Biomedical subjects
Publications and source records attributed to W K Hong.
Once considered a futuristic concept, chemoprevention for pre-malignant oral leukoplakia lesions is now a reality. Oral leukoplakia can proceed to invasive disease and expose the upper aerodigestive tract to carcinoma. Risk factors, diagnosis and research in chemoprevention are discussed.
The protective effects of ascorbic acid (AA), n-acetyl-l-cysteine (NAC), alpha-tocopherol acid (ATA), alpha-tocopherol-acid succinate (TAS), and 13-cis-retinoic acid (CRA) on mutagen-induced chromosomal breakage were studied. Mutagen-sensitivity was determined by the bleomycin assay in human lymphoblastoid cell lines (LCLs) and cultures of peripheral blood lymphocytes (PBLs) from head and neck cancer patients. Preincubation with chemopreventive agents statistically significantly decreased mutagen-induced chromatid breakage in LCLs and PBLs in a dose-related manner. As the concentration of the agents was increased in tenfold increments in the study range, mean breakage rates were reduced by 3.0 to 7.7% in LCLs and by 6.0 to 11.1% in PBLs. The effective concentrations are comparable to those achieved in clinical applications and found in human dietary studies. A similar phenomenon in vivo, if identified, may explain the differences in occurrence of head and neck and other cancers between populations with different dietary habits. The bleomycin assay may be used for studying compounds with presumed chemopreventive properties.
To better understand the relationship between specific chromosome changes found in human lung tumors and their phenotypic consequences at the tissue level, an in situ hybridization procedure was optimized for use on formalin-fixed paraffin-embedded tissue sections of human lung tumors. Pretreatment heating of sections, pepsin concentration, duration of pepsin treatment, hybridization conditions, and posthybridization washing conditions were varied to determine optimum conditions. The deparaffinized sections were stained with centromeric probes for chromosomes 7 and 17, and a chromosome index for each tumor was derived by dividing the mean number of chromosome signals found on the tumor cells by the mean number of chromosome signals on normal cells (lymphocytes and fibroblasts) in the same section. This chromosome index was then compared with the DNA index determined in an adjacent section by Feulgen staining followed by image analysis quantitation. The chromosome index correlated well with the DNA index, but in some cases, chromosome 7, or 17 in other cases, was either over- or under-represented compared with the corresponding DNA index. In addition, chromosome and DNA alterations were shown to be differentially expressed within the same tissue section, correlating with a change in tumor differentiation status. These results suggest that in situ hybridization will prove to be an important tool for determining the underlying genetic basis for tissue phenotype heterogeneity by allowing genetic determinations to be made on paraffin-embedded tissue sections where tumor histological architecture is preserved.
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Bronchial micronuclei, small fragments of extra-nuclear DNA formed during cell division, provide a non-specific but quantifiable marker of DNA damage. Micronuclei have been used to assess carcinogen exposure and as an intermediate endpoint in chemoprevention trials. As part of an ongoing chemoprevention trial, heavy smokers underwent screening bronchoscopy, with biopsies taken at 6 standardized sites. Micronuclei counts were obtained for each site in each of the 40 volunteers found to have squamous metaplasia. Unlike squamous metaplasia, the average micronuclei counts among these heavy smokers were not associated with smoking history. Micronuclei counts were also not associated with the presence or extent of metaplasia. A striking degree of intra-individual variability was observed by comparing the micronuclei counts from different biopsy sites within individuals. The findings suggest that use of micronuclei from single sites may be misleading as a marker of carcinogen exposure or as an estimate of cancer risk. Serial measurements in individuals may provide the most useful information concerning carcinogenic exposure and the impact of chemopreventive agents.
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Renewed interest is being directed toward chemoprevention as a means of reducing cancer mortality. To overcome the inherent problems associated with using cancer development as a study end point, there has recently been a great surge of interest in defining the biomarkers associated with specific stages of the carcinogenic process as intermediate end points. We have detailed the evidence supporting the concept of field cancerization, a concept of general importance that is probably applicable to carcinogenesis and chemoprevention at many organ sites in humans, and presented results of tests of the potentially useful biomarkers proliferating cell nuclear antigen and blood group antigen. Because microassay techniques are more readily applicable to small biopsy samples, further expansion of these studies and exploration of panels of additional biomarkers are expected to generate exciting results in the field of chemoprevention.
The field cancerization hypothesis suggests that carcinogen exposure affects the entire epithelial lining of the lungs and upper aerodigestive tract. The concept that common exposures place the entire epithelium at risk for the development of invasive cancer is supported both by the occurrence of premalignant lesions such as leukoplakia and squamous metaplasia, and by the development of multiple primary tumors within the field. Chemoprevention trials in lung and upper aerodigestive tract cancer have included studies to reverse premalignant lesions and to prevent second primary tumors. Promising results have been reported in both settings using the retinoid 13-cis-retinoid acid. Several clinical trials are in progress which attempt both to reduce cancer incidence and to determine the mechanisms and biological markers of successful chemoprevention.
BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.
BACKGROUND: Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease. PURPOSE: In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease. METHODS: Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher. RESULTS: Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal. CONCLUSION: These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.
Chemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non-specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF-beta, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested an association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer.
Differential screening of a cDNA library was used to isolate genes differentially expressed in a nontumorigenic clone and a ras-transformed variant of the human teratocarcinoma cell line PA-1. The RNA transcript for one of the cDNA clones that we identified was expressed at a 25-fold higher level in the ras-transformed PA-1 cells than in the nontumorigenic PA-1 cells. DNA sequence analysis of this clone showed that it had 86% nucleic acid homology to the mouse LLRep3 gene and only differed at a single amino acid codon (codon 198), which is changed from serine in LLRep3 to threonine in this cDNA clone. The rat ribosomal S2 protein is closely related to the yeast omnipotent informational suppressor SUP44, which encodes the yeast ribosomal protein S4; to the mouse protein LLRep3; and to the human cDNA clone we describe in this report. We therefore concluded that this clone codes for the human ribosomal S2 protein. In situ hybridization experiments revealed that expression of this gene was elevated in cultured human head and neck squamous cell carcinomas compared with normal keratinocytes. In situ hybridization experiments also demonstrated that expression of this gene was elevated in histological sections of human premalignant leukoplakia, head and neck squamous cell carcinomas, and colon and breast cancers compared with the adjacent normal tissues. S2 expression may be a useful diagnostic or prognostic marker for grading human tumors.
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We treated 34 chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer with trimetrexate 150-200 mg/m2 intravenously over 30 minutes every two weeks. Six of 31 evaluable patients (19%) achieved a partial response. The major toxic effects from this regimen were myelosuppression, nausea/vomiting, and skin rash. We conclude that this well-tolerated schedule of trimetrexate has significant activity as a single agent against non-small cell lung cancer.
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The anticlastogenic effects of 13-cis-retinoic acid were studied in four human lymphoblastoid cell lines and in primary lymphocyte cultures derived from the peripheral blood of 11 study subjects. Cells were pre-incubated with 13-cis-retinoic acid in the concentration range of 10(-8)-10(-5) mol/l for 24 h and the numbers of chromatid breaks per cell induced by bleomycin were determined. The presence of 13-cis-retinoic acid decreased the number of breaks per cell by 13.0 to 59.5% in lymphoblastoid cell lines and by 0 to 57.4% in primary lymphocyte cultures (in the concentration ranges of 10(-8)-10(-6) mol/l and of 10(-8)-10(-5) mol/l, respectively). Regression analysis showed that there was a statistically significant correlation between the presence of 13-cis-retinoic acid and protection against bleomycin-induced clastogenicity. These data give additional information to the knowledge of possible chemopreventive mechanisms of action of 13-cis-retinoic acid.
Forty-six patients with metastatic non-small-cell lung cancer (NSCLC) were treated with a combination of high-dose cisplatin, etoposide, and mitomycin. Thirty-four patients (74%) had a performance status of 1, and 39 patients (85%) had adenocarcinoma. Of the 42 patients evaluable for response and toxicity, four achieved a partial response (10%); no patient achieved a complete response. Seven patients who had received prior chemotherapy showed no major response. The median survival of all 42 patients was 23 weeks. Myelosuppression was the major dose-limiting toxicity for this regimen, and 12 of 46 patients (26%) developed neutropenic fever requiring hospitalization and parenteral antibiotics. Of the 12 patients with severe neutropenic fever, one patient died because of toxicity. Nonhematologic toxicities, including azotemia, peripheral neuropathy, nausea, vomiting, and hearing loss were transient and modest. We conclude that high-dose cisplatin combined with etoposide and mitomycin is a relatively toxic regimen with a low response rate. Further evaluation of the combination as given in this trial is not warranted.