isotretinoin and Lung-Neoplasms

Objective of the paper was to review the latest scientific reference data on chemoprevention possibilities of lung cancer. Lung cancer is the leading cause of cancer death in Lithuania. The current lung cancer therapy includes surgery, radiation and chemotherapy. These interventions have not produced declines in mortality rates. This overview argues strongly for new approach for controlling this disease. Chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing or preventing carcinogenic progression to invasive cancer. Whether primary, secondary or tertiary prevention has the potential to improve the dismal statistics associated with this cancer? Several randomized clinical or translational chemoprevention trials have been conducted. All have so far produced either neutral (using retinal, retinyl palmitate, N-acetyl cysteine or isotretinoin) or harmful (using beta-carotene) primary endpoint results showing that lung cancer was not prevented in smokers. Secondary results supporting treatment with isotretinoin in "never" and former smokers and data from prevention trials involving selenium and vitamin E, however, are encouraging and offer a promising direction for future clinical study.

Topics: Antioxidants; Disease Progression; Double-Blind Method; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Primary Prevention; Randomized Controlled Trials as Topic; Risk Factors; Selenium; Smoking; Smoking Cessation; Time Factors; Vitamin E

Topics: Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Models, Genetic; Respiratory Mucosa; Retinoids

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Non-Small-Cell Lung; Carotenoids; Clinical Trials as Topic; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Precancerous Conditions; Randomized Controlled Trials as Topic

Topics: Biomarkers, Tumor; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Mouth Neoplasms; Neoplasms, Second Primary; Retinoids

There is a clear change in the treatment strategies for solid tumours towards the treatment of early rather than advanced disease. Retinoids represent a potentially useful class of drugs in chemoprevention. Preclinical data and clinical experience suggests that different retinoids may have different spectra of antitumour activity and synergistic interactions between retinoids and cytokines have also been reported. 13-cis retinoic acid has shown some promising activity in preventing the onset of second primary tumours in head and neck cancer and fenretinide is being tested in the prevention of second primary breast cancers. An understanding fo the role of the different retinoid receptors could lead to the design of compounds with a better therapeutic index. Despite these early indications that retinoids could be useful in this area, the development of such drugs is far from easy. Appropriate study designs for screening differentiating agents in the clinic, and the relevance of preclinical models of chemoprevention are challenges to be addressed. Unresolved issues include optimal patient selection, long clinical trial times, optimal dose, schedule and treatment duration. The use of biological surrogate markers for longer time-dependent trial endpoints could significantly contribute to more rapid development. Ongoing clinical studies, particularly in tobacco-related diseases, will better define the role of retinoids in this clinical setting. Clinicians should be encouraged to enter patients into large well organized clinical studies.

Topics: Breast Neoplasms; Female; Fenretinide; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms; Retinoids; Risk Factors

Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancer's chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Resistance; Etoposide; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Neoplastic Stem Cells; Oncogenes; Phenotype; Tumor Cells, Cultured

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; Vitamin A

Chemoprevention entails using specific agents to suppress carcinogenesis and thereby prevent the development of primary or second primary cancers. Because the concept of chemoprevention in patients with or at risk of lung cancer is new, ongoing clinical trials are based on data from epidemiologic and preclinical research, as well as on results of chemoprevention studies in head and neck cancer. The latter studies have provided a model for such studies in lung cancer, considering the two diseases have a similar etiology and biology of field carcinogenesis. Beta-carotene, natural vitamin A, and the retinoids may be effective chemopreventive agents. However, chronic administration of such agents may be required to prevent the development of cancer. Results of chemoprevention trials in head and neck cancer have demonstrated effective inhibition of the development of second primary tumors with the synthetic retinoid 13-cis-retinoic acid; investigators are hopeful this will be repeated in patients with lung cancer. Results of ongoing phase III trials and continued advances in the epidemiologic and biologic study of lung carcinogenesis should contribute to future research in this area.

Topics: beta Carotene; Carotenoids; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia, Oral; Lung Neoplasms; Neoplasms, Second Primary; Risk Factors; Vitamin A

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Drug Design; Female; Gastrin-Releasing Peptide; Growth Substances; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms, Second Primary; Oncogenes; Peptides; Retrospective Studies; Sputum; Tamoxifen; United States

Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC.. Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs).. Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival.. Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Small Cell; Chemotherapy-Induced Febrile Neutropenia; Cohort Studies; Early Termination of Clinical Trials; Female; Follow-Up Studies; Humans; Interferon-alpha; Isotretinoin; Leukocytes, Mononuclear; Leukopenia; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Severity of Illness Index; Small Cell Lung Carcinoma; Survival Analysis

In 2001, we reported that mortality may have been higher with isotretinoin (30 mg/d for 3 years) than with placebo in the subgroup of current smokers among the 1,166 patients with definitively resected early-stage non-small cell lung cancer who participated in the randomized, controlled Lung Intergroup Trial. We report the overall and cause (cancer, cardiovascular disease, or other)-specific mortality associated with long-term isotretinoin after an extended median follow-up of 6.2 years that included the capture of cause-of-death data from 428 deceased patients. Overall mortality was 36.7% in each of the two trial arms, about two thirds related to cancer and one third to other or unknown causes. Overall and cancer deaths increased in current smokers in the isotretinoin arm during the treatment and the extended follow-up period. No mortality end point increased among never smokers and former smokers taking isotretinoin, and cancer deaths decreased marginally in this combined subgroup. Isotretinoin also increased deaths from cardiovascular disease in current smokers. The present analysis supports the safety of protracted isotretinoin use in the combined group of never smokers and former smokers, which has important public health implications, for example, for treating acne in young people. The increased mortality in current smokers in this study is further evidence of the multifaceted danger of active smoking. The overall indications of this study have public health implications for treating acne in young people and other uses of retinoids in smokers.

Topics: Acne Vulgaris; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cardiovascular Diseases; Cause of Death; Cocarcinogenesis; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Isotretinoin; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pneumonectomy; Proportional Hazards Models; Smoking

No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of alpha tocopherol did not affect toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bronchoscopy; Female; Humans; Isotretinoin; Lung; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Risk Factors; Smoking; Tocopherols

Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma.. Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1-14 for six cycles. The end points included the objective response rate and median survival.. Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44-79 years) and the median Karnofsky performance status was 80% (range 60-100%). The median follow-up was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6-21.6 months).. The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gemcitabine; Humans; Isotretinoin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Palliative Care; Pancreatic Neoplasms; Pilot Projects; Prognosis; Ribonucleotide Reductases; Survival Rate; Treatment Outcome

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma, Renal Cell; Deoxycytidine; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Germany; Humans; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins; Survival Analysis

The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up.. National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed.. Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%.. Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Prospective Studies

The absence of iodine uptake in metastases of differentiated thyroid carcinoma makes them unresponsive to treatment with radioiodine 131I. In many of such cases symptomatic treatment remains the only available therapy. The results of studies on partial redifferentiation of metastases of thyroid cancer achieved after cis-retinoid acid therapy have drawn attention to the possibility of restoration of iodine uptake in metastases after pretreatment with cis-retinoic acid (Roaccutane). 5 patients with iodine uptake-negative metastases of differentiated thyroid carcinoma were given Roaccutane in a dose 1.5 mg/kg/24 h daily for 6 weeks before the therapy with radioiodine. In none of the patients restoration of radioiodine uptake in metastases has occurred as shown in post-therapeutic total body scintigraphy.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Bone Neoplasms; Carcinoma, Papillary; Female; Humans; Iodine Radioisotopes; Isotretinoin; Lung Neoplasms; Premedication; Thyroglobulin; Thyroid Neoplasms

Retinoids, a large group of compounds structurally related to vitamin A, are able to induce redifferentiation of thyroid cancer cells. The aim of the study is to present our early results of retinoids redifferentiation therapy of thyroid cancer patients. In 15 patients with advanced thyroid cancer, whose cancer foci did not concentrate radioiodine, 13-cis retinoic acid (Roaccutan) was given for 6 weeks before radioiodine treatment. Radioiodine therapy was performed under exogenous TSH stimulation (Thyrogen). Three patients were treated twice. The planned retinoid dose was delivered to 11 patients. In the other four patients the reduction of retinoids dose was necessary due to severe side effects. In post-therapeutic scintigraphy radioiodine uptake was visible in two out of seven patients (29%) with lung metastases, in 5 out of 9 (56%) with locoregional disease and in two with bone metastases. On the whole, in 50% of patients reinduction of radioiodine uptake was visible, however, in most patients only a very discrete one. Thyroglobulin concentration before and after retinoids therapy did not differ significantly.. In a subgroup of patients 13-cis retinoic acid can induce radioiodine uptake, however, prospective studies in larger groups of patients are necessary to prove its clinical application.

Topics: Adult; Aged; Bone Neoplasms; Female; Humans; Iodine Radioisotopes; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Premedication; Thyroglobulin; Thyroid Neoplasms

Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients.. We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided.. After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm.. Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Neoplasms, Second Primary; Placebos; Smoking

Clinical chemoprevention trials seek to intervene in the carcinogenic process to suppress, reverse, or delay the development of invasive cancer. Dysregulated cell growth is a hallmark of epithelial carcinogenesis, and proliferating cell nuclear antigen (PCNA) is a marker of dysregulated proliferation that is highly expressed in non-small cell lung cancers. Squamous metaplasia of the bronchial epithelium is found in chronic smokers and has been considered an early premalignant change. To evaluate the effect of 13-cis-retinoic acid (13-cRA) on PCNA modulation, we evaluated PCNA expression in a total of 706 bronchial biopsy specimens from histologically normal, hyperplastic, metaplastic, and dysplastic bronchial tissues obtained from 86 healthy smokers at baseline, of whom 69 subjects had completed 6 months of treatment on a randomized placebo-controlled chemoprevention trial of 13-cRA and had repeat bronchoscopic biopsies. PCNA expression was evaluated with respect to bronchial metaplasia and as an intermediate end point for response in the trial. In the bronchial biopsies obtained from six standardized pretreatment and posttreatment sites, high PCNA expression correlated significantly with more advanced histological grade (P < 0.001). Furthermore, smoking cessation during therapy correlated well with reduced PCNA expression (P = 0.006), although multivariate analysis indicated that this reduction in PCNA expression was associated with the reversal of squamous metaplasia. The level of PCNA expression appeared to correlate with the level of epidermal growth factor receptor expression both at baseline and at 6 months. In those patients who ceased smoking during the intervention, the 13-cRA also appeared to be more effective than placebo in reducing PCNA expression (P = 0.034 in all of the layers; P = 0.026 in basal layers). The efficacy of 13-cRA in the down-regulation of PCNA in quitters was independent of baseline PCNA expression levels. Our study demonstrated that increased PCNA expression was associated with histological progression from normal bronchial epithelium to squamous metaplasia and dysplasia. The modulation of PCNA by 13-cRA in patients who quit smoking suggests a potentially important role for regulating this proliferation marker in retinoid chemoprevention studies of former smokers.

Topics: Adult; Aged; Biomarkers; Biopsy; Cell Division; Cell Transformation, Neoplastic; Epithelium; Female; Humans; Isotretinoin; Lung; Lung Neoplasms; Male; Metaplasia; Middle Aged; Proliferating Cell Nuclear Antigen; Smoking; Smoking Cessation

This randomized phase II multi-center study was designed to determine the time to progression, duration of response and the feasibility of an intensified maintenance regime consisting of a combination of interferon (IFN)-alpha and retinoic acid after high-dose combination chemotherapy and radiotherapy in patients with small cell lung cancer. The patients received four courses of combination chemotherapy consisting of ifosfamide, carboplatin and etoposide, with higher doses of ifosfamide and carboplatin given in the first course, with routine growth factor support. Responding patients were then randomly assigned to one of three maintenance therapy arms. All patients with limited disease (LD) were given thoracic radiotherapy before maintenance therapy and those who had also achieved a complete response (CR) or minimal residual disease (MRD) received prophylactic cranial irradiation. In Arm 1 patients received IFN-alpha-2a, 6 MIU s.c. TIW for 4 weeks, followed by 3 MIU s.c. TIW, and 13-cis-retinoic acid 1 mg/kg/day p.o. BID daily. In Arm 2 patients received trophosphamide 100-150 mg/day p.o. BID. No maintenance treatment was given in Arm 3, the control group. Maintenance therapy was continued for 1 year. Eighty-five patients were treated according to the protocol. Twenty-one patients achieved CR, four achieved MRD and forty-two achieved partial responses to chemotherapy and radiotherapy. Sixty patients (71%) were randomly assigned for maintenance treatment. Median survival was 17.1 months in the IFN-alpha-retinoic acid arm, 12.4 months in the trophosphamide arm and 13.5 months in the control arm. One-year survival rates were 82, 56 and 55%, respectively. Duration of response was 6.5, 5.5 and 4.7 months, respectively. Time to progression was 8.6, 8.0 and 6.8 months, respectively The differences were not statistically significant. The IFN-alpha-retinoic acid maintenance treatment was well tolerated. Patients who received IFN-alpha-retinoid maintenance therapy lived longer after the onset of progressive disease. The treatment regime was effective, feasible and well tolerated.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Finland; Humans; Ifosfamide; Injections, Subcutaneous; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged

To establish the incidence of abnormalities in the expression of retinoic acid receptor-beta (RARbeta) in bronchial cells and determine the capacity of 13-cis-retinoic acid (13-CRA) to correct such abnormalities.. One hundred eighty-eight smokers had a medical indication for bronchoscopy and were studied with bronchial brushings. Bronchial brushing samples were obtained for cytology analysis and for molecular analysis. After RNA was extracted, RARbeta sequences were amplified by reverse transcriptase polymerase chain reaction and Southern blots were performed to assess RARbeta expression. Forty-four eligible individuals with diminished RARbeta expression consented to double-blind randomization to receive a placebo or 13-CRA 30 mg orally daily for 6 months. A second bronchoscopy was performed at the end of the treatment period. An analysis of variance was used to analyze changes in RARbeta expression before and after treatment.. The 6-month treatment course was completed by 27 patients, and results were obtained for a total of 18 patients (eight patients treated with 13-CRA and ten treated with the placebo). In the placebo group, there was no difference between the results of RARbeta expression before and after treatment (P =.43). In the 13-CRA group, there was an upregulation of RARbeta expression at the end of 13-CRA treatment (P =.001). Cytologic changes were uncommon. Toxicities were primarily of grade 1. Palatal brushings were compared with bronchial brushings in 40 smokers. A perfect correlation of the results of RARbeta expression was obtained from 27 patients.. RARbeta expression is frequently decreased in the bronchial epithelium of smokers and is upregulated at the end of 13-CRA treatment. These results support undertaking a phase III chemoprevention trial of 13-CRA treatment for lung cancer.

Topics: Analysis of Variance; Bronchi; Bronchoscopy; Double-Blind Method; Feasibility Studies; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; Smoking; Up-Regulation

This study of the effect of 13-cis-retinoic acid on serum levels of retinol was a laboratory correlate of a clinical chemoprevention trial in asymptomatic chronic smokers. All study participants had squamous metaplasia of the bronchial epithelium and received 6 months' treatment of either 13-cis-retinoic acid (1 mg/kg/day) or placebo. Baseline serum retinol levels were compared with levels taken immediately post-treatment. The placebo group (N = 38) had little change, whereas the 13-cis-retinoic acid group, (N = 35) experienced a decline in retinol levels (p = 0.06). Within the 13-cis-retinoic acid group, women's (N = 13) mean serum retinol levels dropped significantly, from 531 +/- 191 ng/ml (baseline) to 436 +/- 115 ng/ml (post-treatment) (p = 0.03); men's (N = 22) levels virtually did not change (p = 0.43). Therefore, the borderline-significant overall decline in the 13-cis-retinoic acid group was due entirely to the decline among women subjects. The etiology of this effect is unknown. Our results suggest that chronic 13-cis-retinoic acid administration may lead to a clinically significant reduction in serum retinol levels in females. This finding may have implications for currently ongoing chemoprevention trials that administer 13-cis-retinoic acid for 3 years.

Topics: Adult; Anticarcinogenic Agents; Bronchi; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Metaplasia; Middle Aged; Smoking; Vitamin A

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Topics: Anticarcinogenic Agents; Diterpenes; Etretinate; Head and Neck Neoplasms; Humans; Isotretinoin; Leukoplakia; Lung Neoplasms; Mouth Neoplasms; Retinoids; Retinyl Esters; Vitamin A

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Treatment Outcome

Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.. We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.. In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke.. Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.

Topics: Adult; Aged; Bronchi; Epithelium; Female; Humans; Infant, Newborn; Isotretinoin; Lung Neoplasms; Male; Metaplasia; Middle Aged; Placebos; Precancerous Conditions; Regression Analysis; Smoking

The combination of interferon (IFN)-alpha 2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-alpha 2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Recombinant Proteins

Topics: Acetylcysteine; Animals; Antineoplastic Agents; Diet; Digestive System Neoplasms; Diterpenes; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Retinyl Esters; Smoking Prevention; Vitamin A

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Drug Design; Female; Gastrin-Releasing Peptide; Growth Substances; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Male; Neoplasms, Second Primary; Oncogenes; Peptides; Retrospective Studies; Sputum; Tamoxifen; United States

Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.

Topics: Actins; Adrenal Gland Neoplasms; Animals; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Chromogranin A; Female; Immunohistochemistry; Isotretinoin; Lovastatin; Lung Neoplasms; Mice; Mice, Nude; Muscle, Smooth; Pheochromocytoma; Time Factors; Transplantation, Homologous; Treatment Outcome; Tumor Burden; Tyrosine 3-Monooxygenase

Erlotinib is useful in advanced non-small cell lung cancer although compliance and efficacy are diminished by skin rash in a high proportion of patients, often necessitating dose reduction or drug withdrawal. No effective treatment for the rash is available.. We carried out a preliminary investigation on isotretinoin and clindamycin. Among 56 advanced lung cancer patients treated with erlotinib, 31 (53%) developed rash. Seven (35%) of the 20 G2/G3 cases agreed to treatment with clindamycin (450 mg/d, days 1-10; 300 mg/d, days 11-20) plus isotretinoin (20 mg/d, days 11-20) after being informed of the experimental nature of the combination.. In 6 of 7 (86%) patients, the rash resolved (G1/G0) without dose reduction; in the other patient (G3), the erlotinib dose also had to be reduced. Median time to resolution was 14 days (range 7-20 days). No rash-treatment adverse events occurred during 20 days of administration.. Isotretinoin plus clindamycin promises to be the first effective treatment for erlotinib rash and is being tested further.

Topics: Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Clindamycin; Dermatologic Agents; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Humans; Isotretinoin; Lung Neoplasms; Protein Kinase Inhibitors; Quinazolines; Survival Rate; Treatment Outcome

Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model.. Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin.. Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13-cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice.. These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo.

Topics: Acitretin; Alitretinoin; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cisplatin; Culture Media, Conditioned; Etretinate; Fibroblasts; Fluorouracil; Humans; In Vitro Techniques; Isotretinoin; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Retinoids; Tretinoin

A relatively newer class of chemotherapy agents, known as the epidermal growth factor receptor inhibitors (EGF-RIs), is being used to treat advanced stages of solid tumors. Acneiform eruptions are a frequent adverse effect and one which has been associated with increased survival in some studies. We describe 3 patients who presented shortly after initiation of EGF-RI therapy. Characteristics included an absence of comedones, facial and truncal involvement, and a perifollicular lymphoneutrophilic infiltrate detected on biopsy. Lesion counts were reduced with topical adapalene and oral tetracyclines in two patients. Patient 3 had dramatic clearance with low-dose isotretinoin (20 mg daily) until completion of EGF-RI therapy. Acneiform eruptions are a common adverse reaction to EGF-RI therapy and can be treated with traditional acne therapy. This should not be considered a drug hypersensitivity eruption or allergy, and patients should continue therapy. For patients with severe eruptions, oral isotretinoin is a consideration.

Topics: Acne Vulgaris; Adapalene; Administration, Oral; Administration, Topical; Adult; Anti-Bacterial Agents; Antineoplastic Agents; Colonic Neoplasms; Dermatologic Agents; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Minocycline; Naphthalenes

Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk for lung cancer compared with lifetime never-smokers. Chemoprevention is the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention.. Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations.. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. For facilitating the evaluation of promising agents and for lessening the need for a large sample size, extensive time commitment, and expense, focus is now turning toward the assessment of surrogate end point biomarkers for lung carcinogenesis. With the understanding of important cellular signaling pathways, various inhibitors that may prevent or reverse lung carcinogenesis are being developed.. By integrating biological knowledge, more trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points.

Topics: Acetylcysteine; alpha-Tocopherol; Anticarcinogenic Agents; Aspirin; beta Carotene; Chemoprevention; Clinical Trials, Phase III as Topic; Evidence-Based Medicine; Humans; Isotretinoin; Lung Neoplasms; United States; Vitamin A

The growth inhibitory effects of four retinoic acid (RA) derivatives, 9-cis RA, 13-cis RA, N-(4-hydroxyphenyl) retinamide (4-HPR), and all-trans retinoic acid (ATRA) were compared. In addition, the effects of various combinations of these four agents were examined on non-small cell lung carcinoma (NSCLC) cell-lines, and on the expressions of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) on these cells. At the clinically achievable concentration of 1 microM, only 4-HPR inhibited the growths of H1299 and H460 cells-lines. However, retinoic acid receptor beta(RAR beta) expression was up-regulated on H460 and H1299 cells treated with 1 microM of ATRA, 13-cis RA, or 9-cis RA. All NSCLC cell lines showed growth inhibition when exposed sequentially to 1 microM ATRA and 0.1 microM 4-HPR. In particular, sequential treatment with 1 microM ATRA or 13-cis RA and 4-HPR markedly inhibited H1703 cell growth; these cells exhibited no basal RAR beta expression and were refractory to 4-HPR. However, in NSCLC cell lines that expressed RAR beta, the expressional levels of RAR beta were up-regulated by ATRA alone and by sequential treatment with ATRA and 4-HPR. 4-HPR was found to be the most active of the four agents in terms of NSCLC growth-inhibition. Moreover, sequential treatments with ATRA or 13-cis RA followed by 4-HPR were found to have synergistic growth-inhibitory effects and to regulate RAR expression.

Topics: Alitretinoin; Base Sequence; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Primers; Drug Therapy, Combination; Fenretinide; Gene Expression; Humans; Isotretinoin; Lung Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Tretinoin

Lung cancer is the leading cause of cancer death worldwide. A diet rich in fruit and vegetables has been shown to reduce the lung cancer risk. However, clinical trials with beta-carotene and retinoids have disappointed, resulted in increased mortality from lung cancer and cardiovascular disease.. We have investigated the effects of the two major retinol metabolites, 9-cis-retinoic acid (9-Cis-RA), and 13-cis-retinoic acid (13-Cis-RA), on cell proliferation (MTT assays), intracellular cAMP (cAMP immunoassays), PKA activation (non-radioactive PKA activation assays), and ERK1/2 phosphorylation (Western blots) in immortalized human small airway epithelial cells, HPL1D, a human lung adenocarcinoma cell line, NCI-H322, immortalized human bronchial epithelial cells, BEAS-2B, and in the human small cell lung carcinoma cell line, NCI-H69.. Both retinoids increased intracellular cAMP and PKA activation in all cell lines. In BEAS-2B and NCI-H69 cells, the stimulation of cAMP/PKA reduced the phosphorylation of ERK1/2 and inhibited cell proliferation whereas phosphorylation of ERK1/2 and cell proliferation were increased in HPL1D and NCI-H322 cells.. Our data have identified a novel mechanism of action of 9-Cis-RA and 13-Cis-RA: activation of PKA in response to increased cAMP. The observed stimulation of cAMP/PKA may inhibit the development of small cell lung carcinoma and other tumors derived from large airway epithelia whereas it may selectively promote the development of lung tumors derived from small airway epithelial cells, such as adenocarcinoma.

Topics: Adenocarcinoma; Alitretinoin; Blotting, Western; Bronchi; Carcinoma, Small Cell; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Epithelial Cells; Humans; Immunoassay; Isotretinoin; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Respiratory Mucosa; Signal Transduction; Tretinoin; Tumor Cells, Cultured

Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator-activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein-directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPARalpha and gamma expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARgamma on lung cancer cell lines. Non-small-cell cancer cell line A549 revealed dose-dependent PPARgamma reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-Delta12,14-prostaglandin J2 compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR)alpha mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPARgamma-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPARgamma and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.

Topics: Acetophenones; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arachidonic Acid; Caspases; Cell Growth Processes; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Indoles; Isotretinoin; Ligands; Lung Neoplasms; Peroxisome Proliferator-Activated Receptors; Prostaglandin D2; Pyrimidines; Retinoid X Receptor alpha; RNA, Messenger; Tetrazoles; Thiazolidinediones

The clinical outcome of interferon-gamma treatment of metastatic renal cell carcinoma remains unsatisfactory. To overcome this, a reagent that has a different action on cancer cells is desired. One such candidate may be 13-cRA (cis retinoic acid), a vitamin A derivative known to markedly regulate the differentiation and proliferation of normal and neoplastic cells. Moreover, 13-cRA demonstrates a remarkable synergistic effect with IFN-gamma in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-gamma. The in vivo anti-tumor effects were evaluated in a lung metastasis model using a mouse renal cell carcinoma cell line (RenCa). The in vitro anti-tumor effects were also assessed by MTT assay. The presence of retinoic acid receptors (RAR)-alpha, -beta and -gamma was examined by PCR analysis. The influence of IFN-gamma on these retinoic acid receptors was evaluated by Northern blotting. IFN-gamma showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-alpha, and -gamma, but not -beta according to PCR analysis. IFN-gamma treatment increased the expression level of RAR-alpha and RAR-gamma according to Northern blot analysis. Combination therapy using IFN-gamma and 13-cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-gamma treatment increased RAR-alpha and RAR-gamma expression. Thus, the augmented anti-tumor effects of IFN-gamma and 13-cRA may be attributable to enhanced expression of RAR-alpha and RAR-gamma by IFN-gamma treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; DNA Primers; Drug Synergism; Female; Interferon-gamma; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; RNA, Messenger; Tumor Cells, Cultured

Topics: Administration, Inhalation; Aerosols; Animals; Anticarcinogenic Agents; Isotretinoin; Lung Neoplasms; Mice; Mice, Inbred A

In previously treated head-and-neck cancer patients, p.o. administered isotretinoin (13-cis retinoic acid) reduced the occurrence of second aerodigestive tumors, including lung tumors, but side effects made chronic therapy problematic. We reasoned that inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity, and we proceeded with the pilot study reported here. Male A/J mice were given single i.p. doses of urethane, a common experimental lung carcinogen, or benzo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), putative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 microg/l were initiated. After 2 weeks, the high dose caused severe toxicity on the snout skin, necessitating a reduction of dose frequency to twice a week. As a precaution, the mid dose was reduced to three exposures per week. The weekly total deposited doses after the dose frequency reductions were calculated to be 0.24, 1.6, and 24.9 mg/kg for the low, mid, and high doses, of which 16% was estimated to be deposited in the lungs. The weekly deposited pulmonary drug doses were calculated to be 0.01, 0.07, and 1.1% of a previously reported ineffective oral dose in urethane-treated A/J mice. After 10-16 weeks, mice were sacrificed to count areas of pulmonary hyperplasia and adenomas. For all carcinogens, the mice exposed to the high isotretinoin dose showed reductions of tumor multiplicity ranging from 56 to 80% (P < 0.005). The mid dose was associated with reductions of tumor multiplicity by 67 and 88% (P < 0.005) in BaP- and NNK-treated mice, respectively, and was tolerated until approximately 12 weeks, when both these and the high-dose mice began losing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.13) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without any evidence of side effects. For BaP- and NNK-treated mice, numbers of hyperplastic areas directly correlated to dose level and inversely to tumor number, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relative to vehicle-exposed mice, RARalpha (3.9-fold vehicle), RARbeta (3.3-fold), and RARgamma (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results from this pilot study sug

Topics: Administration, Inhalation; Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Carcinogens; Dose-Response Relationship, Drug; Isotretinoin; Lung Neoplasms; Male; Mice; Mice, Inbred A; Particle Size; Pilot Projects; Receptors, Retinoic Acid

We present a case of increased I-131 uptake in a patient with papillary thyroid carcinoma with local recurrence and distant metastases after a second treatment with retinoic acid as a sign of redifferentiation of the tumor cells. When fine-needle aspiration cytology before and after a second course of retinoic acid treatment were compared, signs of tumor cell redifferentiation were found. This was accompanied by biochemical reexpression of thyroid marker proteins.

Topics: Carcinoma, Papillary; Humans; Iodine Radioisotopes; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Radionuclide Imaging; Thyroid Neoplasms

The synergistic anti-tumor effect of 13-cis retinoic acid (13-cRA) and interferon-alpha/beta (IFN-alpha/beta) was investigated using a highly metastatic mouse renal cell carcinoma cell subline (RenCa/F). Although 13-cRA inhibited tumor growth in vivo as well as in vitro, IFN-alpha/beta did not. Combined administration of 13-cRA and IFN-alpha/beta significantly enhanced the anti-tumor effect of 13-cRA. The retinoic acid receptor (RAR)-alpha and RAR-gamma were expressed in RenCa/F cells. Treatment with IFN-alpha/beta did not influence the expression level of these receptors at the mRNA level, which suggests that the synergism of 13-cRA and IFN-alpha/beta is not mediated through the RAR.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Drug Synergism; Female; Interferon-alpha; Interferon-beta; Isotretinoin; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; RNA, Messenger; Tumor Cells, Cultured

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Feasibility Studies; Female; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Uterine Cervical Neoplasms

Topics: Aged; Antineoplastic Agents; Chemotherapy, Adjuvant; Humans; Isotretinoin; Lung Neoplasms; Lymphatic Metastasis; Male; Thyroid Neoplasms

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it also will enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered on clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community. It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician's Data Query (PDQ). We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients not in a study. This month's installment of Clinical Trials Referral Resource is devoted to cancer chemoprevention trials. For patient entry information contact the person listed in each individual trial.

Topics: Adult; Aspirin; Colorectal Neoplasms; Double-Blind Method; Head and Neck Neoplasms; Humans; Isotretinoin; Lung Neoplasms; Neoplasms; Neoplasms, Second Primary

13-cis-Retinoic acid can mediate differentiation of transformed cells and slow the proliferation of malignant cells, suggesting its use as a potential intervention tool. Specific cDNA probes for retinoic acid receptors demonstrated the expression of mRNAs for the different retinoic acid receptor isoforms in small cell lung cancer cell lines. Addition of 13-cis-retinoic acid to small cell lung cancer cells cultured using serum-free, hormonally defined medium resulted in a 5-8-fold increase in the level of the retinoic acid receptor-beta mRNAs; in medium containing serum, the increase in expression of the retinoic acid receptor-beta mRNAs was less pronounced, usually no more than 2-fold. Using an in vitro proliferation assay, addition of 13-cis-retinoic acid resulted in a significant dose-dependent, growth-inhibitory effect on the small cell lung cancer cell lines tested using serum-free conditions. These inhibitory effects decreased when cells were cultured in medium containing serum or serum components. Molecular size exclusion chromatography and native gel electrophoresis showed that the causative serum component eluted and migrated with serum albumin. Preincubating serum with triglycerides restored the inhibitory effects of 13-cis-retinoic acid demonstrated in serum-free systems. These data suggest that 13-cis-retinoic acid preferentially binds to serum albumin, restricting its inhibitory effects on epithelial cell receptors. Blocking retinoic acid-albumin interactions with a fatty acid source may improve the bioavailability of 13-cis-retinoic acid and significantly enhance the inhibitory effect in vivo.

Topics: Blotting, Northern; Carcinoma, Small Cell; Cell Division; Chromatography, Gel; Culture Media, Serum-Free; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Lung Neoplasms; Receptors, Retinoic Acid; RNA, Messenger; RNA, Neoplasm; Serum Albumin; Triglycerides; Tumor Cells, Cultured

Phase II trials of the novel biologic combination of 13-cis-retinoic acid plus interferon (IFN)-alpha have achieved major activity in advanced squamous cell carcinomas of the skin and cervix, but not of the lung or head and neck. Very limited study of this combination has occurred in cancers other than those of squamous type. Although uncommon, cases of unresectable or metastatic endometrial adenocarcinoma are virtually incurable, and chemotherapy has had no impact on survival in these cases. This report describes our use of 13-cis-retinoic acid plus IFN-alpha to treat a case of cisplatin- and hormone-resistant, locally advanced and distantly metastatic adenocarcinoma of the endometrium. In this worst-prognosis case, the biologic therapy achieved a major response, which persisted for 4 months. Based on the dramatic activity in this case, we believe that depthful mechanistic and clinical study of this promising new biologic combination should be expanded to include non-squamous tumors of many different sites and histopathologic types.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Endometrial Neoplasms; Female; Humans; Interferon-alpha; Isotretinoin; Lung Neoplasms; Middle Aged; Prognosis

We assessed the antiproliferative effect of human recombinant interferon -alpha (IFN-alpha) or -beta in combination with 5-fluorouracil (5-FU), cisplatin, or cis- or trans-retinoic acid on two human nonsmall cell lung carcinoma cell lines (SK-LU-1 and SK-MES-1) and on one human small cell lung carcinoma cell line (NCI-H69). Results were obtained by direct cell count and/or by the clonigenic assay. The three cell lines differed in their sensitivities to the antiproliferative effects of the different agents. However, both NSCLC cell lines were more responsive to IFN-beta than to IFN-alpha. The SK-MES cell line was more resistant to both IFNs than the SK-LU-1. The NCI-H69 cells were resistant to all the drugs tested, except trans-retinoic acid. The dose and time of exposure were found to be important factors in the case of IFNs and cytotoxic agents, with lower surviving fractions obtained with the higher doses and longer exposures. This finding, however, did not hold true for the retinoic acids, which showed no antiproliferative effect. Within the sensitivity of our system, we did not identify any synergistic interaction in any of the cell lines with IFN-alpha or IFN-beta and 5-FU or cisplatin. A slight synergistic interaction was observed with IFN and cis- or trans-retinoic acid in the SK-LU-1 cell line which was not thought to be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Cisplatin; Drug Synergism; Fluorouracil; Humans; Interferon Type I; Interferon-beta; Isotretinoin; Lung Neoplasms; Recombinant Proteins; Tretinoin; Tumor Cells, Cultured

Murine squamous carcinoma cells (KLN205) grown in a medium supplemented with the retinoid, 13-cis retinoic acid (RA), had dose-dependent, selective increases in the expression of certain lectin receptors, which correlated with a dramatic decrease in the ability to form pulmonary colonies (P = .0003) (Couch MJ, Pauli BU, Weinstein RS, Coon JS: JNCI, 78:971-977, 1987). These findings suggest a possible relationship between the RA-induced glycoconjugate alterations and the decreased experimental metastatic behavior. We further define the mechanism of RA's action. The finding that RA treatment (5 X 10(-6) M, 5 X 10(-7) M) did not perturb the cell cycle of KLN205 cells provides further proof that the decreased metastatic behavior is not attributable to any inhibition in the rate of growth or to alterations in the cell cycle. Furthermore, since stable subpopulations with variable lectin binding could not be detected, the mechanism of RA's action does not appear to be due to selection of variant tumor-cell subpopulations. Finally, in a series of experiments designed to determine the reversibility of the RA treatment, the RA-induced decrease in metastatic behavior reverted back to a more metastatic state in the same time frame (3 days) as the reversion of the RA-induced changes in cell-surface glycoconjugate expression. This reversion provides further evidence for a close relationship between the RA-induced modulation of tumor cell-surface glycoconjugate expression and the decreased metastatic behavior; it suggests that transient, reversible modulation of the tumor cell surface may play a role in determining metastatic behavior.

Topics: Animals; Carcinoma, Squamous Cell; Cell Cycle; Flow Cytometry; Glycoconjugates; Isotretinoin; Lectins; Lung Neoplasms; Male; Mice; Neoplasm Metastasis; Receptors, Mitogen; Tretinoin; Tumor Cells, Cultured

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Diagnosis-Related Groups; Drug Evaluation; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Tretinoin

KLN 205 murine squamous carcinoma cells were grown in medium supplemented with the retinoid 13-cis-retinoic acid (RA) to study the relationship between RA-induced cell surface changes and alterations of the metastatic phenotype. Modulation of the cell surface glycoconjugate expression was measured by flow cytometric analysis of the RA-treated tumor cells stained with fluoresceinated lectins. RA treatment (5 X 10(-6) and 5 X 10(-7) M) altered the glycoconjugate expression of KLN 205 cells in a selective, dose-dependent fashion. Tumor cells grown in RA-supplemented medium for more than 4 days demonstrated greatly increased binding of fluoresceinated Griffonia simplicifolia I lectin, peanut lectin, wheat-germ lectin, concanavalin A, and soybean lectin (P less than .001), but the increased binding of Ulex europaeus lectin was of a much smaller magnitude (P = .02). After 15 days of growth in these noncytotoxic or cytostatic concentrations of RA, malignant KLN 205 cells had a greatly decreased proclivity to metastasize, as measured by the lung colony assay (P = .0003). The RA-induced cell surface glycoconjugate changes preceded the decrease in experimental metastatic potential. Since enzymatic (neuraminidase) alteration of the tumor cell surface to produce glycoconjugate expression similar to that seen in RA-treated cells also reduced the ability of the KLN 205 cells to form lung colonies (P = .0022), it is suggested that RA-induced alteration of the cell surface carbohydrate antigens is related to the decreased experimental metastatic potential seen in tumor cells treated with RA.

Topics: Animals; Antigens, Neoplasm; Carbohydrates; Cell Division; Dose-Response Relationship, Drug; Fluorescence; Isotretinoin; Killer Cells, Natural; Lung Neoplasms; Mannose; Mice; Neoplasm Metastasis; Phenotype; Time Factors; Tretinoin

The effect of 13-cis-retinoic acid (13-cis-RA) on 1,2-dimethylhydrazine (DMH)-induced colon cancer in male, random bred, Sprague-Dawley (S-D) and inbred Wister/Furth (W/Fu) rats and on isograft tumor growth and metastases in a Brown Norwegian (BN) X W/Fu F1 rat was studied. 13-cis-RA (300 mg/kg diet) was administered to S-D rats 1 week before commencing DMH injections and for the duration of the experiment. W/Fu rats received 13-cis-RA (10 mg/kg weight X 5 days) 6 weeks after DMH injection had begun and monthly thereafter. Primary tumors were detected by serial laparotomy under ether anesthesia in both strains. The time to tumor onset was significantly delayed in treated groups, S-D and W/Fu, P = 0.0339 and 0.0322, respectively (Mantel-Haenszel test), compared with placebo-treated controls. 13-cis-RA (15 mg/kg weight) administered 2 days before and for the duration of isograft tumor growth (DMH 2054, a well-differentiated mucin-producing colon adenocarcinoma that spontaneously metastasized to lung) had no effect on tumor growth or metastasis in the BN X W/Fu F1 rat. The findings suggest that the role of 13-cis-RA is in colon cancer prevention and not in its treatment either in an adjuvant or established setting.

Topics: Animals; Colonic Neoplasms; Dimethylhydrazines; Isotretinoin; Lung Neoplasms; Male; Rats; Tretinoin

In treating a patient with a malignant eccrine poroma, in-vitro studies suggested resistance to dactinomycin and doxorubicin. A trial of weekly 5-fluorouracil produced no response. Likewise, a cycle of cisplatinum and cytarabine was associated with continued progression of the disease. Use of 13-cis retinoic acid induced a partial remission that lasted for 8 weeks with minimal toxicity. The mechanism of action is not known, but local tumor necrosis with sparing of the adjacent normal tissue suggests high specificity.

Topics: Adenoma, Sweat Gland; Antineoplastic Agents; Drug Therapy, Combination; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Sweat Gland Neoplasms; Thigh; Tretinoin

The inhibitory effect of 13-cis-retinoic acid was tested in conjunction with ethyl carbamate (urethane) induced murine pulmonary adenomas. Continuous feeding of the retinoic acid for 20 weeks did not significantly reduce the number of surface adenomas. No physical evidence of toxicity due to the vitamin A analog was observed in any of the mice. All mice showed a steady weight gain during the 20-week period, and there was no evidence of eye lesions, hemorrhage, bone fractures, fur changes or lethargy.

Topics: Adenoma; Animals; Isotretinoin; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Tretinoin