Oral L-2-oxo-4-thiazolidine reduces bacterial translocation after radiation in the Fischer rat.

Glutathione (GSH) is important in protecting rapidly dividing intestinal cells against free radicals generated following radiation. L-2-Oxo-thiazolidine (OTZ) promotes GSH synthesis through increased cysteine delivery. We hypothesize that oral supplementation with OTZ will augment GSH levels and decrease the incidence of bacterial translocation after abdominal radiation, and these effects will be abrogated by treating with a blocker of GSH synthesis, buthionine sulfoximine (BSO). Fischer rats received by oral gavage either OTZ (OTZ/rad), OTZ plus BSO (OTZ/BSO/rad), or saline (sal/rad) 4 hr prior to and 18 hr after radiation. One group underwent saline gavage and no radiation (ctl/sal). On Day 4, animals were sacrificed and mesenteric lymph nodes (MLN) were cultured. Liver and jejunum were removed for GSH analysis by HPLC. Nonradiated, ctl/sal had higher levels of hepatic and jejunal GSH than ctl/rad (13.0 +/- 1.2 vs 9.7 +/- 1.5, 11.2 +/- 1.0 vs 7.8 +/- 2.5 micromol/g dry wt, P < 0.05). Supplementation with OTZ (OTZ/rad) increased hepatic and jejunal GSH levels but treatment with OTZ and BSO (OTZ/BSO/rad) eliminated this benefit (12.0 + 2.6 vs 9.5 + 1.7, 10.1 + 2.4 vs 5.9 + 1.3 micromol/g dry wt, P < 0.05). Ctl/rad had a high rate of positive MLN cultures (80%) compared to ctl/sal and OTZ/rad (10 and 30%, P < 0.05). Treatment with OTZ and BSO (OTZ/BSO/rad vs OTZ/rad, 70 and 30%, P < 0.05) reversed the benefit of OTZ supplementation. This study demonstrated whole abdominal radiation depleted both hepatic and jejunal levels of GSH. Uniquely, OTZ supplementation restored hepatic and jejunal levels of GSH and decreased rate of bacterial translocation.

Isolated lung perfusion with doxorubicin reduces cardiac and host toxicities associated with systemic administration.

BACKGROUND: For patients with malignant neoplasms metastatic to lung, systemic chemotherapy in doses high enough to achieve significant survival improvement is often limited by host toxicity. Isolated single-lung perfusion offers the advantage of delivering high-dose organ-specific chemotherapy while minimizing systemic toxicity. We compared the cardiac and systemic toxicities associated with intravenous administration versus isolated single-lung perfusion with doxorubicin. METHODS: Thirty-three male Fischer 344 rats weighing 275 to 300 g were randomized into three groups: normal control rats (n = 11), intravenous doxorubicin (7/mg/kg) (n = 11), and isolated left lung perfusion with 320 micrograms doxorubicin/mL (n = 11). Animals undergoing isolated single-lung perfusion were anesthetized with pentobarbital, intubated, and ventilated, and then had left thoracotomy with cannulation of the pulmonary artery and a pulmonary venotomy; pulmonary artery and vein were clamped proximally. Animals were perfused for 10 minutes at a rate of 0.5 mL/min, followed by a 5 minute rinse with buffered hespan solution. Arteriotomy and venotomy were repaired and circulation was restored. Daily weights were recorded. On day 24, cardiac output was determined in all groups by injection of radiolabeled chromium 51 microspheres. RESULTS: Animals treated with 7 mg/kg intravenous doxorubicin had a significant weight loss as compared with those treated with isolated lung perfusion (209.2 +/- 29.9 g versus 302.3 +/- 10.1 g; p < 0.01). Animals treated with isolated single-lung perfusion, after recovering from surgical stress, resumed normal growth pattern. Significant cardiac toxicities were seen in intravenously treated animals; cardiac index (27.4 +/- 6.9 versus 39.4 +/1 6.3 mL/min/100g body weight and heart weights (0.56 +/- 0.04 versus 0.88 +/- 0.09 g) were reduced in the intravenously treated group as compared with the group treated with isolated single-lung perfusion. In addition, severe hematologic toxicities are associated with intravenous doxorubicin administration. CONCLUSIONS: Intravenous administration of doxorubicin is associated with severe host toxicities, which include weight loss, decreased cardiac function, and hematologic toxicity. Isolated lung perfusion with high-dose doxorubicin is well tolerated and is associated with minimal host toxicity.

Pulmonary artery perfusion of doxorubicin with blood flow occlusion: pharmacokinetics and treatment in a metastatic sarcoma model.

BACKGROUND: We compared pharmacokinetics, toxicity, and treatment efficacy of pulmonary artery perfusion of low-dose doxorubicin with blood flow occlusion to intravenous doxorubicin injection in a metastatic sarcoma model in the rat. METHODS: Animals received left pulmonary artery perfusion with 0.1, 0.2, or 0.5 mg/kg doxorubicin at a rate of 0.1 mL/min for 1 minute with 20 minutes of blood flow occlusion. Doxorubicin levels of the lung, heart, and serum were assayed. Body weights after treatment were recorded and right pneumonectomy was performed. The results were compared with those in rats that received 5 mg/kg doxorubicin by intravenous injection or the saline group. Pulmonary sarcoma metastases were treated with 0.5 mg/kg doxorubicin through lung perfusion or intravenously, or with saline solution. RESULTS: Doxorubicin levels in the lung, heart, and serum were 112.1 +/- 9.2 micrograms/g, 1.7 +/- 0.2 microgram/g, and 0.3 +/- 0.1 microgram/mL in the group with 0.5 mg/kg doxorubicin perfusion, versus 24.8 +/- 1.9 microgram/g, 10.1 +/- 1.3 microgram/g, and 0.7 +/- 0.2 microgram/mL in the intravenous group (p < 0.05). Animals had normal growth patterns and survived after right pneumonectomy in the perfused group, whereas the intravenous group failed to thrive. No tumors were found or a significant reduction in nodules was noted in the lungs treated with perfusion as compared with untreated right lungs or the intravenous and saline groups. CONCLUSION: This chemotherapy model has important pharmacokinetic advantages and causes an increased treatment response for pulmonary metastatic sarcoma with minimal systemic and local toxicity as compared with systemic doxorubicin administration.

Hypercalcemia and malignant melanoma.

Malignant melanoma occurs in approximately 1.7 per cent of all patients admitted to the Clinical Center, National Institutes of Health, and approximately 1.8 per cent of patients admitted with hypercalcemia and malignant disease. The incidence of hypercalcemia and malignant melanoma is 1.1 per cent. Bone metastases are diagnosed before death in approximately 5.2 per cent of patients with malignant melanoma. The cause of hypercalcemia in our patients appears to be bone metastases in 83.3 per cent and primary hyperparathyroidism in 16.9 per cent.