Role of Sensory Nerve Peptides Rather than Mast Cell Histamine in Paclitaxel Hypersensitivity

Abstract

Paclitaxel is one of the most extensively used anticancer agents, however, its use is often limited by severe hypersensitivity reactions, including respiratory distress, bronchospasm, and hypotension, which can occur despite premedication with dexamethasone and histamine H1 and H2 antagonists. The present study was designed to determine the mechanisms of paclitaxel hypersensitivity. In rats, paclitaxel (15 mg/kg, intravenously) caused a marked increase in pulmonary vascular permeability and edema. PaO2 decreased, whereas PaCO2 increased, transiently after paclitaxel injection. The paclitaxel-induced pulmonary vascular hyperpermeability was blocked by dexamethasone but not by histamine H1 or H2 antagonists. Paclitaxel increased the vascular permeability in lungs of mast cell-deficient rats Ws/Ws(-/-) to almost the similar extent as that elicited in wild-type rats. On the other hand, the paclitaxel-induced pulmonary vascular hyperpermeability was reversed by sensory denervation with capsaicin or pretreatment with LY303870 and SR48968, NK1 and NK2 antagonists, respectively. Consistent with these findings, a marked elevation of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide was observed in rat bronchoalveolar lavage fluid after paclitaxel injection. These findings suggest that sensory nerves rather than mast cells are implicated in the etiology of paclitaxel hypersensitivity.

Prophylactic effect of pemirolast, an antiallergic agent, against hypersensitivity reactions to paclitaxel in patients with ovarian cancer

“…11 We also found that pemirolast, an antiallergic agent that possesses mast-cell-stabilizing action, 12,13 attenuates pulmonary vascular hyperpermeability and edema induced by paclitaxel, by lowering the concentrations of sensory peptides in bronchoalveolar lavage fluids in rats.…”

“…We have recently shown that paclitaxel causes pulmonary vascular hyperpermeability and edema and the decrease in arterial partial oxygen pressure in rats. 11 The toxic effects of paclitaxel in rat lungs are attenuated by neurokinin NK 1 and NK 2 receptor antagonists, or chemical sensory denervation with repeated capsaicin treatment, but not by histamine H 1 or H 2 antagonists, thereby suggesting that the pulmonary adverse reactions induced by paclitaxel are mediated by sensory nerve peptides such as substance P and neurokinin A, but not by mast cell histamine. 11 Indeed, the concentrations of these sensory nerve peptides, but not histamine, are elevated in bronchoalveolar lavage fluids of rats after paclitaxel injection.…”

“…11 The toxic effects of paclitaxel in rat lungs are attenuated by neurokinin NK 1 and NK 2 receptor antagonists, or chemical sensory denervation with repeated capsaicin treatment, but not by histamine H 1 or H 2 antagonists, thereby suggesting that the pulmonary adverse reactions induced by paclitaxel are mediated by sensory nerve peptides such as substance P and neurokinin A, but not by mast cell histamine. 11 Indeed, the concentrations of these sensory nerve peptides, but not histamine, are elevated in bronchoalveolar lavage fluids of rats after paclitaxel injection. 11 We also found that pemirolast, an antiallergic agent that possesses mast-cell-stabilizing action, 12,13 attenuates pulmonary vascular hyperpermeability and edema induced by paclitaxel, by lowering the concentrations of sensory peptides in bronchoalveolar lavage fluids in rats.…”

“…11 Indeed, the concentrations of these sensory nerve peptides, but not histamine, are elevated in bronchoalveolar lavage fluids of rats after paclitaxel injection. 11 We also found that pemirolast, an antiallergic agent that possesses mast-cell-stabilizing action, 12,13 attenuates pulmonary vascular hyperpermeability and edema induced by paclitaxel, by lowering the concentrations of sensory peptides in bronchoalveolar lavage fluids in rats. 14 In the present study, we investigated the clinical effect of pemirolast for prevention of HSRs associated with paclitaxel in patients with ovarian cancer who undertook postoperative paclitaxel and carboplatin combination chemotherapy.…”

Effect of paclitaxel (Taxol®) on the biodistribution of sodium pertechnetate (Na99mTcO4) in female Wistar rats

“…Paclitaxel, commercially known by Taxol ® , is a compound with intense antitumoral activity extracted from the Taxus species. It is presently one of the most important drugs used in cancer chemotherapy (Itoh et al 2004;Feldweg et al, 2005). Paclitaxel is an unique anticancer agent with tubulin-stabilizing action, and widely used for several malignancies, including ovarian, breast, stomach and non-small cell lung cancers (Sparreboom et al, 1997;Akerley, 2000;Souza, 2004;Itoh et al 2004;Feldweg et al, 2005).…”