Category Archives: Lung Cancer

Chemoprevention of Lung Cancer in Transgenic Mice: Use of Transgenic Mouse Model in Chemoprevention Studies

Chemoprevention of Lung Cancer in Transgenic Mice: Use of Transgenic Mouse Model in Chemoprevention StudiesWe examined the effects of two potential agents on the development of adenomas/adenocarcinomas in these mice. The two classes of agents examined were budes-onide’ and the FTI inhibitor L778,123. The former is a glucocorticoid that presumably interacts with the glucocorticoid receptor, and has been shown to be a profoundly effective agent in the A/J mouse model. L778,123 inhibits the farnesyltransferase enzyme that transfers farnesyl onto proteins and allows their transport to and activation in the cell membrane. FTI inhibitors were initially produced because they should block the farnesylation of the mutant Ras oncogenes (H-ras, N-ras, and K-ras). Although they effectively block H-ras and N-ras farnesylation and activation, they do not block farnesylation of K-ras due apparently to the high affinity of this protein for the farnesyltransferase enzyme. We examined the abilities of these agents to inhibit tumor formation either in a prevention setting in which budes-onide was administered beginning prior to benzo(a)pyrene and throughout the study or in a delayed experiment, which we feel may be closer to that achieved in former or current smokers.

Chemoprevention of Lung Cancer in Transgenic Mice: Lung tumors

The incidence of lung tumors in all four groups of treated mice was 100%. p53+/-Ink4a/Arf+/+, and p53+/-Ink4a/ Arf+/- mice carrying a mutant p53 transgene (Val135) with or without Ink4a/Arf heterozygous deletion had a higher number of lung tumors (an average of 25 tumors per mouse) after treatment with benzo(a)pyrene than wild-type and p53+/+Ink4a/Arf+/- mice (an average of 12.0 tumors per mouse). More interestingly, mice with p53-dominant negative mutation and Ink4A/Arf heterozygous deficiency (p53+/-Ink4a/Arf+/-) exhibited a striking increase in tumor volume (approximately 23-fold) compared to a ninefold increase in tumor volume in mice with only the p53-dominant negative mutation (p53+/-Ink4a/Arf+/+). There was also an approximate 50% and an approximate fourfold increase in tumor volume in Ink4a/Arf heterozygous-deficient mice (p53+/+Ink4a/Arf+/-), indicating that the effect of Ink4A/Arf heterozygous deficiency is mostly on late-stage lung tumor progression. In addition, most of the lung tumors (approximately 60%) from mice with a p53 mutation and deletion of Ink4A/Arf (p53+/-Ink4a/ Arf+/-) were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in < 10% of the lung tumors from the wild-type mice, and approximately 50% of the lung tumors from either p53 transgenic mice or Ink4a/Arf heterozygous-deficient mice. These results clearly indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression.

Chemoprevention of Lung Cancer in Transgenic Mice: Transgenic Mouse Model for Lung Adenocarcinomas

Chemoprevention of Lung Cancer in Transgenic Mice: Transgenic Mouse Model for Lung AdenocarcinomasAlthough the A/J mouse lung adenoma model is valuable because of similar histology to a subtype of human adenocarcinoma, there are some features yet to be desired in order to make this model better. For example, the progression of lung adenomas to adenocarcinomas is rare in A/J mice. The most common genetic alteration associated with these tumors being carcinogen-specific mutations is K-ras. The limited number of large adenocarcinomas produced in this model has been shown to produce characteristic LOH changes. However, even most of these larger adenocarcinomas do not show mutations or loss of the p53 tumor suppressor gene or lost expression of the cyclin D1/cyclin D kinase inhibitor p16 gene, although these or closely related genes are routinely altered in human lung cancer. In order to incorporate these specific alterations into the A/J tumor model, we placed two different transgenes onto the A/J background. canadian pharmacy

Chemoprevention of Lung Cancer in Transgenic Mice: Use of A/J Mice in Chemoprevention Studies

The A/J mouse lung model of chemical carcinogenesis has been the most frequently employed murine model both for testing for potential chemical carcinogens and to screen for agents that prevent carcinogenesis (chemopre-ventive agents). The model has been shown to respond to a wide variety of potential chemical carcinogens, including the tobacco-related carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene, yielding multiple peripheral adenomas. Among the agents tested in A/J mice, several groups of chemicals have shown significant efficacy against mouse lung tumor development.

Chemoprevention of Lung Cancer in Transgenic Mice

Chemoprevention of Lung Cancer in Transgenic MiceLung cancer is the leading cause of cancer deaths in men and women in the United States. Epidemiologic and laboratory animal model studies have demonstrated that smoking and environmental exposure to carcinogens are closely linked to increased lung cancer risk. Tobacco exposure has been implicated in 90% of lung carcinomas, and smokers have a 20-fold greater risk of acquiring lung cancer compared with persons who have never smoked. Although approximately one half of all people who had ever smoked are now former smokers, many people are unable or unwilling to stop smoking. For these reasons, chemoprevention is a potentially important approach to reduce the large number of tobacco-caused cancer deaths, especially for former smokers. Chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer.

Treatment of Stage IIIA Non-small Cell Lung CancerPotentially Resectable N2 Disease

6. Induction (Neoadjuvant) Therapy: Patients with stage IIIA (N2) lung cancer identified preoperatively have a relatively poor prognosis when treated with surgery as a single modality. Several small trials of induction chemotherapy have yielded conflicting results about its effect on survival. The relative roles of surgery and radiation therapy as the local treatment modality are also not clearly defined. Definitive treatment recommendations are difficult to make in this setting. Therefore, patients in this subset should be referred for multidisciplinary evaluation before embarking on definitive treatment. Level of evidence: poor; benefit: none; grade of recommendation: I
7. Induction (Neoadjuvant) Therapy: Whenever possible, induction (neoadjuvant) therapy followed by surgery for stage IIIA disease should be carried out in the setting of a clinical trial. Level of evidence: fair; benefit: moderate; grade of recommendation: B

Treatment of Stage IIIA Non-small Cell Lung Cancer: Summary of Recommendations

Treatment of Stage IIIA Non-small Cell Lung Cancer: Summary of RecommendationsDespite many earlier studies, the optimal treatment recommendations in the various clinical presentations of stage IIIA (N2) disease are unclear. Hopefully, as the current phase III trials accrue and mature and the much-needed, subsequent randomized trials with newer chemotherapy agents and radiotherapy schemata are started and completed, more definitive treatment guidelines will emerge. Until that time, it is critically important that whenever possible the clinician who manages locally advanced NSCLC enroll their patients in every available clinical trial.
A. Incidental (Occult) N2 Disease Found at Thoracotomy
1. Surgical Consideration: In patients with an occult single-station mediastinal node metastasis that is recognized at thoracotomy and when a complete resection of the nodes and primary tumor is technically possible, then proceed with the planned lung resection and a mediastinal lymphadenectomy. Level of evidence: poor; benefit: small; grade of recommendation: C canadian health&care mall

2. Surgical Consideration: In every patient undergoing a lung resection for lung cancer, systematic mediastinal lymph node sampling or complete mediastinal lymph node dissection must be performed. Level of evidence: good; benefit: substantial; grade of recommendation: A

Treatment of Stage IIIA Non-small Cell Lung Cancer: Combination Chemotherapy and Radiotherapy

B. Neoadjvuant (Induction) Therapy Phase III Randomized Trials in Resectable Stage IIIA
North American Intergroup 0139: This trial compares concurrent combination chemotherapy with cisplatin and etoposide plus radiotherapy followed by surgery or radiotherapy in stage IIIA (N2) disease (completed accrual and now closed).
EORTC 08941: A European study comparing platinum-based chemotherapy of choice followed (in responders only) by surgery or radiotherapy.

Treatment of Stage IIIA Non-small Cell Lung Cancer: Ongoing Clinical Trials

Treatment of Stage IIIA Non-small Cell Lung Cancer: Ongoing Clinical TrialsPerhaps the greatest challenge to the clinician in the optimal management of stage IIIA disease is the lack of meaningful, definitive data from large randomized trials on which to base treatment decisions.
A large number of phase I and II trials are accruing involving locally advanced disease with newer chemotherapy agents, newer radiotherapy delivery techniques and fractionation schedules, and novel interventions such as vaccines and gene-based therapy. Fortunately, a number of large, multicenter phase III randomized trials are also ongoing, and on completion should provide results that serve as the basis for rationale treatment recommendations in the various clinical presentations of stage IIIA disease.

Treatment of Stage IIIA Non-small Cell Lung Cancer: unresectable IIIA (N2) disease

Newer-generation chemotherapeutic agents, alone or in combination with the platinum agents, are being incorporated into combined modality chemotherapy plus radiotherapy for locally advanced disease. As an example, a recent phase II trial in locally advanced disease used induction paclitaxel with carboplatin followed by weekly doses concurrent with radiotherapy. This treatment yielded a good response rate (55%) in 38 evaluable patients, with a 1-year survival of 72% and a tolerable toxicity profile.
Other phase I and II trials have reported the feasibility of combining docetaxel, gemcitabine, and irino-tecan in concurrent design with radiotherapy but also do report a range of toxicity profiles. Phase III trials are needed that incorporate these newer, active agents in various dosing schedules with radiotherapy in standard and altered fractionation schedules to define the optimal role of these agents in treatment strategies for unresectable IIIA (N2) disease.

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