Pilot study with weekly chemotherapy for patients with extensive small cell lung cancer: an Eastern Cooperative Oncology Group Study (PA586).

PURPOSE: Six of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach. PATIENTS AND METHODS: Thirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation. RESULTS: Twenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months. DISCUSSION: This 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.

Identification of an inducible regulator of c-myb expression during T-cell activation.

Resting T cells express very low levels of c-Myb protein. During T-cell activation, c-myb expression is induced and much of the increase in expression occurs at the transcriptional level. We identified a region of the c-myb 5' flanking sequence that increased c-myb expression during T-cell activation. In vivo footprinting by ligation-mediated PCR was performed to correlate in vivo protein binding with functional activity. A protein footprint was visible over this region of the c-myb 5' flanking sequence in activated T cells but not in unactivated T cells. An electrophoretic mobility shift assay (EMSA) with nuclear extract from activated T cells and an oligonucleotide of this binding site demonstrated a new protein-DNA complex, referred to as CMAT for c-myb in activated T cells; this complex was not present in unactivated T cells. Because the binding site showed some sequence similarity with the nuclear factor of activated T cells (NFAT) binding site, we compared the kinetics of induction of the two binding complexes and the molecular masses of the two proteins. Studies of the kinetics of induction showed that the NFAT EMSA binding complex appeared earlier than the CMAT complex. The NFAT protein migrated more slowly in a sodium dodecyl sulfate-polyacrylamide gel than the CMAT protein did. In addition, an antibody against NFAT did not cross-react with the CMAT protein. The appearance of the CMAT binding complex was inhibited by both cyclosporin A and rapamycin. The CMAT protein appears to be a novel inducible protein involved in the regulation of c-myb expression during T-cell activation.

Decreased levels of 1,2-sn-diacylglycerol in human colon tumors.

We have found that in 15 of 15 primary human colon tumors there was a significant decrease (by about 40%) in the levels of diacylglycerol when compared to paired adjacent normal mucosa samples. Assays on the same samples indicated that this decrease was seen both in tumors that did and did not display mutations in codon 12 of c-K-ras. These results, taken together with previous studies on protein kinase C, suggest that the protein kinase C signal transduction pathway is suppressed in human colon cancer.