Drug interactions of 5-fluorouracil with either cisplatin or lobaplatin--a new, clinically active platinum analog in established human cancer cell lines.

Lobaplatin [1,2-diaminomethylcyclobutane platinum(II)-lactate] is a new platinum compound which appears to possess incomplete cross-resistance to cisplatin and might have a favorable pattern of side effects. Since lobaplatin has activity in esophageal cancer, combination protocols with 5-fluorouracil (5-FU) are evaluated. In order to assess the mode of action of lobaplatin when combined with 5-FU, two human cancer cell lines were treated with various combinations of 5-FU given for either 2 or 24h and lobaplatin. Drug interactions were evaluated by isobologram analysis. Lobaplatin showed basically the same interaction pattern when combined with 5-FU as cisplatin. The combination of either platinum analog with a 24 h exposure to 5-FU was superior to a short-term 5-FU exposure. Furthermore, when 5-FU was given for 24 h, no additional effect of folinic acid was seen. From these data we conclude that cisplatin and lobaplatin show similar interactions with 5-FU. Protracted infusion schedules of 5-FU appear to be more active than bolus application.

Genotoxicity of aloeemodin in vitro and in vivo.

The present in vitro and in vivo experiments were undertaken to clarify the genotoxic potential of the hydroxyanthrachinone aloeemodin which can be found in different plant derived products for therapy of constipation. The results demonstrate that aloeemodin is able to induce mutagenic effects in vitro. Positive results were obtained in the chromosomal aberration assay with CHO cells, as well as in the Salmonella reverse mutation assay (frameshift mutations in strains TA 1537, TA 1538 and TA 98). No mutagenic potential of aloeemodin, however, was observed in the gene mutation assay with mammalian cells in vitro (HPRT assay in V79 cells). Each assay was performed in the presence and absence of an extrinsic metabolic activation system (S9-mix). In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot text [DBA/2JxNMRI]) no indication of a mutagenic activity of aloeemodin was found. Information about a possible reaction of aloeemodin with DNA was derived from an in vivo UDS assay. Hepatocytes of aloeemodin-treated male Wistar rats did not show DNA damage via repair synthesis. All these data suggest that aloeemodin is able to interact with DNA under certain in vitro conditions. However, in vivo the results that were negative did not indicate a genotoxic potential. Therefore, it may be assumed that a genotoxic risk for man might be unlikely.

Studies on the in vitro and in vivo genotoxicity of [2,2-dimethyl-6- (4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (CAS 156897-06-2, ML 3000) was examined for genotoxic activity in bacteria and mammalian cells in vitro as well as in vivo. The substance did not increase gene mutation frequencies either in a bacterial system or in a cultured V79 cell line of the Chinese hamster. Both in vitro tests were conducted in the presence and absence of S9-mix. In the unscheduled DNA synthesis assay in vitro with primary rat hepatocytes, negative results were also obtained. A cytogenetic analysis of the bone marrow of male and female Wistar rats was performed. After oral application ML 3000 did not increase the number of cells with structural chromosomal aberrations. The results suggest that ML 3000 has no genotoxic potential in vitro and in vivo.

[Detection of mycobacterial DNA from paraffin-embedded tissue in lung and lymphoid epithelial granulomas]. / Nachweis mykobakterieller DNA aus Paraffin-eingebettetem Lungen- und Lymphknotengewebe mit Epitheloidzell-Granulomen.

Standard techniques for the detection of mycobacteria in granulomatous diseases can be inadequate. We analysed 71 formalin fixed and paraffin-embedded tissue blocks from 68 non-immunocompromised patients with caseating, non-caseating, scarred, and miliary granulomas of lung and lymph nodes. A reamplification PCR protocol was established to detect a 123 bp product of the repetitive insertion sequence IS986/IS6110. After exclusion of 6 PCR-negative cases with clinical sarcoidosis 97% of lung tissue blocks with more than 10% caseating and non-caseating granulomas contained mycobacterial DNA. By routine microbiology mycobacteria could be detected in 78% of the patients. Scarred granulomas were PCR-negative. All miliary granulomas were PCR-positive. Lymph nodes showed comparable results. We think that this method facilitates aetiologic analysis of granulomatous diseases especially when the suspicous tissue is fixed and microbiology is not available.

The genotoxicity status of senna.

Genotoxicity tests were performed by several laboratories with the drug fructus sennae, senna extract, sennosides, rhein and aloe-emodin. The drug fructus sennae, the sennosides and rhein did not increase mutation frequencies in the following test systems: bacterial systems (Salmonella reverse mutation test and/or Escherichia coli forward mutation test); mammalian cell cultures [hypoxanthine guanine phosphoribosyl transferase (HGPRT) test; mouse lymphoma test; chromosome aberration test with Chinese hamster ovary cells]; bone marrow (micronucleus test; chromosome aberration test); melanoblast cells (mouse spot test) of rodents. With aloe-emodin mutagenic effects were observed only in vitro in the chromosome aberration test with CHO cells and in the Salmonella reverse mutation test (frameshift mutations in strains TA 1537, TA 1538 and TA 98). In the in vitro gene mutation test with V79 cells (HGPRT test) no mutagenic potential of aloe-emodin was observed. In in vivo studies [micronucleus test with bone marrow cells of NMRI mice, chromosome aberration test with bone marrow cells of Wistar rats, mouse spot test (crossing DBA/2J x NMRI) no indication for a mutagenic activity of aloe-emodin was found. The relevance of the absence of a mutagenic potential in in vivo test systems was strengthened by the fact that aloe-emodin could be found in the blood serum after oral administration. Additional information on the interaction of aloe-emodin with DNA was obtained from an ex vivo unscheduled DNA synthesis test performed with hepatocytes of male Wistar rats: aloe-emodin did not induce unscheduled DNA synthesis as expression of DNA damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetic studies in lymphocytes of workers exposed to 2,3,7,8-TCDD.

Chromosome aberrations and sister chromatid exchanges (SCEs) were evaluated in 27 workers with current 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) blood lipid concentrations exceeding 40 parts per trillion (ppt) and in 28 unexposed referents of similar age. No statistical differences were found between the two groups in the percentages of gaps, chromatid or chromosome exchanges, chromatid or chromosome breaks/fragments/deletions, multiple aberrations, or the overall percentage of aberrations including gaps (1.33% in the exposed group vs 1.75% in the referent group) or excluding gaps (0.54% in each group). There was an increased rate of SCEs per cell (P = 0.051) and a higher percentage of cells with more than 10 SCEs (P = 0.064) in the exposed group; however, these associations were no longer significant when smoking status was included as covariate. Additionally, neither current nor back-calculated TCDD concentration was a significant predictor of these parameters based on multiple linear and rank regression analyses.

SCE frequency and lymphocyte proliferation in a Down's syndrome mosaic developing an acute lymphoblastic leukemia.

Sister chromatid exchange and cell proliferation time were examined by differential chromatid staining in a Down's syndrome, mosaic case suffering from acute lymphoblastic leukemia. The SCE frequency in stimulated blood lymphocytes had already increased before treatment was started. The therapy was correlated with a further SCE increase in the trisomic cells but not in the normal ones. The trisomic cells showed a shortened cell cycle time in the remission phase, as well as during therapy. In both cell lines, a very similar slow down in cell proliferation was observed after treatment, as indicated by a high number of mitoses from the first and second mitotic cycle. The results indicate that the trisomic cells are more sensitive to the mutagenic effect of the antileukemic treatment than are normal cells.

Sister chromatid exchange and lymphocyte proliferation in a Down syndrome mosaic.

The number of SCE was compared in the normal and trisomic cell lines of a trisomy 21 mosaic case. It was found that in the trisomic cells the SCE-frequency was twice as high as in the normal cells. The mitoses with high numbers of SCE (above 10) were increased 4-5 fold. Differential chromatid staining also allowed us to determine the mitotic cycle of the mitoses. The percentage of mitoses from the fourth or a later mitotic cycle was significantly higher in the trisomic cell line than in the normal one. From this result, it can be concluded that the cell cycle time was distinctly shortened in the cells with trisomy 21.