Further study of nebulisation chemotherapy, a new chemotherapeutic method in the treatment of lung carcinomas: fundamental and clinical

Abstract

Summary Nebulisation chemotherapy, a chemotherapeutic method for the treatment of lung cancer that involves the administration of anticancer agents through the inhalation of nebulised aerosols, has been found to be highly effective (Tatsumura et al., 1983a,b). We confirmed that 5-FU administered by this method accumulates in the trachea, bronchi and regional lymph nodes of patients treated before surgery, along with 5-FU metabolites, FUR and FUdR, indicating that 5-FU is directly incorporated and metabolised in the respiratory tract. Parallel result were obtained using mongrel dogs. The 5-FU levels in other organs, such as the heart and liver, were found to be extremely low. Only a trace of 5-FU was found in the serum of both the patients and the dogs. We further investigated the anti-tumour effect of this therapy in ten selected patients and observed a satisfactory anti-tumour response of 60.0%. These results, along with our previous finding that the retention time of isotope tracers inhaled as aerosol is considerably longer in tumour tissues than in normal parts (Tatsumura et al., 1983a) al., 1983a,b). The present study further supports the therapeutic value of this method and presents some data which help explain how this therapy works. Materials and methodsAdministration and analysis of 5-FU in mongrel dogs The concentrations of 5-FU and its metabolites, FUR and FUdR, in the tissues and sera were measured using a recently developed, high-performance liquid chromatographic (HPLC) method (Masuike et al., 1985).Eighteen mongrel dogs weighing 15.5-16.5 kg were used in the experiment. All dogs were anaesthetised with ketamine hydrochloride (Ketalar) (10-20 mg kg-') and atropine sulfate (0.03-0.04 mg kg-'). They were then intubated, mechanically ventilated, and given supplementary oxygen. Anaesthesia was maintained by an intravenous administration of pentobarbital (5-10 mg kg-'). The inhalant was prepared by mixing 5-FU (50 mg kg-') with expectorant, was nebulised by an ultrasonic nebuliser, and was then sent into the respiratory apparatus. Oxygen was supplied to the circuit at a rate of 2 1/min and ventilation was carried out at 100-150 ml min-' at 20 times/min. This circuit carried the aerosol to the bronchial trees at the alveolar level.Cardiac arrest was induced by an intravenous injection of KCI after each procedure. Tissue samples were collected after

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

“…A secondary treatment pathway may involve the diffusion of the 5-FU cytotoxic metabolite through the pleura porous to the lymphatic circulation 46,47 , as it has been previously observed that different concentrations of administered drug formulations enter the lymphatic circulation through the pleura porous. 48 Gene therapy studies in advance stage lung cancer patients with MPE treated with intracostal instillation of adenovirus have presented promising results. In a Phase I trial by Sterman et al (2007) 43 , effectiveness and safety of the Ad.…”

The Airways: A Promising Route for the Pulmonary Delivery of Anticancer Agents

“…Similarly, the concentration of aeorosolised 5-Fluorouracile (5-FU) in the lung tissue was 1000 times higher than in the serum of hamsters (Hitzman et al, 2006). High concentrations of 5-FU were detected in the trachea and bronchi of dogs after airways delivery, whereas a lower concentration was measured in the peripheral lung (Tatsumura et al, 1993). We have used near infrared imaging to analyze the distribution of cetuximab, an anti-EGFR antibody, in a xenograft model of lung tumour following systemic and pulmonary delivery, (Maillet et al, in press).…”

Inhaled Chemotherapy in Lung Cancer: Safety Concerns of Nanocomplexes Delivered

“…The adverse respiratory effect observed was an acute form of dosedependent pneumonitis, which, in some cases, induced pulmonary edema, alveolar hem orrhage and death in animals [13,21]. These adverse effects were recorded in very low numbers and were not observed in human patients, possibly as a result of the different structure and defense mechanisms of the human respiratory system [7,11,12]. Respiratory evaluation in patients has predominantly included respiratory function tests (e.g., forced expiratory volume in 1 s, forced vital capacity, diffusing capacity of the lung for CO and peak expiratory flow) and broncho alveolar lavage.…”

“…Nevertheless, in some cases, fever remained for a maximum of 3 days and was dose dependent [7,11]. Safety concerns regard ing the medical staff urged the investigators to perform the inhalation administration inside a highefficiency particulate air system and evalu ate whether any inhaled aerosol was not properly absorbed or administered [12]. In this way, the minimal concentrations of escaped aerosol were …”

“…The efficacy and safety of such approaches have been evaluated in vitro and in vivo for several chemo therapeutic drugs, either in their commer cial or nanocomplexed forms [7,[11][12][13][14][15][16][17][18]. The major advantages of inhaled chemotherapeutic agents include reduced systematic side effects and effi cient control of micrometastasis.…”