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Biomedical subjects

Hak Choy

Publications and source records attributed to Hak Choy.

At least 37 records · Page 2Linked to original sources
PubMed2004

Potential role for epidermal growth factor receptor inhibitors in combined-modality therapy for non-small-cell lung cancer.

There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology/oncology. The epidermal growth factor receptor (EGFR) has been a molecular target of significant interest and investigation, and preclinical and clinical studies support a role for targeted therapy in a variety of cancers, including non-small-cell lung cancer (NSCLC) via compounds that specifically inhibit EGFR. ZD1839, IMC-C225, and OSI-774 are the most clinically developed of these compounds. Interestingly, preclinical studies have demonstrated that EGFR inhibitors may have radiation-sensitizing properties, as well as increased cytotoxic activity in combination with chemotherapeutic agents, suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of Stage III NSCLC. Therefore, clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of EGFR inhibitors to the standard combined-modality regimen (chemotherapy/radiation therapy +/- surgery) for Stage III NSCLC. This article reviews preclinical and clinical data supporting the role for EGFR inhibitors alone or in combination with chemotherapy/radiation therapy for locally advanced NSCLC. Also, it will provide an overview of ongoing and proposed clinical studies investigating the potential role for EGFR inhibitors in Stage III NSCLC.

Antibodies, Monoclonal↗
PubMed2004

Enhancement of radiation effects by combined docetaxel and flavopiridol treatment in lung cancer cells.

BACKGROUND AND PURPOSE: To evaluate the potential role and mechanism of docetaxel plus flavopiridol in modulating radiosensitivity in vitro and in vivo. PATIENTS AND METHODS: In vitro. H460 human lung carcinoma cells were treated with docetaxel (10 nM for 1 h, at t = 0 h) --> radiation (0-5 Gy, at t = 6 h) --> flavopiridol (120 nM for 24 h, at t = 8 h). Colony forming ability was measured to assess the modulation of sensitivity. Cell cycle redistribution was measured by flow cytometric analysis using propidium iodide. Percent apoptosis was also measured by flow cytometric analysis using 7-amino-actinomycin D staining. In vivo. H460 cell xenografts were used in nude mice. Tumors were grown subcutaneously on the flank, then treated with docetaxel (2.5 mg/kg, at t = 0 h) --> radiation (2 Gy, at t = 6 h) --> flavopiridol (1.25 mg/kg, at t = 8 h) for 5 consecutive days. Tumor growth delay was then measured and compared with the control group. RESULTS: Docetaxel plus flavopiridol enhanced the effect of radiation. The maximum radiopotentiation and apoptosis were observed when the cells were treated with the sequence of docetaxel-->radiation-->flavopiridol both in vitro and in vivo. Flavopiridol and docetaxel induced G1 and G2/M arrest, respectively. CONCLUSIONS: This study shows that docetaxel plus flavopiridol enhances the effects of radiation in vitro and in vivo. Our data suggest that the mechanism of radiopotentiation by combining flavopiridol and docetaxel involves an enhancement of apoptosis and changes of cell cycle by docetaxel and flavopiridol.

Animals↗
PubMed2004

Non-small cell lung cancer and central nervous system metastases: should we be using prophylactic cranial irradiation?

Central nervous system (CNS) failure in patients with locally advanced non-small cell; lung cancer (LA-NSCLC) is a common and debilitating problem. Standard follow-up after local regional therapy does not include routine radiologic evaluation of the brain. Imaging is performed at the onset of symptoms followed by palliative therapy for CNS failure. Some investigators support regular screening with therapy for failures before the onset of symptoms. This alternative may decrease the impact of CNS failures and lengthen survival. Other investigators have shown that prophylactic cranial irradiation (PCI) for LA-NSCLC decreases the incidence of CNS failures. The potential survival, quality of life, and neuropsychological advantage or disadvantage of these two approaches has not been systematically studied. This article will review the problem of CNS failures in patients with LA-NSCLC and the potential risks and benefits of close observation and PCI. The necessity of conducting an ambitious study evaluating the potential survival advantage of PCI will be discussed.

Brain Neoplasms↗
PubMed2004

Rationale for investigation of epidermal growth factor receptor inhibitors in definitive treatment of locally advanced non-small cell lung cancer and head and neck cancer.

Designing targeted therapies has become an important field in cancer therapeutics. The epidermal growth factor receptor (EGFR) is a molecular target that has gained immense attention as preclinical and clinical studies have supported its potential role for therapy of a variety of cancers, including non-small cell lung cancer (NSCLC) and head and neck (HN) cancer. Several compounds that specifically inhibit EGFR have been developed, including ZD1839, C225, and OSI-774. Interestingly, studies suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of NSCLC and HN cancer have been performed in the preclinical and clinical setting. Therefore, determining the potential of EGFR inhibitors to improve the efficacy of standard combined-modality regimens (chemotherapy/radiation therapy +/- surgery) for NSCLC and HN cancer patients is of the utmost importance. An overview of the rationale and the ongoing/proposed studies aimed at determining the role for EGFR inhibitors in combination with radiation therapy for NSCLC and HN cancer patients will be presented.

Journal Article↗
PubMed2004

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study.

PURPOSE: To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. METHODS AND MATERIALS: Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. RESULTS: Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. CONCLUSION: HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.

Adenocarcinoma↗
PubMed2004

Topoisomerase I inhibitors in the combined-modality therapy of lung cancer.

Locally advanced non-small-cell lung cancer represents 30% to 40% of all pulmonary malignancies. Most patients will die of the disease after aggressive contemporary treatments. Therefore, significant improvement in therapeutic methods must be implemented to improve overall survival rates. The arrival of a new generation of chemotherapeutic agents--including the taxanes, gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan (Camptosar) and topotecan (Hycamtin)--offers the hope of significant advances in the treatment of lung cancer. Irinotecan and topotecan are camptothecin derivatives that inhibit topoisomerase I enzyme. It is believed that topoisomerase I inhibitors stabilize a DNA/topoisomerase I complex and interact with replication machinery to cause cell death. A significant amount of data demonstrates that these topoisomerase I inhibitors also act as radiosensitizers. With the increasing data that support concurrent chemoradiation treatment for malignancies, including lung cancer and head and neck cancers, there is an impetus to pursue the additional drugs that may potentially improve local control and survival. Irinotecan is undergoing early clinical trials in the combined-modality setting in several different disease sites. This paper will review the data on the role of camptothecin derivatives as a radiosensitizer and as a component of combined-modality therapy for lung cancer. It is hoped that newer treatment strategies, like the combination of radiation and topoisomerase I inhibitors, will have a significant impact on cure rates in the future.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Chemoradiation in NSCLC: focus on the role of gemcitabine.

Research to identify the optimal drugs for use in chemoradiotherapy has led to the development of the potent radiosensitizing agent gemcitabine (Gemzar), which has exhibited excellent activity in non-small-cell cancer. When used in sequential chemoradiotherapy regimens, gemcitabine has been associated with response rates of 57% to 68%. A full dose of gemcitabine (1,000 mg/m2) can be safely used as induction therapy, and there is no definitive indication of enhancement of radiotoxicity. In addition, results from phase I/II trials support the efficacy of concurrent gemcitabine/radiation therapy in improving overall response rates and overall survival. Rates of 68%, 37%, and 28%, respectively, for 1-, 2-, and 3-year survival have been reported for gemcitabine/cisplatin chemotherapy administered concurrently with radiotherapy. Although the optimal dose has yet to be determined, a weekly dose of 300 mg/m2 appears to be effective with an acceptable toxicity level. Additional clinical trials are warranted to assess the long-term efficacy and safety of gemcitabine in combination with other chemotherapeutic agents and radiation therapy for treatment of non-small-cell lung cancer.

Antimetabolites, Antineoplastic↗
PubMed2003

The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity.

Increased expression of cyclooxygenase (COX) 2 and the production of PGs appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness and the stimulation of angiogenesis. The purpose of this study was to determine whether an angiogenic antagonist, SU5416, could inhibit endogenous and phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 expression. SU5416 (5 micro M) inhibited endogenous as well as PMA-mediated induction of COX-2 expression when analyzed by immunoblot and Northern blot analysis. However, COX-1 expression remained unchanged under similar conditions. PMA is a potent inducer of reactive oxygen species that can play an important role during the induction of COX-2 expression. Our results demonstrated that PMA-mediated induction of COX-2 expression was found to be dependent on NADPH oxidase activity. An inhibitor of NADPH oxidase (diphenyleneiodonium chloride) blocked the PMA-mediated induction of COX-2 expression. The oxidase complex exhibited a temporal pattern of activation after exposure to PMA in which maximum activation was observed at 30 min after the addition of PMA. Activation of NADPH oxidase was also inhibited by SU5416, whereas an inhibitor of epidermal growth factor receptor signaling was unable to prevent the PMA-mediated induction of NADPH oxidase activity. When we blocked the PMA-mediated production of reactive oxygen species by blocking NADPH oxidase with SU5416, COX-2 expression and PGE(2) synthesis were also inhibited. Our results suggest that inhibition of NADPH oxidase activity, blocking of COX-2 expression, and PGE(2) synthesis may represent novel targets for SU5416.

Angiogenesis Inhibitors↗
PubMed2003

Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.

Animals↗
PubMed2003

Concurrent chemoradiotherapy for inoperable stage III non-small-cell lung cancer.

Chemoradiotherapy has become the standard treatment for patients with locally advanced non-small-cell lung cancer on the basis of several large randomized trials. Despite an increase in median survival from 10 months with radiotherapy alone to 16 to 17 months with concurrent chemoradiotherapy, long-term survival in this disease remains modest at best. With the advent of new biologic agents targeting specific cellular pathways associated with malignant progression, combined-modality therapy has the potential to target tumors selectively with less toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Chemotherapy and irradiation interaction.

The combination of chemotherapeutic drugs with radiation therapy has perhaps been one of the most promising strategies for current cancer radiotherapy practice, and has a strong biologic rationale. Concurrent chemoradiotherapy has been shown to improve survival and locoregional control of various cancers compared with radiotherapy alone. This article reviews the biologic rationale and principles fundamental to the use of chemoradiotherapy, and discusses mechanistic interactions between drugs and radiation, the knowledge of which is essential in developing optimal treatment strategies. Chemotherapeutic agents, particularly those shown to augment the radiation response of tumors, will be reviewed, and novel compounds and some of the exciting emerging strategies for chemoradiotherapy will be presented.

Antineoplastic Agents↗
PubMed2003

Potential radiation-sensitizing effect of semisynthetic epothilone B in human lung cancer cells.

BACKGROUND AND PURPOSE: To evaluate a semisynthetic epothilone B, BMS-247550, as a potential radiosensitizer in vitro and in vivo. MATERIALS AND METHODS: Human NCI-H460 lung cancer cells were treated with either BMS-247550 or paclitaxel and in combination with radiation at multiple doses for different time periods. Surviving fractions were then analyzed using a clonogenic assay. Cell cycle redistribution by BMS-247550 was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-amino-actinomycin D staining with flow cytometry. For in vivo studies, the H460 xenograft model was used in athymic nude mice. Tumors were treated with BMS-247550 (5 mg/kg) i.p. injection on days 0, 2, and 4 and/or radiation (2 Gy/day, days 0-4). RESULTS: The in vitro radiation dose enhancement ratios (DER) of 1-h BMS-247550 and paclitaxel were 2.03 and 1.34, respectively. Treatment with BMS-247550 enhanced the G2/M block and induced apoptosis; whereas in combination with radiation, the induction of apoptosis was additive. BMS-247550 in combination with radiation in vivo enhanced the tumor growth delay when compared with either drug or radiation alone. CONCLUSIONS: These results demonstrated that BMS-247550 could enhance the effects of radiation in human lung cancer cells both in vitro and in vivo and that a G2/M block and increased apoptosis might be possible explanations for the enhancement.

Animals↗
PubMed2003

Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting.

Combined modality therapy represents current standard therapy for locoregionally advanced non-small cell lung cancer. In particular, concomitant chemoradiotherapy has emerged as the preferred approach. At the same time, efforts to increase locoregional and systemic antitumor activity are necessary to further improve long-term survival rates for these patients. In recent years, multiple cellular targets have emerged in the development of novel antitumor therapies. Several of these are of high relevance in the carcinogenesis of lung cancer including the epidermal growth factor receptor (EGFR), the ras signaling pathway, tumor angiogenesis, and cyclooxygenase-2 (COX-2) expression. Novel agents directed against these targets are currently under development with promising early results in non-small cell lung cancer when administered as single agents or in combination with chemotherapy in stage IV or recurrent disease. Similarly their use with concurrent radiation therapy is supported by preclinical models. Selected early clinical trials utilizing these agents in combination with radiotherapy or chemoradiotherapy are discussed.

Alkyl and Aryl Transferases↗
PubMed2003

COX-2 inhibitor as a radiation enhancer: new strategies for the treatment of lung cancer.

Lung cancer is one of the most common causes of cancer-related mortality throughout the world, and the incidence continues to increase. Smoking is the number one cause of lung cancer. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of lung carcinoma. In invasive lung tumors, COX-2 upregulation has been reported in up to 90% of cases. COX-2 upregulation is an early event in the development of non-small-cell lung cancer and may be integral to the development of new blood vessels and production of specific proteases that are critical to growth and spread of lung malignancies. COX-2 inhibitors are known to enhance the chemosensitivity in COX-2 overexpressing lung cancer cell lines. Recently, we have demonstrated that selective COX-2 inhibitors also enhance the effect of radiation in COX-2 overexpressed cells. Therefore, inhibitors of COX-2 in combination with chemoradiation therapy may be an alternative strategy that can be tested in clinical trials. The combination of COX-2 inhibitors and radiation suggest a complementary strategy to target angiogenesis while potentially minimizing the impact on quality of life. Currently, several groups are conducting clinical trials in cervix cancer, lung cancer, and brain tumors, using inhibitors of COX-2 in combination with chemotherapy and radiation therapy. These clinical trials will help to elucidate the role of this interesting class.

Animals↗
PubMed2003

Potential for combined modality therapy of cyclooxygenase inhibitors and radiation.

In conclusion, COX-2 inhibitors have potent anti-tumorigenic activity. Results from animal studies strongly indicate that the likely mechanism for enhanced TGD and TCD50 in tumors treated with radiation and COX-2 inhibitors was the inhibition of angiogenesis. In our recent findings we observed that the antagonists of angiogenesis also inhibited the endogenous as well as phorbol-ester-mediated induction of COX-2 expression in human lung cancer cell lines and that in the xenograft model a combination of angiogenic antagonists and radiation significantly delayed tumor growth [ASCO 2002, Vol. 21 (Part 1); p445a, #1779]. In human tumor models, apoptosis was another mechanism of cell death. Furthermore, it was demonstrated that COX-2 inhibitors could change the intrinsic radiosensitivity of human cancer cells [41]. Therefore, inhibition of angiogenesis by COX-2 inhibitors may be the major mechanism for increased radiation effects in tumors. However, other mechanisms such as changes in tumor perfusion, apoptosis, and an increase in intrinsic radiation sensitivity must also be considered. Inhibitors of COX-2 in combination with radiation therapy may be an alternative strategy that can be tested in clinical trials. The combination of COX-2 inhibitors and radiation suggest a complementary strategy to target angiogenesis while potentially minimizing the impact on quality of life. Currently, the Radiation Therapy Oncology Group [www.rtog.org] is just one of the National Cancer Institute sponsored cooperative groups conducting clinical trials in cervix cancer, lung cancer and brain tumors, using inhibitors of COX-2 in combination with chemotherapy and radiation therapy. These clinical trials will help elucidate the role of this interesting class of agents in combination with cytotoxic therapy for the treatment of cancer.

Angiogenesis Inhibitors↗
PubMed2002

Standards of care for anemia management in oncology: focus on lung carcinoma.

BACKGROUND: Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum-based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally. METHODS: A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment. RESULTS: The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50-60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin-alpha]). Darbepoetin-alpha represents a new generation of erythropoiesis-stimulating proteins. Biochemically distinct from epoetin-alpha, darbepoetin-alpha has a greater sialic acid content and biologic half-life than epoetin-alpha, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer-related anemia have shown that darbepoetin-alpha has a threefold longer half-life than epoetin-alpha, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin-alpha in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting. CONCLUSIONS: Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin-alpha into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer-related anemia.

Anemia↗
PubMed2002

Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an angiogenic factor that acts by binding to specific high-affinity tyrosine kinase receptors. SU5416 is an antiangiogenic agent that acts as a potent and selective inhibitor of the VEGF Flk-1/KDR receptor tyrosine kinase. SU5416 has been shown to inhibit VEGF-dependent mitogenesis of human endothelial cells and to decrease the growth of xenografts of melanoma, lung carcinoma, ovarian carcinoma, and gliomas. The effect of pre- or perioperative use of this drug on angiogenesis and wound healing in the postoperative setting has not been shown. We sought to analyze the efficacy and safety with respect to functional dosing of SU5416 in the setting of wound healing. This represents an important step forward in the use of this and similar drugs in the perioperative setting of treatment for multiple types of cancers. The use of an inhibitor of VEGF receptors such as SU5416 is distinct and it is likely complementary to other agents in the treatment of such cancers. METHODS: We injected 8-week-old male Sprague-Dawley rats with SU5416 (8 or 12 mg/kg) or dimethyl sulfoxide intraperitoneally, daily for 14 days. We then performed a right pulmonary lobectomy and 6-mm full-thickness punch biopsies of the back. Tissue perfusion measured via laser Doppler on Postoperative Day 2 was 1.65, 1.22, and 1.14 perfusion units (P < 0.0004) for control, 8 mg/kg, and 12 mg/kg groups, respectively. RESULTS: We successfully treated a murine model with functional doses of the anti-VEGF drug SU5416 so as to achieve decreased vascularity and blood flow in postoperative wounds. There was no effect on gross wound healing or infection in either control or treatment groups. Also, no drug-related impairment of histologic healing or decrease in wound tensile strength was demonstrated at either 6 or 14 days. CONCLUSION: Preoperative therapy with functional dosing of SU5416 does not appear to have any major effect on postoperative morbidity or mortality in rats. We additionally conclude that preoperative therapy with SU5416 should be investigated further with careful attention to wound integrity.

Angiogenesis Inhibitors↗