Lung Metastases In Rats Research Articles

Design, construction and application of a neutron shield for the treatment of diffuse lung metastases in rats using BNCT

A model of multiple lung metastases in BDIX rats is under study at CNEA (Argentina) to evaluate the feasibility of BNCT for multiple, non-surgically resectable lung metastases. A practical shielding device that comfortably houses a rat, allowing delivery of a therapeutic, uniform dose in lungs while protecting the body from the neutron beam is presented. Based on the final design obtained by numerical simulations, the shield was constructed, experimentally characterized and recently used in the first in vivo experiment at RA-3.

Biodistribution of the boron carriers boronophenylalanine (BPA) and/or decahydrodecaborate (GB-10) for Boron Neutron Capture Therapy (BNCT) in an experimental model of lung metastases

BNCT was proposed for the treatment of diffuse, non-resectable tumors in the lung. We performed boron biodistribution studies with 5 administration protocols employing the boron carriers BPA and/or GB-10 in an experimental model of disseminated lung metastases in rats. All 5 protocols were non-toxic and showed preferential tumor boron uptake versus lung. Absolute tumor boron concentration values were therapeutically useful (25–76ppm) for 3 protocols. Dosimetric calculations indicate that BNCT at RA-3 would be potentially therapeutic without exceeding radiotolerance in the lung.

Selective pulmonary artery perfusion with melphalan is equal to isolated lung perfusion but superior to intravenous melphalan for the treatment of sarcoma lung metastases in a rodent model

Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy. Pharmacokinetics: forty-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations. twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days. Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05). SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both). SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted.

Effects of nefazodone on the development of experimentally induced tumors in stressed rodents.

Anxiety and depression are commonly encountered in patients with cancer and constitute risk and prognostic factors for the disease. Although previous findings do not support an overall association between the use of antidepressants and higher prevalence of cancer, results for serotonin uptake inhibitors are not entirely reassuring. We evaluated the effects of nefazodone, a serotonin and norepinephrine (NE) reuptake inhibitor and 5-HT(2A) receptor antagonist antidepressant, on the appearance of breast cancer induced by mammary tumor virus (MTV) in mice, and on the development of lung metastases in rats injected intravenously with Walker 256 (W-256) carcinosarcoma cells. Female C3H/He mice carrying the MTV were monitored for mammary tumor incidence and latent periods while being treated with a daily intraperitoneal injection with placebo or nefazodone. Rats were administered 10(4) W-256 cells, exposed to a chronic auditory stressor for 8 days, and then killed to evaluate metastatic nodules in the lungs. Although all of the mice were potential candidates for MTV-induced breast cancer, those treated with nefazodone were partially protected against adverse effects of stress induced by the daily administration of placebo on both parameters. Relative to placebo, nefazodone reduced the stress-induced increase in the number and percentage area of metastases in the frontal section through pulmonary hilus and increased the survival periods of rats given W-256 cells and exposed to a chronic auditory stressor. Our results provide evidence of the beneficial effects of nefazodone against the adverse effects of stress on tumor development and metastaticity in rodents, but did not show significant effects in unstressed rodents.

Effects of thrombin/thrombosis in angiogenesis and tumour progression

Laboratory, histopathological, pharmacological and clinical evidence support the notion that a systemic activation of blood coagulation is often present in cancer patients. On the other hand, epidemiological studies provide evidence of an increased risk of cancer diagnosis following primary thromboembolism. Moreover, the metastatic ability of human breast cancer cells is correlated with the number of thrombin receptors of these cells, and thrombin treatment of B16 melanoma cells dramatically increases the number of lung metastases in rats. We have proposed that these tumour-promoting effects of thrombin can be explained by the ability of thrombin to activate angiogenesis, an essential requirement for tumour progression. Many of the cellular events involved in the angiogenic cascade can be activated by thrombin. At the molecular level, brief exposure of endothelial cells to thrombin causes an upregulation of the receptors (KDR and Flt-1) of VEGF, the key angiogenic mediator. This results in a synergistic effect of thrombin and VEGF in the activation of angiogenesis. In addition, thrombin activates cancer cells to secrete VEGF, thus causing a mutual stimulation between EC and CA cells. Cancer cells exposed to thrombin secrete metalloproteinase 92 KD and overexpress the integrin a(v)b(3), all of which are involved in tumour metastasis.

Effects of fluoxetine on the development of lung metastases induced by operative stress in rats

Experiments were performed in order to evaluate the effects of fluoxetine, a selective inhibitor of neural serotonin transporter antidepressant, on the development lung metastases in rats subjected to laparotomy and injected (i.v.) with 10 4 Walker 256 (W-256) carcinosarcoma cells. The number of metastatic nodules on the surface of the lungs, as well as the percentagearea of metastases in the frontal section through pulmonary hilus were increased in rats subjected to sham-surgery or laparotomy. Treatment with fluoxetine (5 mg/kg) partially reversed those adverse effects of surgery, but the difference was clearer when it was administered before surgery was performed. Survival periods were also assessed and fluoxetine was found to decrease the lethality of rats exposed to surgery.

Stimulatory effects of amphetamine on the development of Walker-256 carcinoma lung metastases in rats

Experiments were performed in order to evaluate the effects of amphetamine (0.4 mg/kg/day) on the development of lung metastases in rats injected i.v. with 10(4) Walker 256 (W-256) carcinosarcoma cells, The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats injected with amphetamine in comparison with those injected with placebo. Survival periods were also assessed and amphetamine was found to increase the lethality of rats.

Isolated lung perfusion with FUDR is an effective treatment for colorectal adenocarcinoma lung metastases in rats

Currently, the only treatment capable of significantly prolonging survival in patients with isolated pulmonary metastases from colorectal adenocarcinoma is complete resection. Systemic chemotherapy has been shown to provide little benefit. We evaluated the efficacy of highdose, organ-specific 2'-deoxy-5-fluorouridine (FUDR) using a model of isolated single-lung perfusion (ILP) in the rat. On day 0, 28 BDIX rats were inoculated intravenously with 10(6) viable Sp-5 colorectal adenocarcinoma cells. On day 10 after-tumor inoculation, animals were randomized into five treatment groups. Group I received a continuous intravenous infusion of FUDR (1 mg.kg-1.d-1) for 7 days administered by an osmotic minipump. Group II underwent isolated left lung perfusion with a buffered Hespan solution, groups III to V underwent ILP with 3.5, 7, and 14 mg of FUDR per milliliter of the buffered Hespan solution, respectively. Animals undergoing ILP were anesthetized with pentobarbital, intubated, and ventilated, and then underwent left thoracotomy with cannulation of the pulmonary artery; the pulmonary artery and vein were clamped proximally. Groups II to V were perfused for 20 minutes at a rate of 1 mL/min, followed by a 5-minute washout with FUDR-free buffered Hespan solution. On day 26 after tumor inoculation, the animals in all groups were sacrificed and their lungs were stained and counted. Animals that underwent ILP with 14 mg of FUDR per milliliter of the buffered Hespan solution showed a significant decrease in the number of tumor nodules on the treated side versus the number on the untreated side (455.2 +/- 87.3 versus 11 +/- 6.4; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

INHIBITORY EFFECTS OF ALPRAZOLAM ON THE ENHANCEMENT OF LUNG METASTASES INDUCED BY OPERATIVE STRESS IN RATS

Experiments were performed in order to evaluate the effects of alprazolam (I mg/kg s.c.), a central benzodiazepine agonist anxiolytic, on the development of lung metastases in rats subjected to laparotomy and injected (i.v.) with 10(4) Walker 256 (W-256) carcinosarcoma cells. The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats subjected to sham-surgery or laparotomy. Treatment with alprazolam partially reversed those adverse effects of surgery, but the difference was clearer when it was administered before surgery was performed. Survival periods were also assessed and alprazolam was found to decrease the lethality of rats exposed to surgery. Pretreatment with Ro 15-1788, a central benzodiazepine antagonist, suppressed the inhibitory effects of alprazolam on tumor growth.

Synergistic effect of coumadin and cytoxan in reducing lung metastases

Lung metastasis is a frequent cancer complication resulting in significant mortality. This study evaluates the effect of coumadin and cytoxan alone and in combination on lung metastases in rats challenged with Morris hepatoma 3924A. Seventy-seven male American Cancer Institute (ACI) rats weighing 200 g were studied. Thirty-seven rats received coumadin orally for six days, which resulted in a prothrombin time 2 times that of controls (30 sec). All rats received 1 × 10 5 clumped Morris hepatoma cells via tail vein injection. Animals were divided into four groups: Group I (controls, n = 20) received no antitumor treatment; group II rats (n = 20) received 25 mg/kg cytoxan intraperitoneally at the time of tumor challenge; group III animals (n = 19) received coumadin alone; while group IV (n = 18) received both coumadin and cytoxan. Rats were evaluated for number of lung metastases and lung weight at 3 weeks postinjection. Data was subjected to statistical analysis by the Student's t test. The mean number of lung metastases were 580 ± 45 in group I, 350 ± 310 in group II, 330 ± 263 in group III, and 200 ± 161 in group IV ( P < .005 [IV] v [I], P < .05 [IV] v [II], [III]), ( P < .05 [II] v [I]), ( P < .05 [III] v [I]). Mean lung weights were 2.597 g ± 1.65 in group I, 2.049 g ± 0.75 in group II, 1.898 g ± 0.80 in group III, and 1.677 g ± 0.31 in group IV. ( P < .025 [IV] v [I], P < .05 [IV] v [II]). These data indicate coumadin and cytoxan act synergistically in reducing lung metastases. These observations suggest the synergistic effect of these two agents may prove useful in the prevention of lung metastases in the clinical setting.

Application of magnetic emulsions for sustained release and targeting of drugs in cancer chemotherapy

Magnetic oil-in-water emulsions were evaluated as a carrier system for site-specific and sustained delivery of lipophilic antitumor agents. Two types of magnetic emulsions containing ethyl oleate-based magnetic fluid and nitrosoureas, 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU) or 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), were prepared. Both antitumor agents were stable in the oil phase, whereas they degraded rapidly in aqueous solutions. The in vitro drug release from oil drops of the emulsions to the aqueous phase was slow. The release rate of ACNU dispersed in the oil phase of the emulsions was higher than that of methyl-CCNU dissolved. The magnetic emulsions could be guided into a target site in vivo (lung) by magnetic means. A larger amount of entrapped ACNU was directed to that site than after injecting the free drug. In addition, antitumor effects of both nitrosoureas on AH 7974 lung metastases in rats after injecting of the magnetic emulsions and subsequent exposure of a magnetic field to the lungs were higher than after injecting the free drugs. The results indicated that the magnetic oil-in-water emulsions could be a useful vehicle for the sustained and site-specific delivery of lipid-soluble drugs.

Enhancing effect of thoracotomy and/or laparotomy on the development of the lung metastases in rats after intravenous inoculation of tumor cells.

To evaluate the effect of operative stress on the tumor growth, thoracotomy and/or laparotomy were performed 48 hours after the inoculation of Sato lung cancer cells in Donryu rats. The survival time, the number of metastatic foci on the surface of the lung and the per cent-area of metastatic foci in the frontal section through the pulmonary hilus were observed. Thoracotomy and laparothoracotomy reduced significantly the survival time as compared with the control but no significant difference was found between the two test groups subjected to operative stress. The number of percent-area of metastatic foci found were inversely related to the length of the survival time.

A factor preventing the development of lung metastases in rats with sarcomas.

An immunologically specific factor circulating in lymph and blood prevents the occurrence of lung metastases in rats with sarcomas growing in the leg. Removal of thoracic duct lymph causes such tumours to metastasize to the lung. This is due to the removal of a plasma factor and not of lymphocytes.