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L W Wattenberg

Publications and source records attributed to L W Wattenberg.

At least 19 recordsLinked to original sources
PubMed2003

Effect of chemopreventive agents on separate stages of progression of benzo[alpha]pyrene induced lung tumors in A/J mice.

The effects of aerosol budesonide and dietary myo-inositol on progression of benzo[alpha]pyrene (B[alpha]P) induced carcinogenesis were studied in A/J mouse lung. First, we determined when to intervene in the carcinogenesis process by exposing several animals to B[alpha]P at 100 and 150 mg/kg of body wt. Groups of these animals were necropsied from 1 to 36 weeks post-carcinogen. The presence of different categories of lung tumors was noted over the 36 week time period. Hyperplasia first appeared approximately 6 weeks post-carcinogen followed by adenoma at 9 weeks, then by carcinoma at 26 weeks. From this temporal sequence we determined we could test for effects of preventive agents on progression to hyperplasia by intervening at 3 weeks, for effects on progression to adenoma by intervening at 6 weeks and for effects on progression to carcinoma by intervention at 12 weeks. Intervention at 3 weeks post-carcinogen with aerosolized budesonide delayed both hyperplasia and adenoma formation. Once hyperplasia appeared in budesonide treated animals, however, it increased at the same rate as in control animals, indicating a delay in progression. Progression from adenoma to carcinoma was reduced when budesonide was given 12 weeks post-carcinogen. Dietary myo-inositol failed to suppress progression from adenoma to carcinoma when started 12 weeks post-carcinogen. In summary, budesonide is a chemopreventive agent that has inhibitory effects on B[alpha]P induced carcinogenesis of the lung in A/J mice at all stages of progression from hyperplasia formation to cancer.

Adenoma↗
PubMed2000

Drug solubilization in lung surfactant.

The relative affinity of glucocorticosteroids for lung surfactant was determined for the purpose of identifying chemopreventive agents with a high therapeutic index for lung cancer. The aqueous solubility and the extent of solubilization in Survanta, a native extract of bovine lung, of budesonide, triamcinolone acetonide, dexamethasone, and flunisolide were determined as a function of temperature by a dialysis technique. The aqueous solubilites at 37 degrees C were 19.6, 35.8, 104 and 120 microg/ml for the above listed compounds, respectively. The temperature dependence of the solubilities was modest consistent with the hydrophobic properties of the steroids. The amount of drug in solution was significantly enhanced in the presence of Survanta with solubilization ratios of 0. 019, 0.023, 0.014, and 0.02 microg drug dissolved per microg of Survanta phospholipid, respectively. In addition, the extent of solubilization also generally increased with temperature, although the phase transition of the surfactant lipid appeared to complicate the functional relation between temperature and solubilization. These results show that there is enhanced solubilization of glucocortosteroids by lung surfactant which is secreted by the cancer susceptible type II cells of the lung.

Animals↗
PubMed2000

Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol.

This investigation is part of an effort to develop chemoprevention for carcinogenesis of the lung. It focuses on the efficacy of low doses of synthetic glucocorticoids administered either as single agents or in combination with a second compound, myo-inositol. Glucocorticoids are potent inhibitors of carcinogenesis. The use of low doses is important to avoid potential side-effects. The synthetic glucocorticoid budesonide, administered by aerosol for 20 s three times a week, was studied to determine its effects on benzo[a]pyrene-induced pulmonary adenoma formation in female A/J mice. Two dose levels were employed, 10 and 25 microg/kg body wt. The lower dose produced a 34% reduction in lung tumor formation and the higher dose level a 60% reduction in lung tumors. In additional groups of mice, the effects of 0.3% myo-inositol added to the diet was found to reduce pulmonary tumor formation by 53%. The two agents given in combination resulted in a greater inhibition of lung tumor formation than either by itself. Budesonide at 10 microg/kg body wt plus 0.3% myo-inositol reduced the number of tumors by 60% and budesonide at 25 microg/kg body wt plus 0.3% myo-inositol reduced lung tumor formation by 79%. To determine whether a glucocorticoid other than budesonide would have inhibitory effects in this experimental model, beclomethasone dipropionate administered by aerosol for 20 s three times a week was studied as a single agent and showed almost identical inhibitory properties to budesonide. The doses of the glucocorticoids calculated on a daily basis are within the range of those used widely for control of chronic allergic respiratory diseases in the human. The capacity of low doses of inhaled glucocorticoids to prevent pulmonary neoplasia and the enhancement of this preventive effect by myo-inositol, an essentially non-toxic compound, are findings that should encourage further work to evaluate the applicability of these agents to the prevention of neoplasia of the lung in the human.

Adenoma↗
PubMed1999

N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps.

This investigation is part of an effort to develop chemoprevention for carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine (NAC). We used as a predictive biomarker, the proliferative index (PI), in a short-term human study. Patients with previous adenomatous colonic polyps are a cohort with increased risk for colon cancer and an increased PI of colonic crypts. They were randomly assigned to an experimental group given 800 mg/day of NAC for 12 weeks or a placebo group. Using proliferative cell nuclear antigen immunostaining, the PI of colonic crypts was measured prior to and after the treatments. The PI of the NAC group was decreased significantly (P < 0.02) while the placebo group showed no difference (P > 0.45). Since this decrease in PI may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted.

Acetylcysteine↗
PubMed1997

Chemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice.

This investigation is part of a continuing effort to develop effective chemoprevention for carcinogenesis of the lung. The present study explores the use of aerosol administrations for this purpose. The agent selected for initial study was the synthetic glucocorticoid budesonide. This selection was based on previous work in which budesonide added to the diet was found to inhibit pulmonary adenoma formation in female A/J mice. However, high dose levels were required, i.e., of the order of 300 microg/kg, of body weight [L. W. Wattenberg and R. D. Estensen, Carcinogenesis (Lond.), 18: 2015-2017, 1997]. For aerosol administration of budesonide, a nose-only technique has been developed that entails nebulization of the compound dissolved in ethanol and subsequent stripping off of the solvent (less than 3 microl ethanol/liter of air remaining at the site of inhalation). The budesonide particles produced by the apparatus had a mass median aerodynamic diameter of less than 1 microm. An experiment has been carried out in which the inhibitory effects of aerosolized budesonide, given for 1 min six times a week, were studied. Concentrations of budesonide of 26, 81, and 148 microg/liter of air (calculated doses of 23, 72, and 126 microg/kg of body weight) were used. The aerosols were started 1 week after three oral administrations of benzo(a)pyrene (2 mg/20 g of body weight) to female A/J mice. All three doses of budesonide resulted in more than 80% inhibition of pulmonary tumor formation compared to the aerosol control and 90% or greater compared to mice not exposed to aerosol. The difference in inhibition is due to the aerosol procedure itself, which produces a reduction in tumor formation. A decrease in splenic weight (evidence of a systemic effect) occurred at all doses of budesonide. To the best of our knowledge, this is the first published effort at the use of aerosol administration to prevent neoplasia of the respiratory tract. The results of the present study show that administration of a potential chemopreventive agent by aerosol at a low dose can inhibit the occurrence of pulmonary carcinogenesis in female A/J mice.

Administration, Inhalation↗
PubMed1997

Studies of chemopreventive effects of budenoside on benzo[a]pyrene-induced neoplasia of the lung of female A/J mice.

The objective of the present investigation was to determine conditions under which the synthetic glucocorticoid, budenoside, will inhibit benzo[a]pyrene (BaP)-induced pulmonary carcinogenesis when administered in the post-initiation period. For this purpose, female A/J mice were employed. The animals were given three administrations of 2 mg of BaP by oral intubation during a 1-week period. Budenoside was fed in the diet subsequent to the last dose of BaP. Using this format, two experiments were carried out to determine the effects of varying the time of administration of budenoside on the magnitude of the inhibition obtained. In both experiments, one group of mice was fed budenoside (1.5 mg/kg of diet) from 1 week after the last dose of BaP until the termination of the experiment, 15 weeks later. The reduction of pulmonary tumor formation under these conditions was 89% in the first experiment and 78% in the second (average 84%). In the first experiment the effects of feeding budenoside only during weeks 1-5 after BaP administration was studied. Under these conditions, inhibition of pulmonary tumor formation was 35%. In the second experiment, the effects of postponing the start of feeding budenoside was determined. In mice in which the budenoside feeding was delayed until 5 weeks after the last dose of BaP and then continued for the duration of the protocol, a 67% inhibition of tumor formation was found. The data obtained indicate that budenoside will produce inhibition of pulmonary adenoma formation when fed either early or late in the post-initiation stage of carcinogenesis, and that feeding throughout the entire post-initiation period gives maximum inhibition.

Adenoma↗
PubMed1997

An overview of chemoprevention: current status and future prospects.

The optimal way of dealing with any disease is by prevention. This is particularly true of cancer, with all of its complexities. A major problem that exists for cancer prevention is that we do not know the cause of over 50% of cancers. Even when causes are known, serious difficulties often exist in removing them. To the extent that causality cannot be dealt with effectively, other strategies merit consideration. One is chemoprevention. A great strength of chemoprevention is that a large number of compounds can prevent the occurrence of cancer, and a variety of mechanisms exist for producing such protection. Much of this review deals with efficacy, toxicity, and mechanisms of action of chemopreventive agents. Gap areas in information are discussed, as well as opportunities for producing compounds with optimal attributes. Chemoprevention is not simple, and successes may not come quickly. However, for both the general population and, even more urgently, for individuals at high risk, chemoprevention has the potential of providing an important means for cancer prevention.

Animals↗
PubMed1996

Chemopreventive effects of myo-inositol and dexamethasone on benzo[a]pyrene and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone-induced pulmonary carcinogenesis in female A/J mice.

The objective of the present investigation was to prevent cancer of the lung by use of chemopreventive agents. Administrations of diets containing added myo-inositol or dexamethasone singly or in combination (the latter being the most potent) are being studied for this purpose. In previous work, the two compounds were shown to inhibit benzo(a)pyrene [B(a)P]-induced pulmonary adenoma formation in female A/J mice when fed during the postinitiation period [ie., starting 1 week after the last of three administrations of B(a)P by oral intubation]. In the present investigation, a longer administration schedule was used, which encompasses both the initiation and the postinitiation stages of carcinogenesis. The feeding of the test compounds was started 2 weeks prior to the first dose of carcinogen and continued for the duration of the experiment. Under these conditions, reductions in tumor formation were: myo-inositol, 64%; dexamethasone, 56%; and both together, 86% (P < 0.001 for all three). Addition of both compounds resulted in the largest inhibition that has been achieved with this experimental model as used in these investigations. Studies have begun of inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenoma formation by myo-inositol and dexamethasone. The two compounds inhibit pulmonary carcinogenesis when fed singly or in combination. When fed throughout the entire protocol, reductions in tumor formation were: myo-inositol, 46%; dexamethasone, 41%; and both together, 71% (P < 0.001 for all three). The results of these investigations demonstrate that myo-inositol and dexamethasone inhibit pulmonary adenoma formation resulting from exposures to two major pulmonary carcinogens, B(a)P and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Adenoma↗
PubMed1996

Inhibition of tumorigenesis in animals.

Animal models are an important component of chemopreventive research. They provide a means of identifying effective compounds, of carrying out fundamental investigations into their mechanisms of action, of determining how they can be used optimally, of evaluating toxicity and, ultimately, of providing an information base for developing intervention trials in humans. They are available for evaluating the effects of chemopreventive agents on the occurrence of cancer in most major organ sites. For some cancers, improved models are required. One such is squamous cell carcinoma of the bronchi, a major cancer in humans. There are three major groups of animal models: the first group involves administration of chemical or physical carcinogens to produce carcinogenesis; the second group consists of mice in which viruses, usually endogenous, are the major causative agents; and the third group entails use of transgenic mice. Most chemopreventive agents investigated in animal models can be placed into three broad categories: compounds preventing attacking molecules from reaching or reacting with critical target sites (blocking agents); compounds decreasing sensitivity of target tissues to carcinogenic stimuli; and compounds preventing the evolution of the neoplastic process (suppressing agents). There is increasing interest in the use of agent combinations rather than single agents as a means of obtaining increased efficacy and minimizing toxicity. Combinations studied thus far entail the use of at least one suppressing agent, in combination with either a blocking agent or a second suppressing agent. The development of optimal strategies for human intervention trials can be facilitated by the use of animal models mimicking the neoplastic process in humans. It is important to exploit this potential to its maximum degree.

Animals↗
PubMed1994

Inhibition of carcinogen-induced pulmonary and mammary carcinogenesis by chalcone administered subsequent to carcinogen exposure.

A study of the capacity of chalcone to inhibit benzo[alpha]pyrene(BP)-induced carcinogenesis of the lungs and forestomach in female A/J mice and N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats has been carried out. Chalcone, 5 mg/g of diet, had a inhibitory effect on pulmonary adenoma formation (29%) and on mammary tumor formation (49%) when the compound was fed starting one week after final carcinogen administration. Chalcone did not inhibit forestomach tumor formation. In an additional study, chalcone started 4 weeks after MNU and fed for 3-week courses alternating with 3-week courses of control diet for the duration of the protocol also inhibited mammary tumor formation by 49%. The data showing that chalcone has inhibitory effects against both pulmonary and mammary carcinogenesis when given after carcinogen administration provides the basis for further investigations of this and possibly other chalcones as chemopreventive suppressing agents.

Adenoma↗
PubMed1993

Studies of chemopreventive effects of myo-inositol on benzo[a]pyrene-induced neoplasia of the lung and forestomach of female A/J mice.

There is a continuing effort at identifying chemopreventive agents that might be useful in preventing cancer of the lung. In the present study, the effects of myo-inositol and dexamethasone on benzo[a]pyrene (B[a]P)-induced pulmonary adenoma formation in female A/J mice was investigated. A diet containing 3% myo-inositol fed beginning 1 week after B[a]P administration reduced the number of pulmonary adenomas by 40% but did not prevent forestomach tumors, which also occur in this experimental model. Under the same conditions, dexamethasone, 0.5 micrograms/g diet, inhibited pulmonary adenoma formation by 57% and also inhibited forestomach tumor formation to a similar extent. Feeding a diet containing both myo-inositol and dexamethasone resulted in an additive effect on the inhibition of pulmonary adenoma formation. The combination of myo-inositol plus dexamethasone produced almost identical inhibition of forestomach tumor formation to that of dexamethasone alone. The results of the present study are preliminary, but may provide a basis for future investigation into strategies for chemoprevention of pulmonary neoplasia.

Adenoma↗
PubMed1992

Inhibition of carcinogenesis by minor dietary constituents.

A major foundation of the field of cancer chemoprevention has resided in an impressive number of animal studies showing that cancer can be prevented by a variety of chemical compounds. In the search for increasingly effective inhibitors, both synthetic and naturally occurring compounds are being investigated. One group of naturally occurring compounds of particular interest consists of minor dietary nonnutrients. Foods of plant origin frequently contain as much as several per cent of these compounds. In recent years there has been a growing awareness that they may have important effects on the consequences of exposure to carcinogenic agents. This information comes from studies of whole diets; individual dietary constituents, particularly those from plants; and finally from investigations of pure compounds. The nonnutrient inhibitors of carcinogenesis have several different mechanisms of action. Some are blocking agents; i.e., they prevent carcinogens from reaching or reacting with critical target sites. Others are suppressing agents; i.e., they prevent evolution of the neoplastic process in cells that otherwise would become malignant. Occasionally, one compound will show both mechanisms. The nonnutrient compounds have the important attribute of there being data on their consumption by humans. Thus, it may be possible to evaluate their impact on cancer risk. Ultimately, information pertaining to these compounds may be useful in terms of diet selection or their use as dietary supplements.

Animals↗
PubMed1991

Nutrients and pancreatic cancer: a population-based case-control study.

A case-control study was conducted in the Minneapolis-St Paul (Minnesota, United States) area to assess the role of dietary factors in the etiology of pancreatic cancer. Cases were White males aged 40 to 84 whose death certificate listed pancreatic cancer (exocrine only). White male controls were ascertained through random-digit dialing. Family members were interviewed about the subject's dietary usage in the two years prior to death (cases, n = 212) or prior to interview (controls, n = 220). Energy-adjusted, nutrient-intake, risk estimates were calculated. Among all respondents, negative trends were observed for polyunsaturated fat, linoleic acid, vitamin C, and beta-carotene. Positive trends were observed for riboflavin and retinol. Point estimates were, in general, comparable between the analyses of all respondents and spouse-only respondents. The nutrients associated with a decreased risk for pancreatic cancer occur primarily in vegetables and fruits, of which the consumption of cruciferous and beta-carotene-rich vegetables and citrus fruits provided the greatest reduction in risk.

Adult↗