Cytostatic drugs and health risks for exposed personnel: search for new biomarkers.
The use of antiblastic drugs has opened up new perspectives in improvement of therapy and life quality for cancer patients. The widespread clinical application of cytostatic drugs implies risks for exposed hospital personnel, due to genotoxic and toxic-reproductive effects. Biological monitoring is fundamental to identify individuals at risk but is limited by the long latency of chronic effects, absence of unique cellular targets and low sensitivity of available laboratory tests. The objective of this study was to investigate toxic mechanisms by a molecular biology approach, searching for biomarkers potentially useful in monitoring programs. The proposed experimental model consisted of cell line exposure to cyclophosphamide, an alkylating agent of wide clinical use. Cellular response has been investigated focusing on potential targets at RNA level, through reverse transcription polymerase chain reaction (RT-PCR) and differential display analysis. We studied the expression of several genes involved in differentiation, apoptosis and chemoresistance: ets1, bax, bcl-2, bag-1, bcl-X, mdr1 and mrp. Specific patterns of mRNA modulations were observed. Differential display analysis revealed candidate genes induced or repressed following exposure: their characterization is in progress. Besides improving the understanding of toxic mechanisms, identification of modulated molecular targets opens up new perspectives in exposure risk assessment, biomonitoring and preventive strategies at occupational level.
Mucci
N
N
Department of Occupational Medicine, ISPESL, Rome, Italy.
Ianni
A
A
Ursini
C L
CL
Orsini
M
M
Arzani
D
D
Romano-Spica
V
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D006282:Health Personnel; D006304:Health Status; D006801:Humans; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016273:Occupational Exposure / Q000009:adverse effects*; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D002352:Carrier Proteins; D003520:Cyclophosphamide; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C494826:BAX protein, human; C091732:BCL2-associated athanogene 1 protein; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; C494041:ETS1 protein, human; C494042:Ets1 protein, mouse