Junzaburo Kabe

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer

Purpose: CPT-11 (60 mg/m2 on days 1, 8 and 15) in combination with CDDP (80 mg/m2 on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m2 together with CDDP at 27 mg/m2 (level 1, 6 patients), 33 mg/m2 (level 2, 12 patients), and 40 mg/m2 (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m2 CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity.

The lungs as the site of delayed-type hypersensitivity reactions in guinea pigs

Guinea pigs immunized by a single intramuscular injection of dry killed tubercle bacilli were exposed to purified protein derivative (PPD). Respiratory frequency and airway resistance showed no obvious changes immediately after inhalation of PPD, but respiratory frequency increased gradually after 6 hours and reached a maximum around 24 to 48 hours. At this time respiratory frequency was 1.5 to 2.5 times more than the control and declined to the control values over the next 48 to 72 hours. The lungs showed gradually increasing hepatization-like changes which reached a maximum around 24 to 48 hours and gradually subsided within 7 days after inhalation of PPD. Histologically, polymorphonuclear cells were predominant initially but mononuclear cells became dominant in 24 to 48 hours. Considerable thickening of the interalveolar septa was observed. Guinea pigs passively sensitized with splenic cells showed identical changes although less marked.