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Biomedical subjects

S M Lippman

Publications and source records attributed to S M Lippman.

At least 109 records · Page 6Linked to original sources
PubMed1997

Accumulation of p53 protein and retinoic acid receptor beta in retinoid chemoprevention.

Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.

Adult↗
PubMed1996

Telomerase activity in head and neck squamous cell carcinoma and adjacent tissues.

The primary function of telomerase is the synthesis of telomeric DNA, which is the main pathway by which telomere length is maintained in the human germline and stem cells. Activation of telomerase is associated with elongation of telomeres and cell immortalization. Recently, telomerase activity has been detected in tissues from many human cancers but not in the majority of normal tissues, suggesting that telomere stabilization and telomerase activation may play a role in tumorigenesis. To explore telomerase activity in head and neck neoplastic and preneoplastic tissues, we studied 16 head and neck squamous cell carcinoma (HNSCC) cell lines and 60 specimens from 29 patients with HNSCC for telomerase activity. We precisely compared telomerase activity with histological features in adjacent tissue sections. We detected telomerase activity in 16 of 16 (100%) HNSCC cell lines, 26 of 29 (90%) invasive tumors, 7 of 7 (100%) dysplastic lesions, and 5 of 5 (100%) hyperplastic lesions, whereas 0 of 17 normal tissues or 2 hyperkeratotic lesions had detectable telomerase activity. Our data indicate that activation of telomerase activity is frequent in HNSCC and may occur early in the tumorigenesis process. The reactivation of telomerase may be a useful marker for cancer risk assessment in the oral cavity.

Aged↗
PubMed1996

Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma? Results of treatment in the era of computerized tomography.

PURPOSE: To assess the outcomes of patients with nasopharyngeal carcinoma (NPC) whose treatment was determined by computerized tomography (CT) and/or magnetic resonance imaging staging and to analyze the impact of induction chemotherapy and accelerated fractionated radiotherapy. METHODS AND MATERIALS: The analysis is based on 122 of 143 previously untreated patients with NPC treated with radiation therapy at The University of Texas M. D. Anderson Cancer Center between 1983 and 1992. Excluded were 4 patients treated with palliative intent, 4 children, 12 patients not staged with CT, and 1 patient who died of a cerebrovascular accident prior to completion of treatment. The stage distribution was as follows: AJCC Stage I-2, Stage II-7, Stage III-12, Stage IV-101; Tl-15, T2-33, T3-22, T4-52; N0-32, N1-10, N2-47, N3-32, Nx-1. Fifty-nine (48%) patients had squamous cell carcinoma; 63 (52%) had lymphoepitheliomas, undifferentiated NPC or poorly differentiated carcinoma, NOS (UNPC). Sixty-seven patients (65 with Stage IV disease) received induction chemotherapy. Fifty-eight patients (24 of whom had induction chemotherapy) were treated with the concomitant boost fractionation schedule. The median follow-up for surviving patients was 57 months. RESULTS: The overall actuarial 2- and 5-year survival rates were 78 and 68%, respectively. Forty-nine patients (40%) had disease recurrence. Thirty-three (27%) had local regional failures; 19 at the primary site only, 8 in the neck and 6 in both. Local failure occurred in 31% of patients staged T4 compared to 13% of T1-T3 (p = 0.007). Sixteen patients failed at distant sites alone. Among Stage IV patients the 5-year actuarial rates for patients who did and did not receive induction chemotherapy were as follows: overall survival: 68 vs. 56% (p = 0.02), freedom from relapse: 64 vs. 37% (p = 0.01), and local control: 86 vs. 56% (p = 0.009). The actuarial 5-year distant failure rate in patients with UNPC who were treated with induction chemotherapy and controlled in the primary and neck was 13%. In patients who did not receive chemotherapy, the actuarial 5-year local control rates for patients treated with concomitant boost or conventional fractionation were 66 and 67%, respectively. CONCLUSIONS: While not providing conclusive evidence, this single institution experience suggests that neoadjuvant chemotherapy for Stage IV NPC patients improves both survival and disease control. Recurrence within the irradiated volume was the most prevalent mode of failure and future studies will evaluate regimens to enhance local regional control.

Adolescent↗
PubMed1996

p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma.

BACKGROUND: The survival rate for head and neck squamous cell carcinoma remains poor despite therapeutic advances over the last two decades. For patients with disease confined to the head and neck, there are two major and biologically distinct patterns of treatment failures after definitive therapy: recurrence of primary disease and development of second primary tumors. Understanding the biological basis of patterns of treatment failure after definitive therapy is needed to guide the development of adjuvant treatment and strategies to prevent second primary tumors. PURPOSE: To determine whether expression of the p53 protein has prognostic significance and/or is associated with patterns of treatment failure, we examined protein expression in primary tumor specimens of patients with head and neck squamous cell carcinoma. METHODS: Immunohistochemical analysis with a monoclonal antibody (DO7) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 69 head and neck cancer patients treated with definitive local therapy (surgery and/or radiotherapy) between January 1980 and October 1983 at The University of Texas M. D. Anderson Cancer Center. We quantitated p53 protein expression and assessed its association with duration of patient survival, patterns of treatment failure (recurrence of primary tumor and development of second primary tumor), and other clinical parameters. All reported P values resulted from two-sided statistical tests. RESULTS: We found detectable levels of p53 protein expression in the tumor cell nuclei of 41 of 69 patients. Thirty-six (52%) of 69 patients whose tumors exhibited p53 protein expression in greater than or equal to 10% of the cell nuclei were grouped as p53 positive, and 33 (48%) of 69 patients whose tumors exhibited less than 10% nuclear expression were groups as p53 negative. The clinical characteristics of the patients in the p53-positive, and p53-negative groups were well balanced. Overall survival was significantly lower, and the times to tumor recurrence, to second primary tumors, and to any treatment failure were significantly shorter in the p53-positive group that in the p53-negative group (P=.0002, P=.047, P=.003, and P=.0009, respectively), mainly because the p53 positivity was associated with earlier development of tumor recurrence and second primary tumors. The rate of second primary tumor development per person per year was also significantly higher in the p53-positive group that in the p53-negative group. By use of multivariate analysis according to the Cox regression model, p53 expression status was identified as the most significant predictor of overall survival duration (P=.007), time to tumor recurrence (P=.053), time to second primary tumors (P=.035), and time to any treatment failure (P=.004). CONCLUSIONS: The expression of p53 protein in primary head and neck squamous cell carcinoma was significantly predictive of shorter survival because of its association with earlier development of both tumor recurrence and second primary tumors. Thus, p53 expression may be a valuable marker for identifying individuals at high risk of developing a recurrence of primary disease and second primary tumors who may benefit from adjuvant therapy and chemoprevention after definitive local therapy.

Adult↗
PubMed1996

Olfactory neuroblastoma and neuroendocrine carcinoma of the anterior skull base: treatment results at the m.d. Anderson cancer center.

Updated information on the pathologic characterization and treatment of olfactory neurobiastoma (ON) and neuroendocrine carcinoma (NEC) diseases is presented. A series of patients with ON or NEC was evaluated and retrospectively staged using the UCLA system. The parameters evaluated were symptoms, age, sex, risk factor assessment, stage of disease, treatment, and clinical outcome. The median follow-up was 3 years (range, 18 months to 23 years). The predominant therapy (63%) for ON was combined surgery and radiotherapy. Surgery alone or in combination with ancillary treatment was used in 58% of patients with NEC. For the most receat years of the study, patients with NEC have been treated successfully with combined chemotherapy and radiotherapy. Seventy percent of the patients with ON and 75% of the patients with NEC were clinically free of disease during the defined follow-up period. Surgical therapy consisting of a craniofacial resection combined with postoperative radiotherapy has resulted in good local and long-term control of ON. Our experience indicates that combined chemoradiation is an appropriate therapeutic approach for NEC.

Journal Article↗
PubMed1996

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors.

BACKGROUND: Paclitaxel is a novel agent with significant activity in several solid tumors. Preclinical data suggested that methotrexate prior to paclitaxel would be synergistic. To determine the qualitative and quantitative toxicity of this regimen we performed a phase I study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more than two prior chemotherapy regimens were given methotrexate intravenously on day 1, followed by paclitaxel, as a 24-hour infusion on day 2. The starting dose (level '0') was 40 mg/m2 for methotrexate and 135 mg/m2 for paclitaxel. RESULTS: After achieving a maximum tolerated dose, additional patients were enrolled with the addition of G-CSF 5 mu g/kg/d on days 4-13. At the starting dose level, dose-limiting toxicity consisting of neutropenic fever occurred in 3 of 4 patients. At dose level -1, methotrexate 30 mg/m2 and paclitaxel 110 mg/m2, neutropenic fever occurred in 7 of 10 patients during the first course. At dose level -2, methotrexate 23 mg/m2 and paclitaxel 85 mg/m2, neutropenic fever occurred in 1 of 7 patients. To abrogate the neutropenia we explored the same combination with the addition of G-CSF. Neutropenic fever remained the only dose-limiting toxicity. At dose level '0' with G-CSF, 1 of 7 patients developed dose-limiting toxicity. At dose level 1 plus G-CSF, methotrexate 40 mg/m2 and paclitaxel 170 mg/m2, dose-limiting neutropenic fever occurred in 4 of 6 patients. Partial responses occurred in 4 of 41 patients entered on this study. Pharmacokinetic data suggested that methotrexate did not increase paclitaxel levels. CONCLUSION: The combination of methotrexate and paclitaxel is feasible, but neutropenic fever, even with the addition of G-CSF prevents further escalations of paclitaxel beyond 135 mg/m2 following methotrexate.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

A phase II study of ifosfamide in recurrent squamous cell carcinoma of the head and neck.

Chemotherapy has not significantly altered the overall survival of patients with recurrent squamous cell carcinoma of the head and neck; therefore, the development of new agents is essential. The purpose of the current phase II study was to define the efficacy of ifosfamide in the treatment of recurrent squamous cell carcinoma of the head and neck. All patients were required to have squamous cell carcinoma of the head and neck that had recurred following surgery or radiotherapy or both. Patients may have received prior chemotherapy. Patients were initially treated with ifosfamide 2 g/m2/day for 4 days (dose level 0). Dose level-1 was 2 g/m2/day for 3 days, and dose level-2 was 2 g/m2/day for 2 days. All patients received mesna 400 mg/m2/day prior to and 1,200 mg/m2/day as a continuous infusion after ifosfamide. Thirty-eight patients were enrolled in the study. Five patients were inevaluable for toxicity or response. Overall, the regimen was well tolerated, with grade 4 granulocytopenia the only significant toxicity occurring in 16 patients. Overall, eight of 31 evaluable patients (25.8%) had a major response. Only one of the 10 patients (10%) with prior chemotherapy responded, but seven of the 21 patients (33.3%) with no prior chemotherapy had major responses. Ifosfamide is an active agent in recurrent squamous cell carcinoma of the head and neck. Further studies of ifosfamide in combination with other agents, particularly as induction therapy in patients with locally advanced disease, are warranted.

Adult↗
PubMed1996

Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy.

PURPOSE: This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC with measurable disease in nonradiated fields were eligible. Other eligibility criteria were Zubrod performance status (PS) < or = 2 and adequate renal and liver function. TPT was administered at a dose of 1.5 mg/m2/d for 5 days over 30 minutes every 21 days. Of 48 registered patients, 40 were fully assessable. Nineteen patients had adenocarcinoma (AD), 14 squamous carcinoma (SCC), and seven poorly differentiated carcinoma. RESULTS: Six patients (15%) achieved a partial remission (PR) (durations: 8, 14, 18, 28, 56, and 61 weeks) and four patients a minor response; 10 patients had stable disease and 20 patients progressive disease. The PR rate was 36% (five of 14 patients) in patients with SCC versus 4% (one of 26 patients) in those with other histologies (P = .014). The overall median survival time was 38 weeks and 30% of patients were alive at 1 year. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 76% and 10% of courses administered, respectively. No grade 3 to 4 nonhematologic toxicities were observed. Grade 1 or 2 nonhematologic toxicities consisted of nausea (46% and 5%), vomiting (31% and 7%), and fatigue (53% and 16%). CONCLUSION: TPT at the dose and schedule used has moderate antitumor activity in NSCLC; its activity is mostly limited to patients with SCC. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.

Adenocarcinoma↗
PubMed1996

Detection of chromosome instability of tissue fields at risk: in situ hybridization.

Many human tumors are thought to develop along a multistep pathway in tissues that have encountered long periods of carcinogen exposure and thus have accumulated genetic hits in functional targets relevant to tumor evolution. The cumulative degree of genetic change is dependent on both exogenous (e.g., degree of carcinogen exposure) and endogenous factors (e.g., metabolism of procarcinogens, repair or misrepair capacity, proliferation properties of the tissue, capability of damaged cells to survive). Thus one approach to risk estimation is to measure the accumulated amount of genetic damage in a target tissue at risk for tumor development. Since one cannot predict the exact site of the future tumor, the risk assay must detect a generalized ongoing process of genetic instability from small, random biopsies. The technique of chromosome in situ hybridization involves the use of chromosome- or region-specific probes and provides an ability to directly visualize genetic change (e.g., random or clonal chromosome polysomy and monosomy) on thin tissue sections (where tissue architecture is maintained) or exfoliated cells. Analyses of normal and premalignant lesions adjacent to tumors (e.g., head and neck, lung, bladder, cervix, breast) have demonstrated that chromosome instability can be detected in the field of the tumor (i.e., in normal and premalignant cells in a tissue at 100% risk of tumor development) and the degree of chromosome instability increases with the degree of histologic progression toward cancer. Analyses of premalignant lesions (e.g., oral leukoplakia and erythroplakia from individuals at risk for aerodigestive tract cancer) by chromosome in situ hybridization have uncovered varying degrees of chromosome instability. However, approximately half of those individuals who showed a high degree of chromosome instability in biopsies subsequently developed aerodigestive tract cancer. Of interest, half of these tumors have developed away from the biopsied site, suggesting that the detection of a chromosome instability process in one aspect of the tissue might yield risk information for the total tissue field. These studies also suggest that chromosome in situ hybridization might be useful for identifying individuals with high tumor risk who might benefit from chemopreventive intervention.

Bronchi↗
PubMed1996

Retinoids and interferons in non-melanoma skin cancer.

Retinoids alone and in combination with interferon-alpha are the best systemic agents to study in the reversal of skin carcinogenesis and in the treatment of advanced squamous cell carcinoma of the skin. This article reviews the major laboratory advances in the mechanistic study of retinoids and interferons alone and in combination. Recent data in several cancer cell lines suggest that retinoic acid can potentiate the interferon signal-transduction pathway. Also reviewed is the current status of clinical studies of systemic retinoids and interferon in (i) skin cancer prevention (as single agents) and (ii) treatment of advanced squamous cell carcinoma (as single agents and in combination). Future clinical studies with translational laboratory correlates are necessary to determine the roles of retinoids and interferons in the prevention and treatment of skin cancer.

Animals↗
PubMed1996

Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium.

Epidermal growth factor receptor (EGFr) is expressed in human bronchial epithelial cells, and non-small cell lung cancers express increased EGFr. Squamous metaplasia of the bronchial epithelium occurs in chronic smokers and is considered an early premalignant change. In this study, EGFr expression was examined in biopsies of histologically normal and metaplastic bronchial tissues obtained from 69 smokers who were enrolled in a randomized placebo-controlled chemoprevention trial. This trial tested the effects of 6 months of treatment with 13-cis retinoic acid (13cRA) on bronchial metaplasia. EGFr expression was examined as a marker of bronchial metaplasia and response to 13cRA treatment. In bronchial biopsies obtained from patients in this study, EGFr expression was higher in metaplastic biopsies than in normal biopsies (P = 0.02). Smoking cessation during treatment correlated with reduced metaplasia (P < 0.001) and EGFr expression (P = 0.02), but multivariate analysis suggested that this effect of smoking cessation on EGFr expression was dependent upon reversal of bronchial metaplasia. 13cRA treatment did not alter EGFr expression (P = 0.23). Baseline EGFr expression levels in metaplastic biopsies did not predict metaplasia reversal. This study demonstrated that increased EGFr expression is a biomarker of bronchial metaplasia, but it did not support the hypothesis that EGFr is a biomarker of retinoid response in lung cancer chemoprevention trials.

Analysis of Variance↗
PubMed1996

Phase I trial of 9-cis retinoic acid in adults with solid tumors.

Retinoids have been shown to be potent inhibitors of epithelial carcinogenesis. Recent evidence has demonstrated that retinoid actions are mediated through nuclear receptors, which are proteins encoded by the retinoic acid receptor and retinoid X receptor gene families. These receptors are activated by binding to specific retinoids; of the known naturally occurring retinoids, 9-cis retinoic acid is unique in its ability to bind to both receptor families. Because of its unique receptor-binding characteristics, 9-cis retinoic acid may have biological activity not possible with other retinoids. For this reason, we conducted a Phase I trial of 9-cis retinoic acid in adult patients with solid tumors. Twenty-two patients were treated twice daily with p.o. 9-cis retinoic acid at doses ranging from 20 mg/m2/day to 150 mg/m2/day. The patients had non-small cell lung cancer (n = 8), breast cancer (n = 5), colorectal cancer (n = 3), head and neck cancer (n = 2), nonmelanoma skin cancer (n = 2), or ovarian cancer (n = 2). The dose-limiting (WHO grade III) toxic effects, which occurred at the 150-mg/m2/day dose level, were headaches and diarrhea. Less severe (grades I and II) toxic effects included cheilitis, dry skin, conjunctivitis, fatigue, hypertriglyceridemia, alkaline phosphatase elevation, myalgia/arthralgia, and hypercalcemia. Of the 15 patients evaluable for tumor response, no objective responses were observed. Pharmacokinetic analysis revealed a reduction in peak 9-cis retinoic acid plasma levels with chronic administration. Based on this study, the recommended Phase II dose of 9-cis retinoic acid in adult patients with solid tumors is 100 mg/m2/day administered in a divided dose twice daily.

Adult↗
PubMed1995

Anti-retinoic acid (RA) antibody binding to human premalignant oral lesions, which occurs less frequently than binding to normal tissue, increases after 13-cis-RA treatment in vivo and is related to RA receptor beta expression.

Nuclear retinoic acid receptor beta (RAR-beta) expression decreases in human premalignant oral lesions (POLs). RAR-beta suppression could result from a decrease in the cellular level of retinoids because RAR-beta gene transcription is enhanced by retinoids. To explore this hypothesis, we compared the binding of a monoclonal antibody (mAb) against all-transretinoic acid (RA; anti-RA mAbs) to normal oral tissue and POLs. All 7 normal specimens stained positive with the antibody compared to only 20 of 43 POLs; similarly, 7 of 7 normal specimens contained RAR-beta mRNA compared to only 14 of 43 POLs. Twenty-four specimens were available before and after a 3-month treatment with 13-cis-RA in vivo. Anti-RA mAb binding to these specimens increased from 10 of 24 before to 22 of 24 after treatment, and the expression of RAR-beta mRNA increased from 7 of 24 before to 21 of 24 after treatment, respectively. There was a strong agreement between the binding of anti-RA mAbs and the expression of RAR-beta. Thus, we propose that the binding of anti-RA mAbs reflects the level of retinoids in the tissues and that this level is related strongly to RAR-beta expression.

Antibodies, Monoclonal↗
PubMed1995

Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin.

BACKGROUND: Retinoids are effective in the treatment and prevention of certain human cancers. Most of their actions are thought to result from changes in gene expression mediated by nuclear retinoic acid receptors and retinoid X receptors. We conducted a study to determine whether the expression of these receptors was altered in premalignant oral lesions and, if so, whether their expression could be restored by treatment with isotretinoin. METHODS: We performed in situ hybridization of retinoic acid receptors and retinoid X receptors using antisense riboprobes in specimens of oral mucosa from 7 normal subjects and specimens of premalignant oral lesions from 52 patients before treatment with isotretinoin and from 39 of the 52 patients after three months of treatment. RESULTS: All the normal specimens expressed retinoic acid receptor-beta messenger RNA (mRNA). In contrast, retinoic acid receptor-beta mRNA was detected in only 21 of the 52 premalignant oral lesions (P = 0.003). Thirty-five of the 39 specimens available for evaluation after treatment expressed retinoic acid receptor-beta mRNA (P < 0.001). All normal and premalignant specimens expressed similar levels of mRNA for retinoic acid receptor-alpha and retinoic acid receptor-gamma and the three types of retinoic X receptors, alpha, beta, and gamma. The levels of retinoic acid receptor-beta mRNA increased in the specimens from 18 of the 22 patients who had responses to isotretinoin and in 8 of the 17 specimens from the patients without responses (P = 0.04). CONCLUSIONS: The expression of retinoic acid receptor-beta mRNA is selectively lost in premalignant oral lesions and can be restored by treatment with isotretinoin. Restoration of the expression of retinoic acid receptor-beta mRNA is associated with a clinical response. Retinoic acid receptor-beta may have a role in mediating the response to retinoids and may be a useful intermediate biologic marker in trials of these agents for the prevention of oral carcinogenesis.

Adult↗
PubMed1995

p53 and retinoid chemoprevention of oral carcinogenesis.

We studied p53 protein's pattern of expression, association with retinoid response or resistance, and modulation by retinoid intervention in oral premalignancy. These p53 analyses were included in a prospective trial of the retinoid isotretinoin (1.5 mg/kg/day for 3 months) in 40 patients (45 oral premalignant lesions). Seven nonsmoking subjects (eight oral biopsies) were included as a control. Protein levels of p53 were determined separately for the whole epithelium and the basal, parabasal, and superficial layers. A wide range of accumulated p53 protein levels occurred in 40 (89%) of 45 lesions in basal and parabasal but not superficial layers. No p53 protein was detected in any normal controls. Accumulation of p53 increased in direct association with histological grade (P = 0.0004). An inverse relationship occurred between the levels of accumulated p53 protein and response to isotretinoin (P = 0.006). High-dose isotretinoin did not modulate accumulated p53 protein expression.

Adult↗
PubMed1995

Retinoids and chemoprevention: clinical and basic studies.

Retinoids, which include natural vitamin A (retinol) and its esters and synthetic analogues, are the best-studied class of agents in chemoprevention. There are more than 4,000 different retinoids which have a wide spectrum of preclinical activities, structures, pharmacological profiles, tissue distributions, receptor specificities, and toxicities. A number of retinoids have significant activity in many in vivo experimental systems including skin, bladder, lung, breast and oral carcinogenesis. In clinical trials, several retinoids have achieved significant activity in the reversal of head and neck, skin, and cervical premalignancy, and in the prevention of second primary tumors associated with head and neck, skin, and non-small cell lung cancer. Since 1984, our group has conducted a series of clinical trials to explore the chemopreventive potential of 13-cis-retinoic acid (13cRA) in the aerodigestive tract. We have conducted two consecutive randomized studies in subjects with premalignant lesions of the oral cavity. These studies showed that high-dose 13cRA alone can achieve significant short-term reversal of oral premalignancy, and that high-dose followed by low-dose 13cRA can maintain suppression of oral carcinogenesis. Three other randomized trials have confirmed significant retinoid activity in this human carcinogenic system. We also developed a randomized, placebo-controlled trial of adjuvant high-dose 13cRA in patients with head and neck cancer. Second primary tumor development was significantly decreased in the 13cRA group, but 13cRA had no impact on primary disease recurrence or survival. This presentation will update the current status of clinical trials and correlative laboratory studies of potential intermediate endpoint biomarkers in retinoid chemoprevention of aerodigestive tract carcinogenesis.

Anticarcinogenic Agents↗
PubMed1995

Phase II study of 13-cis-retinoic acid plus interferon-alpha 2a in heavily pretreated squamous carcinoma of the cervix.

The combination of 13-cis-retinoic acid (13-cRA) and interferon (IFN)-alpha 2a has been reported to be highly active in previously untreated squamous carcinoma of the cervix. In this phase II study, 13-cRA was given at a dose of 1 mg/kg/day and IFN-alpha 2a was given subcutaneously at a dose of 3 million units/m2/day. Thirteen of 14 patients enrolled in this study are evaluable for response and toxicity. There were no complete or partial responses. Ten patients had progressive disease and the remaining three had stable disease. Principle toxicities were fatigue, nausea, and vomiting. This regimen appears cross-resistant with radiotherapy and/or platinum-based cytotoxic therapy in heavily pretreated patients with squamous carcinoma of the cervix.

Adult↗