus either P=S clusterin ASO, 2'-MOE clusterin ASO, or mismatch control oligonucleotides for 28 days. Weekly body weights and serum parameters were measured to assess toxicity. Tissue half-life of P=S and 2'-MOE ASO in PC-3 tumors was assessed using capillary gel electrophoresis (CGE). Both 2'-MOE and P=S ASO decreased clusterin mRNA levels in a dose-dependent and sequence-specific manner. 2'-MOE ASO more potently suppressed clusterin mRNA (80 versus 40% at 500 nM) compared with P=S ASO. IC(50) of paclitaxel was equally reduced (50--75%) by both compounds. In vivo tissue half-life was significantly longer for 2'-MOE-modified ASO than for P=S ASO (5 versus 0.5 days). Using CGE, >90% of detected 2'-MOE ASO in tumor tissue was full length. Weekly administration of 2'-MOE clusterin ASO was equivalent to daily P=S clusterin ASO in enhancing paclitaxel efficacy in vivo. 2'-MOE-modified ASO potently suppressed clusterin expression and prolonged tissue half-lives with no additional side effects. These results support the use of 2'-MOE-modified ASO over conventional P=S ASO by potentially increasing potency and allowing longer dosing intervals in clinical trials.

Animals↗

PubMed1999

Decision model for optimizing respirator protection.

Respirators are widely used for protection against inhaled toxins. The emphasis of research and implementation effort has evolved through several stages: the respirator device itself, use situation, respirator program factors under employer control, individual worker factors not under employer control, and occupational health systems. For this study, a computer-simulation decision assistance model was developed to assess the impact of various factors on the number of workers receiving adequate protection. Factors include the respirator protection factor, identification of sites needing respirator protection, selection of proper device, availability when needed, frequency of ever use, regularity of use among users, and variability in personal susceptibility or other factors. This analysis demonstrates that for both moderate-risk and high-risk (i.e., IDLH, immediately dangerous to life and health) exposures under current circumstances, the actual protection afforded depends upon the optimization of program factors and detection of atypical outlier persons and worksites. Therefore, programs and research must focus on these areas. Occupational medicine specialists should help optimize these areas and, in addition, use each case of respiratory protection failure as an index case to improve the overall programs.

Computer Simulation↗

PubMed1992

Expression of an elongation factor 1 gamma-related sequence in adenocarcinomas of the colon.

The authors have previously reported that a messenger RNA (mRNA) bearing 60% homology to elongation factor 1 gamma in Artemia salina was overexpressed in 7 of 9 pancreatic tumors relative to normal appearing adjacent tissue. The purpose of the present study was to determine if this pattern of overexpression is also detected in colorectal carcinoma. Overexpression was observed in 25 of 29 colorectal carcinomas, relative to normal adjacent tissue. Of them, mRNA was overexpressed in 2 tumors classified as Dukes' D, in 8 of 11 tumors classified as Dukes' B2, and in 15 of 16 tumors classified as Dukes' C2.

Adenocarcinoma↗

PubMed1987

Monoclonal antibody study of the subcellular localization and DNA-stimulating activity of murine sarcoma virus-activated transformation-associated proteins.

Previously, we reported the monoclonal antibody detection of transformation-associated proteins (TAP) in ts110 murine sarcoma virus-transformed normal rat kidney (6M2) cells (Chan et al., 1986). In this study, we used the same monoclonal antibody to investigate the subcellular localization, the fate and the mitogenic activity of TAP, as well as the correlationship between TAP synthesis and the expression of transformation properties of 6M2 cells. It was found that TAP were localized in the cytoplasm (probably the Golgi apparatus) of 6M2 cells. TAP were found as three intracellular polypeptides (mol wt of 66K, 63K, and 60K, respectively), and were rapidly released into extracellular medium. Upon release, TAP changed to two extracellular polypeptides (mol wt of 68K and 64K, respectively). Furthermore, the synthesis of TAP was temperature sensitive and correlated closely with the expression of transformation properties of the 6M2 cells. TAP have been purified by monoclonal antibody-affinity column chromatography and found to have a synergistic effect with insulin in stimulating the DNA synthesis of normal rat kidney cells.

Animals↗