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Biomedical subjects

W K Hong

Publications and source records attributed to W K Hong.

At least 253 records · Page 14Linked to original sources
PubMed1994

Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852.

PURPOSE: Tumor tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) and localization of anti-EGFR monoclonal antibody RG 83852 were studied in patients with non-small-cell lung cancer (NSCLC) and head and neck cancer. PATIENTS AND METHODS: Fifteen patients were treated with escalating doses of RG 83852 by continuous intravenous infusion for 5 days. Fresh tumor specimens were obtained 24 hours after therapy in 10 patients (of whom five had a pretherapy sample taken). Tumor EGFR tyrosine kinase activity was determined in fresh tumor samples by autophosphorylation of EGFR isolated in immunocomplexes with RG 83852. Tumor EGFR saturation with RG 83852 was assessed semiquantitatively by comparing the EGFR tyrosine kinase activity in immunocomplexes of tumor specimens obtained after therapy with total EGFR tyrosine kinase activity assessed by exogenous addition of RG 83852 to tumor lysates. Modulation of EGFR tyrosine kinase activity after the administration of RG 83852 was assessed by comparing EGFR tyrosine kinase activity from the same malignant lesion obtained before and after therapy. Tumor localization of RG 83852 and EGFR saturation were also assessed by immunohistochemistry. RESULTS: No significant side effects were observed up to a total dose of 600 mg/m2. Based on tyrosine kinase activity, a high degree of EGFR saturation (> or = 50%) was observed at doses > or = 200 mg/m2, and EGFR saturation was estimated to be 100% at a dose level of 600 mg/m2 both in tumor tissue and skin used as surrogate EGFR-positive tissue. Immunohistochemistry studies showed that RG 83852 localized in tumor tissue and skin, but not in stroma, at doses > or = 400 mg/m2, and high EGFR saturation was observed at 600 mg/m2. Tumor EGFR tyrosine kinase activity was studied in five patients (four with EGFR-positive tumors) before and 24 hours post-therapy; a threefold to fourfold upregulation of EGFR tyrosine kinase activity in posttherapy specimens was observed in two patients. Moderate upregulation of EGFR itself was suggested in both of these patients and in two additional patients by immunohistochemistry. CONCLUSION: RG 83852 causes no toxic effects at doses that result in high tumor EGFR saturation. Treatment with RG 83852 may enhance EGFR tyrosine kinase activity and/or EGFR expression. Because high EGFR expression by tumors has been associated with increased sensitivity to cytotoxic therapy, the suggestion of antibody-mediated upregulation of EGFR by agents such as RG 83852 may prove useful in enhancing chemotherapeutic efficacy.

Antibodies, Monoclonal↗
PubMed1994

Cancer chemoprevention.

PURPOSE: To review the most important recent advances in clinical trials and biologic studies within the growing field of chemoprevention. METHODS: The most critical methods issue concerns the definitive end point of phase III trials, which is now cancer incidence. This end point usually needs thousands of subjects monitored for 5 to 10 or more years to determine efficacy. Biologic markers of potential intermediate end points are under intensive study and may one day replace cancer incidence. Validated intermediate end point biomarkers could greatly reduce phase III trial populations, durations, and costs. RESULTS: Randomized clinical trials over the last 5 years have produced significant activity in reversing oral, skin, colon, and cervical premalignancy; in preventing primary skin and stomach cancer; and in preventing second primary tumors associated with head and neck and lung cancer. These clinical advances have been paralleled at the basic science level by elegant molecular studies of premalignant carcinogenesis and of chemopreventive agents' mechanisms of action. One major laboratory advance is the discovery of nuclear retinoic acid receptors and strong evidence of their roles both in carcinogenic progression and in its response to retinoids. CONCLUSION: Chemoprevention has matured greatly in recent years with the significant reversal or suppression of premalignancy by chemopreventive agents in several sites. The future of chemoprevention will be determined largely by several ongoing phase III trials, including trials of retinoids, beta-carotene, and alpha-tocopherol in the aerodigestive tract, of tamoxifen and fenretinide in the breast, and of finasteride in the prostate.

Anticarcinogenic Agents↗
PubMed1994

Biomarkers in chemoprevention for upper aerodigestive tract tumors.

A chemopreventive approach to cancers of the upper aerodigestive tract (including those of head and neck and lung) to reduce the incidence and mortality rates for these cancers has become an important strategy because therapies such as surgery, radiation, and chemotherapy have only marginally improved the five-year survival rate over the last two decades. However, chemopreventive trials have been hampered by serious feasibility problems, including high cost, the requirement of large numbers of patients, and long-term follow-up necessary to determine cancer incidence, which served as the study end point. Thus, the use of biomarkers, the identification of which would serve as an intermediate end point of the study has recently emerged as a subject of great interest. To try to understand the process of tumorigenesis from normal tissues through the premalignant tissue stage to malignant lesions, there has recently been a search for genetic and/or phenotypic changes that qualify as candidates for biomarkers. These candidates include genomic markers, certain specific genetic markers (such as oncogenes, growth factors and their receptors, and tumor suppressor genes), cell proliferation markers, and cell differentiation markers. This review covers genomic markers (including micronuclei and specific chromosomal alterations) and specific genetic markers (such as the ras gene family, the myc family, erb B1, int-2/hst-1, and the p53 tumor suppressor gene). As a consequence of genetic alteration, we also reviewed cell proliferation markers such as proliferating cell nuclei antigen (PCNA) and the squamous cell differentiations markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates are important adjuncts to the development of the new chemopreventive agents and to the rational design of future intervention trials. However, it should be emphasized that these biomarkers must first be validated in clinical trials; only then can they replace cancer incidence as the sole end point in chemoprevention trials.

Biomarkers, Tumor↗
PubMed1994

Evolution of aerodigestive tract 13-cis-retinoid acid chemoprevention: the M.D. Anderson experience.

The ultimate goal of our chemoprevention research is to prevent or inhibit the development of aerodigestive cancer in humans. We have made substantial progress from our trials 10 years ago. The chemopreventive strategies utilized in our clinical trials involve the use of retinoids and carotenoids as chemopreventive agents. The choice of these agents was based upon their important anticarcinogenic and differentiation properties. It is important to understand how retinoids interact with cells to carry out their modulating activities, and we hope to increase our understanding through molecular analysis of retinoid receptors. In the case of aerodigestive epithelial tissues at risk, normal, non-keratinizing epithelial cells often express inappropriate squamous differentiation. Retinoids are thought to suppress premalignant lesions by suppressing these inappropriate squamous differentiation pathways. The role of retinoids in suppressing squamous differentiation markers and reversing premalignant lesions will be elucidated from this retinoid project. The development of a fundamental understanding of tumorigenesis in the aerodigestive tract can lead to novel preventive approaches. A relative degree of risk for cancer development in individuals depends on several components, including the extent of carcinogenic exposure, inherent sensitivity of the individual to carcinogens, the individual's nutritional status, etc. Individuals with a genetic component of increased carcinogen sensitivity appear to be at increased risk for developing primary and secondary tumors. Our chemoprevention research program is designed to develop innovative strategies for aerodigestive tract epithelial cancer prevention. The strength of our program is to bridge the gap between fundamental and cellular molecular studies in clinical chemoprevention trials. The outcome of our research efforts may have an enormous impact on public health in controlling aerodigestive epithelial cancers and other epithelial cancers as well.

Antineoplastic Agents↗
PubMed1994

Combination 13-cis-retinoic acid and interferon alpha-2a in the therapy of solid tumors.

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two nonsquamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high liklihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Retinoid chemoprevention of second primary tumors.

Retinoids, natural or synthetic derivatives of vitamin A, have been studied as cancer chemopreventive agents and as therapeutic agents in the treatment of solid tumors. Intensive clinical research has focused on the role of retinoids in preventing second primary tumors following head and neck or lung cancer. The frequent occurrence of second primary tumors in these areas provides clinical support for the hypothesis of field carcinogenesis. Based on evidence of its efficacy in reversing oral premalignancy, the synthetic retinoid 13-cis-retinoic acid (13cRA) was studied in a 1-year trial to prevent the incidence of new cancers in patients who had been treated for squamous cell carcinoma (SCC) of the head and neck. Second primary tumors developed in only 4% of 49 patients treated with 13cRA, as compared with 24% of 51 patients treated with placebo (P = .005). These findings have led to two ongoing large-scale trials of 13cRA in North America. One study, performed through the M.D. Anderson Cancer Center and its affiliated Community Clinical Oncology Program and the institutions of the Radiation Therapy Oncology Group (RTOG), will determine whether long-term administration of low-dose 13cRA will prevent second primary tumors following an initial head and neck cancer. Another intergroup study using a similar randomized double-blind design is being performed among patients who have undergone resection of a stage I non-small-cell lung cancer. In Europe, a large chemoprevention study called Euroscan is currently examining the efficacy of another retinoid, retinyl palmitate, in preventing second primary tumors following head and neck or lung cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Head and Neck Neoplasms↗
PubMed1994

Retinoic acid and interferon in human cancer: mechanistic and clinical studies.

Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid-tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction.

2',5'-Oligoadenylate Synthetase↗
PubMed1994

Biomarkers in upper aerodigestive tract tumorigenesis: a review.

Because therapeutic efforts such as surgery, radiotherapy, and chemotherapy have only marginally improved the 5-year survival rate from cancers of the upper aerodigestive tract (including head and neck and lung cancers) over the past 2 decades, chemoprevention has become an important strategy in reducing the rates of incidence and mortality of these cancers. However, chemoprevention trials have been hampered by serious feasibility problems; they require large numbers of subjects and long-term follow-up for accurate determination of cancer incidence and they are very costly. Because the use of intermediate end points would reduce the duration and costs of these studies, biomarkers that could serve as such end points have recently become a subject of great interest. With the strengthening of the assumption that tumorigenesis is a multistep process of transformation from normal tissues to malignant lesions, there has been a great effort to examine each of these steps for genetic and/or phenotypic alterations that might be candidates for such biomarkers. These candidates include genomic markers, certain specific gene alterations, such as tumor suppressor genes, oncogenes, growth factors and their receptors, proliferation markers, and differentiation markers. In this review, we describe several genomic markers, including micronuclei, chromosomal alterations, and specific genetic markers, e.g., the ras gene family, erb B1, int-2/hst-1, and p53 tumor suppressor gene. We also review the proliferation markers, including proliferating cell nuclear antigen, and squamous cell differentiation markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates have the potential to be important adjuncts to the development of new chemopreventive agents and to the rational design of future intervention trials. However, we can not overemphasize that these markers need to be validated in clinical trials; only then can they replace cancer incidence as the sole end point for chemoprevention trials.

Biomarkers↗
PubMed1994

Combination 13-cis-retinoic acid and interferon alpha-2a in the therapy of solid tumors.

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two non-squamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high likelihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Carcinoma, Squamous Cell↗
PubMed1993

Chemoprevention. Strategies for the control of cancer.

High incidence and low survival rates of many epithelial cancers remain beyond the control of established preventive and therapeutic modalities. Chemoprevention is a new approach under study that involves the intervention within the premalignant process with specific chemical agents to reverse carcinogenesis and prevent the development of invasive cancer. The two biologic concepts that underlie this research are multistep carcinogenesis and field carcinogenesis. Major clinical issues include trial design and drug development in head and neck, lung, and breast cancer chemoprevention. Within the area of trial design, intermediate end point biomarkers will become very important for providing biologic insights in the short term and greater trial efficiencies in the long term. Drugs that are under the strongest investigation include retinoids and beta-carotene in the head and neck and lung, calcium in the colon, and tamoxifen in the breast. This new field has the potential to make an important contribution toward increasing our control over many deadly epithelial cancers Cancer 1993; 72:984-90.

Antineoplastic Agents↗
PubMed1993

Sequential increases in proliferating cell nuclear antigen expression in head and neck tumorigenesis: a potential biomarker.

BACKGROUND: Proliferating cell nuclear antigen (PCNA) is a 36-kd nuclear protein whose expression is associated with DNA synthesis and cell proliferation. Tumorigenesis in head and neck squamous cell carcinoma is proposed to be a multistep process; dysregulation of proliferation is a potential marker of this process. PURPOSE: PCNA dysregulation was analyzed in squamous cell carcinoma tissue samples containing premalignant lesions (hyperplasia and/or dysplasia) and in adjacent normal epithelium to better understand proliferative changes during head and neck tumor development. METHODS: Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded sections by using a monoclonal anti-PCNA antibody. PCNA expression was analyzed in 33 head and neck squamous cell carcinomas and in their adjacent premalignant lesions from different sites and compared with that in the control samples, which had never been exposed to first-hand tobacco smoke. PCNA expression was assessed by semiquantitative scoring (scale 0-3) in three epithelial layers (basal, parabasal, and superficial). The labeling index and the weighted mean index of PCNA expression were calculated. RESULTS: Normal epithelium adjacent to the tumor had much more proliferative activity than the controls: The weighted mean index of PCNA expression was four-fold higher in the basal layer and sixfold higher in the parabasal layer. PCNA expression increased as tissues progressed from adjacent normal epithelium to hyperplasia (P < .001), hyperplasia to dysplasia (P < .001), and dysplasia to squamous cell carcinoma (P = .065); the total increase in PCNA expression ranged from fourfold to 10-fold from adjacent normal epithelium to squamous cell carcinoma. PCNA expression was higher in the parabasal than in the basal layer at all premalignant stages (23 of 25 samples in adjacent normal epithelium, 12 of 13 in hyperplasia, and 17 of 22 in dysplasia). As the tissue progressed from normal through premalignant stages to squamous cell carcinomas, we observed not only incremental increases in the labeling index, but also incremental increases in PCNA expression per labeled cells. CONCLUSIONS: These results indicate that PCNA could be a useful biomarker for multistep carcinogenesis in head and neck cancer and may serve as an intermediate end point in chemopreventive trials.

Antigens, Neoplasm↗
PubMed1993

Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis.

Head and neck cancer development has been proposed to represent a multistage process characterized by dysregulation of proliferation and differentiation and driven by an accumulation of genetic alterations in an anatomic field repeatedly exposed to carcinogens. To visualize the accumulation of genetic alterations during head and neck tumorigeneses and to determine the extent of the genetically altered field, we probed 25 squamous cell carcinomas of the head and neck and their adjacent premalignant lesions for numerical chromosome aberrations by nonisotopic, in situ hybridization using chromosome-specific centromeric DNA probes for chromosomes 7 and 17. Normal control oral epithelium from individuals free of cancer showed no chromosome polysomy (i.e., cells with > or = 3 chromosome copies), whereas histologically normal epithelium adjacent to the tumors showed squamous cells with polysomies for chromosomes 7 and 17. Moreover, the frequency of cells with polysomy increased as the tissues passed from histologically normal epithelium to hyperplasia to dysplasia to cancer. The finding of genotypic abnormalities in histologically normal and precancerous regions adjacent to the tumor supports the concept of field cancerization. The finding of progressive genetic changes as the tumor develops supports the concept of multistep carcinogenesis in the head and neck region. Such genotypic parameters could serve as biomarkers in the assessment of the risk of progression to malignancy and as intermediate end points in chemoprevention trials.

Adult↗
PubMed1993

Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract.

Patients with primary head and neck malignancies have a 3-7% yearly incidence of second primary cancers. It is thought that these second primary cancers arise independently following exposure to a common carcinogen by a process that has been called field cancerization. Since mutations in the p53 tumor suppressor gene represent a genetic alteration occurring during the evolution of premalignant lesions to malignancies of the upper aerodigestive tract, we analyzed mutations in the p53 gene of patients with cancer of the head and neck who developed second primary tumors of the upper aerodigestive tract epithelium to test the field cancerization hypothesis. DNA was extracted from primary head and neck cancers and second primary cancers of 31 patients. DNA from exons 5-8 of the p53 gene was analyzed by the single strand conformation polymorphism technique to identify the locations of the mutations in different regions of the gene. DNA from 6 patients was also sequenced by the chain termination method to confirm the presence of mutations and determine the base substitutions. Twenty-one of the 31 patients had 1 or more p53 mutations. In all 21 cases the genetic lesions were discordant such that the presence or location of the mutations in the initial primary cancer differed from those of the second and third primary cancers. In each of the five patients with mutations in both primary tumors, the mutations occurred in different regions of the p53 gene. Of the other 16 patients, 8 had a p53 mutation in the first primary but not the subsequent primary cancer and the other 8 had no mutation in the initial primary but did have a mutation in subsequent primary cancers. Sequencing confirmed the single strand conformation polymorphism analysis and showed that 73% of the mutations were transitions. The discordant p53 mutations in second primary cancers arising in patients with primary epithelial cancer of the upper aerodigestive tract suggest that these cancers arise as independent events. These observations provide the first demonstration of a molecular basis for field cancerization effects in cancers of the upper aerodigestive tract.

Adult↗