title: Plasma MIP-1beta levels and skin toxicity in Japanese non-small cell lung cancer patients treated with the EGFR-targeted tyrosine kinase inhibitor, gefitinib.
abstract: Gefitinib (Iressa() is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways. Skin toxicity has been reported to be the major toxicity observed in patients treated with the EGFR-targeted tyrosine kinase inhibitors, such as gefitinib and erlotinib. Although the mechanisms underlying the development of the skin toxicity remain to be precisely clarified, immunological mechanisms are considered to be involved. We examined the correlations between the plasma levels of several cytokines and the risk of development of adverse events, especially skin toxicity, induced by the administration of gefitinib as first-line monotherapy in non-small cell lung cancer (NSCLC) patients. Paired plasma samples were obtained from a total 28 patients of non-small cell lung cancer; the first before the initiation of gefitinib administration (250 mg/day) (24 patients) and the second 2 or 4 weeks after the initiation of treatment (23 patients). The plasma concentrations of 17 major cytokines were measured using a bead-based multiplex assay. The median concentrations of eight of these cytokines before the start of treatment ranged from 0.06 (IL-5) to 58.26 (MIP-1beta) (microg/ml). The concentrations of the remaining nine cytokines were under the detectable limit (<0.01 microg/ml) in more than 50% of the samples. Comparisons of the levels before and after treatment showed no significant differences for any of the cytokines measured. The MIP-1beta levels were significantly lower in the patients with skin toxicity (16/24) as compared with those in the patients not showing any skin toxicity (59.1+/-10.5 versus 119.0+/-36.8; p=0.042 by the two-sample t-test). The K-Nearest Neighbor Prediction (K=3) showed the classification rate to be 75% for the prediction sets containing MIP-1beta, IL-4 and IL-8. There were no significant associations between the levels of any of the cytokines measured and any other parameters, including the tumor response to the drug. In conclusion, the plasma MIP-1beta level may be a useful predictor of the development of skin toxicity in patients receiving gefitinib treatment.
authors.affiliation: Shien-Lab, National Cancer Center Hospital Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kimura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kasahara
authors.forename: Masaru
authors.initials: M
authors.lastname: Sekijima
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy*; D054407:Chemokine CCL4; D016207:Cytokines / Q000097:blood; D066246:ErbB Receptors / Q000187:drug effects; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy*; D019402:Macrophage Inflammatory Proteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D012867:Skin / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib