Diazaborine resistance in the yeast Saccharomyces cerevisiae reveals a link between YAP1 and the pleiotropic drug resistance genes PDR1 and PDR3.

We have investigated the mechanisms underlying resistance to the drug diazaborine in Saccharomyces cerevisiae. We used UV mutagenesis to generate resistant mutants, which were divided into three different complementation groups. The resistant phenotype in these groups was found to be caused by allelic forms of the genes AFG2, PDR1, and PDR3. The AFG2 gene encodes an AAA (ATPases associated to a variety of cellular activities) protein of unknown function, while PDR1 and PDR3 encode two transcriptional regulatory proteins involved in pleiotropic drug resistance development. The isolated PDR1-12 and PDR3-33 alleles carry mutations that lead to a L1044Q and a Y276H exchange, respectively. In addition, we report that overexpression of Yap1p, the yeast homologue of the transcription factor AP1, results in a diazaborine-resistant phenotype. The YAP1-mediated diazaborine resistance is dependent on the presence of functional PDR1 and PDR3 genes, although PDR3 had a more pronounced effect. These results provide the first evidence for a functional link between the Yap1p-dependent stress response pathway and Pdr1p/Pdr3p-dependent development of pleiotropic drug resistance.

Expression of c-myc and c-fos mRNA in colorectal carcinoma in man.

Thirty colorectal carcinomas, 1 adenoma of the colon, 1 case of Crohn's disease and 13 specimens of non-neoplastic colorectal mucosa were examined for qualitative and quantitative expression of the c-myc and c-fos protooncogenes. These genes encode nuclear proteins, which are both believed to regulate gene transcription. Oncogene expression was evaluated at the mRNA level by in situ hybridization and Northern blot analysis. Densitometric analysis of the specific bands on Northern blots revealed a highly significant overexpression of c-myc mRNA in colorectal carcinomas compared with non-neoplastic tissue (p less than 0.001). Furthermore, increased expression of c-myc mRNA was found in moderately and poorly differentiated carcinomas compared with well differentiated ones. In contrast to c-myc, c-fos mRNA expression was significantly lower in carcinomas than in non neoplastic tissue (p less than 0.02). Neither, c-myc nor c-fos mRNA levels showed a clear-cut correlation with tumor stage. We conclude that c-myc mRNA overexpression plays an important role in the progression of colorectal carcinomas. In contrast enhanced c-fos mRNA expression may be related to cell differentiation, both in tumors and non-neoplastic tissue.

Carcinoma of the oral cavity: on the prognostic significance of the primary tumour site (by organs) in the oral cavity.

The prognostic significance of so-called organ sites was investigated in 585 cases with carcinoma of the oral cavity and lips. For the subsamples studied the numerical distribution of TNM categories, life tables and life table comparisons were computed. This produced the following results: 1. There is no demonstrable difference in prognosis between identical T catagories in the organs of the oral cavity. 2. In some cases there is a significant difference between identical N categories in organs of the oral cavity. In the No category this is, however, attributable to the substantial differences in the numerical distribution of T categories. By contrast, a logical explanation for the computationally demonstrable significant differences in the Nx category is not available. The problem is currently being investigated. 3. An assessment of identical TN combinations in the "organs" of the oral cavity proved to be impossible on account of the inadequate number of cases available. The so-called "organ localization" of primary tumours in the oral cavity need not - at least for the time being - be accorded any prognostic relevance. The findings should, however, be re-examined on the basis of greater numbers.

[A retrospective study of carcinomas of the oral cavity: a preliminary report (author's transl)]. / Karzinome der Mundhöhle. Vorläufiger Bericht über eine retrospektive Studie.

UNLABELLED: The German-Austrian-Swiss Research Team on Maxillofacial Tumours is investigating a series of 585 carcinomas of the oral cavity, lips and oropharynx by biostatistical methods. The aim of the study is the determination of relevant prognostic symptoms of oral cavity carcinomas, classification of the series on the basis of these symptoms, the determination of therapeutic efficacy and the assessment of collective and individual prognosis. PRELIMINARY RESULTS: 1. Factors of prognostic relevance are probably only tumour size and intensity of regional metastases. 2. The classification of the series becomes problematic due to the lack of relevant prognostic factors.

Carcinoma of the oral cavity: on the prognostic significance of the primary tumour site (by levels and areas).

The prognostic significance of primary tumour site in carcinomas of the oral cavity was investigated in a series of 585 cases. For the subsamples (levels and areas of oral cavity) studied, the numerical distribution of TNM categories, life tables and life table comparisons were computed. This produced the following results: Given an identical extension and analogous metastazising rate, there is no computationally demonstrable difference in prognosis between primary tumours sited at different levels and areas of the oral cavity. The exception are the T1Nx categories, for which a difference exists between precanine and retromolar sites. These results should be re-examined on the basis of a larger series.

TNM-classification of carcinomas of the oral cavity-efficacy of clinically available data (TN).

Using adequate number of cases, the influence of the spread of primary tumour and the degree of regional metastasis on prognosis were investigated. Assuming a practicable classification as a prerequisite for clinico-therapeutic cancer research, experience has shown that the assessment of the spread of primary tumour alone does not suffice for the establishment of comparable homogenous data. The investigation on the importance of the degree of regional metastasis has shown, above all, that the percentage of N3-metastasis within the T-groups contributes essentially to the fact that these show a marked difference in their prognosis. It would therefore appear necessary also to examine the importance of other clinically accessible data in the assessment of prognosis. Only then could we be in a position to judge whether, and to what extent a clinically practicable classification and integration into special groups is possible on the basis of clinically available data. The inclusion of more clinics in the joint investigation is encouraged.