SummaryInterferon (IFN) y induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity. We found a third pair ofproteasome subunits expressed reciprocally in response to IFN-y. Molecular cloning of a cDNA encoding one subunit designated as Z, downregulated by IFN-% showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by IFN-% Thus, IFN-~/induces subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for immunological processing of endogenous antigens. When processed from their precursors, three pairs of the 10 homologous, but distinct, [3-type subunits of eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2-terminal threonine residue, assumed to be part of a catalytic center. These findings suggest that the altered molecular organization of the proteasome induced by IFN-y may be responsible for acquisition of its functional change.

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cis-Diamminedichloroplatinum(II) (CDDP) was given as a single agent at a dose of 25 mg/m2 daily for 5 days by continuous infusion; treatment was repeated every 4 weeks in 30 previously untreated patients with advanced non-small-cell lung cancer (NSCLC). The median age of the patients was 61 years; 13 patients had limited disease and 17, extensive disease. The overall response rate was 40% (12/30; 95% confidence limits, 23-58%), with a median survival of 8 months. Vomiting was observed in 37% of patients; elevated serum creatinine levels (greater than 1.5 mg/dl), in 7%; leukopenia (less than 3,000/mm3), in 39%; thrombocytopenia (less than 70,000/mm3), in 26%; and anemia (hemoglobin less than 9.5 g/dl), in 60% of patients. In all cases, these toxicities were mild and transient, requiring no dose modification. The exposure to filterable platinum, determined from the area under the concentration-time curve, was 9.08 +/- 3.21 micrograms h ml-1. We conclude that CDDP given by 5-day continuous i.v. infusion is safe and effective for treatment of NSCLC.

To assess the feasibility and efficacy of rhGM-CSF in ameliorating chemotherapy-induced leukopenia in patients with advanced non-small-cell lung cancer, we conducted a double-blind placebo controlled phase III study in a multicenter setting. Patients were eligible if they had cytologically or histologically proven cancer, no prior chemotherapy, stage IIIB or IV disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an age of less than 76 years, and no symptomatic brain metastasis, disseminated bone metastasis, or previous vertebral/pelvic irradiation. The chemotherapy regimen consisted of mitomycin given at 8 mg/m2 on day 1, cisplatin given at 100 mg/m2 on day 1, and vindesine given at 3 mg/m2 i.v. on days 1 and 8 (MVP). If the granulocyte nadir count recorded after the first cycle of MVP was less than 1,000/mm3, patients were randomly assigned to receive recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo during the second cycle of MVP. The dose of rhGM-CSF was 125 micrograms/m2 given daily s.c. for 14 consecutive days starting on day 2. Of the 52 patients enrolled, 45 were evaluable. The nadir of granulocytes was significantly lower in the placebo group (P = 0.007). The period during which the granulocyte count was less than 1,000/mm3 was significantly longer in the placebo group (median, 6 vs 10 days; P = 0.04). The incidence of adverse effects related to rhGM-CSF, such as fever (> or = 38 degrees C) and skin rash, was significantly higher in the rhGM-CSF group (P = 0.011). The rate of response to chemotherapy did not significantly differ between the two groups. In conclusion, rhGM-CSF reduced the duration of chemotherapy-induced granulocytopenia. The clinical usefulness of this agent may be deminished because of the adverse effects encountered when it is used in combination with a moderately myelotoxic chemotherapy regimen.