ABSTRACT
We conducted a feasibility study to examine whether small numbers of cancer cells could be utilised for analysis of the EGFR gene status using the loop-hybrid mobility shift assay, which is a modified heteroduplex technique. Cytology specimens obtained by transbronchial abrasion were successfully used for analysis of the EGFR gene status in 50 of 52 (96.2%) patients diagnosed with class V non-small-cell carcinoma. Furthermore, the relationship between the EGFR gene status and clinical outcome was analysed in 25 patients treated with gefitinib. Overall, 10 of 11 patients with EGFR mutations in exon 19 or 21 showed tumour regression with gefitinib treatment, compared to only two of 14 patients with wild-type EGFR. The response rate was significantly higher in the EGFR mutation group than in the wild-type EGFR group (90.9 vs 14.3%, P=0.00014). Logistic regression analysis revealed that EGFR mutations in cytology specimens represented an independent predictor of the gefitinib response. The overall and progression-free survivals were significantly longer in the EGFR mutation group than in the wild-type EGFR group (P<0.05). In conclusion, cytology specimens could be useful for analysing the EGFR status in the majority of patients with non-small-cell lung cancer to determine whether they are likely to benefit from gefitinib treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation/genetics , Quinazolines/therapeutic use , Adult , Aged , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Chi-Square Distribution , DNA Mutational Analysis/methods , ErbB Receptors/antagonists & inhibitors , Female , Gefitinib , Humans , Kaplan-Meier Estimate , Logistic Models , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Nucleic Acid Heteroduplexes/genetics , Treatment OutcomeABSTRACT
A galactosaminoglycan (CO-N) obtained by ultrasonication from a protein-bound polysaccharide SN-C, which was isolated from Cordyceps ophioglossoides culture, has a direct cytotoxicity against tumor cells (Ohmori et al., Chem. Pharm. Bull., 37, 1019 (1989). High performance liquid chromatographic analysis revealed that CO-N shows a broad molecular weight distribution with an average molecular weight of 33000. A potent antitumor activity of CO-N was observed in the higher-molecular-weight fraction on gel filtration, and the low-molecular-weight fraction below 6600 showed a weak activity. However, the depolymerized CO-N (ca. 5500) obtained by further ultrasonication of the original CO-N still retained the antitumor activity of CO-N against Ehrlich ascitic carcinoma or MM46 solid mammary carcinoma.
Subject(s)
Antineoplastic Agents , Hypocreales/chemistry , Polysaccharides/analysis , Animals , Male , Mice , Mice, Inbred C3H , Mice, Inbred ICR , Molecular Weight , Polysaccharides/pharmacologyABSTRACT
The effects of oxotremorine and AF102B (cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine), a novel M1-selective muscarinic agonist, on acetylcholine (ACh) and dopamine (DA) release from superfused rat hippocampal and striatal synaptosomes were investigated. Synaptosomes that had been prelabeled with [3H]choline or [3H]DA were depolarized by high K+. Oxotremorine and AF102B decreased the K+-evoked [3H]ACh release from hippocampal synaptosomes and increased the K+-evoked [3H]DA release from striatal synaptosomes. The dose-response curves showed that AF102B was far less potent than oxotremorine at the hippocampal presynaptic muscarinic receptors (autoreceptors). On the other hand, AF102B was more potent than oxotremorine at the muscarinic receptors on the striatal dopaminergic terminals (heteroreceptors). Pirenzepine, a selective M1 antagonist, counteracted the effects of oxotremorine on [3H]DA release more potently than it did the effects of oxotremorine on [3H]ACh release. Our results suggest that AF102B and pirenzepine discriminate pharmacologically between muscarinic autoreceptors and heteroreceptors.