Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer.

PURPOSE: We initiated a large multicenter phase II trial in stage IV non-small-cell lung cancer (NSCLC) to evaluate the activity and safety of an oral gelatin-based formation of vinorelbine. PATIENTS AND METHODS: Twenty-three centers participated in this uncontrolled phase II study, which accrued patients between August 1991 and March 1992. Eligible patients had previously untreated measurable or assessable stage IV NSCLC, age more than 18 years, and Karnofsky performance status > or = 70%. The treatment plan initially was to administer 100 mg/m2/wk of oral vinorelbine or 80 mg/m2/wk for patients who had received prior radiation therapy. After the observation of grade IV granulocytopenia in six of the first 25 patients, subsequent doses were reduced by 40 mg (one capsule) in all patients. RESULTS: One hundred sixty-two patients were treated: 138 with measurable and 24 with assessable disease. One hundred two patients were men and 60 women. The mean age was 62 years (range, 36 to 83). The overall response rate was 14.5% for patients with measurable disease (95% confidence interval, 9.3% to 21.7%). The median time to treatment failure (TTF) for all patients was 9 weeks. The median survival time was 29 weeks; the 1-year survival rate was 22%. Toxicities included grade 3 or 4 neutropenia in 40%, which was dependent on the vinorelbine dose. Other toxicities included mild to moderate nausea/vomiting, diarrhea, and stomatitis. The mean dose intensity of vinorelbine was 53 mg/m2. CONCLUSION: Oral vinorelbine administered once weekly is an active agent in stage IV NSCLC. The median survival time of 29 weeks is similar to that achieved with single-agent intravenous vinorelbine and more aggressive cisplatin-based combinations. Further studies of this compound in the palliative-intent care setting appear to be indicated.

Protein kinase C beta expression in melanoma cells and melanocytes: differential expression correlates with biological responses to 12-O-tetradecanoylphorbol 13-acetate.

Normal human melanocytes require 12-O-tetradecanoylphorbol 13-acetate (TPA) for prolonged growth in vitro. In contrast, the growth of human malignant melanoma cells is often inhibited by TPA. In this study, we have confirmed and extended these observations. Since protein kinase C (PKC) is an important mediator of the effects of TPA, we have investigated the nature of this differential growth response by examining PKC expression and activity in primary cultures of human neonatal melanocytes and metastatic melanoma cell strains. PKC, when measured by immunoreactivity or a functional assay, was found to be more abundant in melanoma cells than in melanocytes. When specific isotypes were examined by Northern analysis, PKC-alpha and -epsilon were expressed in both melanocytes and melanoma. PKC-beta was expressed in melanocytes, but was undetectable by Northern analysis in 10 out of 11 melanoma cell strains. Southern analysis revealed that no gross deletions or rearrangements of the PKC-beta gene had occurred. These data suggest that down-regulation of the PKC-beta gene occurs frequently during the process of transformation of melanocytes. Furthermore, differential expression of PKC isotypes may explain the different effects of TPA on melanocyte and melanoma cell growth.

The transactivating domain of the c-Jun proto-oncoprotein is required for cotransformation of rat embryo cells.

The nuclear phosphoprotein c-Jun, encoded by the proto-oncogene c-jun, is a major component of the AP-1 complex. A potent transcriptional regulator, c-jun is also able to transform normal rat embryo cells in cooperation with an activated c-Ha-ras gene. By deletion analysis, we identified the regions of c-Jun encoding transformation and transactivation functions. Our studies indicate that there is a direct correlation between the ability of the c-Jun protein to activate transcription and cotransform rat embryo cells. The regions involved in these functions include the conserved leucine zipper/DNA binding domain and an effector domain near its N terminus. This N-terminal region spans amino acids 61 to 146 of the c-Jun protein and is highly conserved among all Jun family members. These results support the hypothesis that c-Jun transforms cells by stimulating the expression of transformation-mediating genes.

A complex pattern of translational initiation and phosphorylation in L-myc proteins.

Molecular analysis of the human proto-oncogene L-myc revealed a complex pattern of gene expression including alternative splicing and polyadenylation site selection of mRNA, giving rise to at least four mRNAs. These mRNAs in turn can code for several proteins. In this report, we characterize and define the origins of the major L-myc proteins. In vitro translation revealed that (i) two L-myc proteins (p59 and p65) were derived through alternative translational initiation at a non-AUG (CUG) site in intron 1 and at an AUG site in exon 2 of L-myc, and that (ii) extensive post-translational phosphorylation of these proteins yielded three additional proteins (p60, p66, and p68). Transfection experiments in rat embryo cells revealed the in vivo existence of this unusual CUG-initiated protein and demonstrated that it possessed transforming activity. Further, immuno-precipitation using high titered anti-L-myc peptide antisera, of two L-myc expressing small-cell lung cancer cell lines revealed three major L-myc proteins (p60, p66 and p68) all of which were derived from extensive phosphorylation of a p59 protein.

p53: a frequent target for genetic abnormalities in lung cancer.

Allele loss is a hallmark of chromosome regions harboring recessive oncogenes. Lung cancer frequently demonstrates loss of heterozygosity on 17p. Recent evidence suggests that the p53 gene located on 17p13 has many features of such an antioncogene. The p53 gene was frequently mutated or inactivated in all types of human lung cancer. The genetic abnormalities of p53 include gross changes such as homozygous deletions and abnormally sized messenger RNAs along with a variety of point or small mutations, which map to the p53 open reading frame and change amino acid sequence in a region highly conserved between mouse and man. In addition, very low or absent expression of p53 messenger RNA in lung cancer cell lines compared to normal lung was seen. These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.

Tracheoesophageal fistula in the patient with lymphoma: case report and review of the literature.

Tracheoesophageal fistula (TEF) occurs only rarely in the patient with lymphoma. Two cases are presented to illustrate the challenges in managing TEF in this patient population. Most of the 38 previously reported cases have occurred in patients who have undergone radiation therapy, although several patients have had TEF as an initial manifestation of lymphoma. TEF is usually, but not universally, associated with the presence of active lymphoma. The surgical approach should be individualized, based on the patient's overall condition, the site and size of the fistula, and sites of disease. Often a conservative surgical approach is warranted with the expectation that many of these fistulas will close after radiation therapy or chemotherapy. Patients with lymphoma-related TEF have a better prognosis than do those with TEF caused by carcinoma of the lung or esophagus.