Endovascular lung perfusion using high-dose cisplatin: uptake and DNA adduct formation in an animal model

Mean survival after diagnosis of unresectable pulmonary metastases is less than one year. Isolated lung perfusion (ILP) is a technique that delivers chemotherapy into the pulmonary artery via a thoracotomy. Human trials are limited. We report an animal model for endovascular lung perfusion (ELP). Twelve swine were used. Treatment swine (N=6) received 150-mg of cisplatin (CDDP) into the pulmonary artery via a balloon occlusion catheter while nine grams of thiosulfate was given IV. Control swine (N=6) received 50-mg CDDP IV with sham pulmonary artery perfusion. Animals were sacrificed immediately (0 h), 4 or 24 h after infusion. Pulmonary and renal platinum/DNA adducts and serum CDDP levels were measured at all time points. Area under the adduct-time curve (AUA) was determined as a measure of systemic exposure. Pathologic study of the lungs was performed. At 0 h, ELP elevated pulmonary adduct levels by 17.38 times while thiosulfate led to reduction in renal DNA adducts despite the elevated CDDP dose. At all time points, pulmonary adducts were at least 6.9 times higher for ELP compared to IV administration. The AUA was 7 times greater for the ELP group. Serum CDDP levels were significantly higher after ELP (p<0.05). There was no evidence of toxic pulmonary injury from ELP. Direct pulmonary artery infusion of CDDP results in greater DNA adduct formation than would be expected from simple dose escalation. Further study of ELP evaluating the acute and chronic effects of repeated treatment administration is warranted.