Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours

Background: Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure.

The overexpression of the efflux pump Tpo1 leads to the bleomycin resistance in Saccharomyces cerevisiae.

La bléomycine est un antibiotique cytotoxique, son potentiel génotoxique est plus important quand elle est utilisée en combinaison avec des agents antinéoplasiques sur le cancer testiculaire, que sur les autres types qui développent souvent une résistance envers la drogue. Notre but consiste alors de mettre en évidence ce mécanisme de résistance en utilisant l’organisme modèle Saccharomyces cerevisiae. Nous avons démontré au sein de notre laboratoire, que les levures délétées au niveau de leur coactivateur transcriptionnel Imp2, présentent une hypersensibilité à la bléomycine, en raison de son accumulation toxique dans la cellule. Ceci suggère que Imp2 pourrait réguler l’expression d’une ou de plusieurs pompes à efflux, capables d’expulser la bléomycine à l’extérieur de la cellule. Pour tester notre hypothèse, nous avons recherché des suppresseurs multicopies capables de restaurer la résistance à la bléomycine chez le mutant imp2, et c’est ainsi que nous avons identifié l'activateur transcriptionnel Yap1. Ce dernier se lie à une région spécifique localisée au niveau du promoteur et permet d’activer l'expression d'un sous-ensemble de gènes, codant pour des pompes à efflux, impliquées dans la résistance aux drogues. Selon la littérature, au moins 27 pompes à efflux ont été identifiées chez la levure Saccharomyces cerevisiae, certaines d’entre elles disposent du site de liaison pour Yap1, tels que Qdr3, Tpo2 et Tpo1. Afin de déterminer si une de ces pompes expulse la bléomycine, nous avons créé des mutations simples et doubles en combinaison avec IMP2, aussi nous avons verifié si les mutants étaient sensibles à la drogue et enfin, nous avons testé si la surexpression de Yap1 pouvait restaurer le phénotype sauvage chez ces mutants, via l’activation de pompes à efflux.

Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Bleomycin sensitivity in patients with familial and sporadic polyposis: a pilot study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of turmeric and its active principle, curcumin, on bleomycin-induced chromosome aberrations in Chinese hamster ovary cells

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Differential susceptibility to chromatid breaks induced by bleomycin in sub-fertile and fertile bovines

The rate of chromatid breaks was studied in cows with a history of sub-fertility by means of a test based on measurement of the average of breaks induced in lymphocytes of peripheral blood cultures. Fourteen female specimens were divided into two groups: fertile and sub-fertile. Peripheral blood lymphocytes were cultured and prepared for cytogenetic analysis. Two types of culture were established for each animal to evaluate the response of peripheral blood lymphocyte cultures to the genotoxic effects of bleomycin. The first culture did not receive bleomycin treatment (spontaneous chromosome aberrations). Our results showed that median breaks per cell (b/c) (+/-semirange) for spontaneous culture of the fertile and sub-fertile animals and bleomycin sensitivity assay for fertile and sub-fertile animals were 0.00 +/- 0.06, 0.02 +/- 0.03, 0.08 +/- 0.05 and 0.22 +/- 0.09, respectively. There was no significant difference (P > 0.05) in the chromosomal breakage in lymphocytes not exposed to bleomycin; however, in comparing the number of chromatid breaks per cell in cultures treated with bleomycin, the sub-fertile group showed a significantly higher (P < 0.05) level than the fertile group. These findings have implications both for identifying cattle with less than optimum fertility as well as for providing potential avenues to study the origins of sub-fertility. (C) 2004 Elsevier B.V. All rights reserved.

Genetic susceptibility to bleomycin: A twin study

The frequency of chromatid breaks was analysed in peripheral lymphocytes obtained from sixteen healthy monozygotic (MZ) and sixteen healthy dizygotic (DZ) pairs of twins. In addition, increases in the frequency of chromatid breaks, following in vitro treatment of whole blood with 0.03 unit/ml bleomycin (BLM), were analysed in the same twins. There was a highly significant intrapair difference in the variance of the frequency of chromatid breaks among MZ and DZ twins, before and after BLM treatment. The coefficient of heritability was 85,5% and it was concluded that genetic factors contributed significantly to the individual variation observed in BLM induced chromatid break rates.

Chromosome sensitivity to bleomycin in G2 lymphocytes from Down syndrome patients

Several studies have demonstrated that lymphocytes from patients with Down syndrome (DS) exhibit an increased frequency of chromosome aberrations when they are exposed to ionizing radiation or to chemicals at the G0 or G1 phases of the cell cycle, but not at G2 when compared to normal subjects. To determine the susceptibility of DS lymphocytes at G2 phase, bleomycin, a radiomimetic agent, was used to induce DNA breaks in blood cultures from 24 Down syndrome patients. All the patients with DS showed free trisomy 21 (47,XX + 21 or 47,XY + 21). Individuals that showed an average number of chromatid breaks per cell higher than 0.8 were considered sensitive to the drug. No control child showed susceptibility to bleomycin, and among the 24 patients with DS, only one was sensitive to the drug. No significant difference was observed between the two groups, regarding chromatid break frequencies in treated G2 lymphocytes. The distribution of bleomycin-induced breaks in each group of chromosomes was similar for DS and controls. No significant difference was found in the response to bleomycin between male and female subjects. Probably, the main factor involved in chromosome sensitivity of lymphocytes from patients with DS is the phase of the cell cycle in which the cell is treated.

Autotransplant for Hodgkin lymphoma after failure of upfront BEACOPP escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone)

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) escalated is the preferred upfront Hodgkin lymphoma (HL) treatment in a number of countries. Upon failure, high-dose chemotherapy with autologous stem cell support (HDT/ASCT) is performed, but its effectiveness has not been verified in this setting. We analyzed all Swiss cases of chemosensitive HL autografted after failure of BEACOPP escalated (n = 22) and compared outcomes with 22 cases of HDT/ASCT following frontline ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) failure. Five-year progression-free survival (PFS) was 76% for ABVD and 42% for BEACOPP escalated (p = 0.029). Two- and 5-year overall survival (OS) was 90% and 71% for ABVD and 72% and 65% for BEACOPP escalated, respectively (p = not significant). Three patients in the ABVD and four in the BEACOPP escalated groups underwent allotransplant for relapse after HDT/ASCT. Grade 3-4 toxicities were comparable in both groups. Three cases of therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) were recorded in the BEACOPP escalated group. The acceptable PFS and OS of chemosensitive patients with HL autografted after failure of upfront BEACOPP escalated seem to justify this approach.