VP16 hypersensitivity and increased faulty recombination in ataxia telangiectasia lymphocytes characterized by the tandem translocation t(14;14)(q11;q32).
Ataxia telangiectasia (AT) patients show variable degrees of immunodeficiency and a higher than normal predisposition to lymphoid malignancies. AT cells are characterized by spontaneous chromosome instability resulting in chromosome breakage and in non random chromosome rearrangements. Sequential cytogenetic studies on T-lymphocytes from an AT patient showed the progressive development of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosome rearrangements. Compared to non clonal cells, the abnormal clone displayed a higher frequency of spontaneous chromosome rearrangements. In only the clonal cells we observed two particular and predominant rearrangements: isodicentric chromosomes and telomeric associations which may derive from faulty recombination. Chromosome instability induced by the etoposide VP16, a DNA topoisomerase II inhibitor, was evaluated in terms of chromosome breakage and SCE frequency. T-lymphocytes from the AT patient showed hypersensitivity to VP16 significantly higher than normal T-lymphocytes. The chromosome instability induced by VP16 is significantly higher in clonal than in non clonal cells, whilst the chromosome instability induced by the radiomimetic drug bleomycin is not significantly different in the two AT lymphocyte subpopulations. The different spontaneous chromosome instability in clonal and non clonal cells together with their different behavior after treatment with only VP16, suggest that clonal cells bearing the tandem translocation could have increased faulty recombination. Given the presence of translocations t(14;14)(q11;q32) in T-prolymphocytic leukemias and T-cell tumors of non AT patients, our findings suggest that VP16 could be considered an antineoplastic treatment particularly indicated in these patients.
Petrinelli
P
P
Dipartimento di Biopatologia Umana, Università La Sapienza, Rome, Italy.
Elli
R
R
Marcucci
L
L
Barbieri
C
C
Ambra
R
R
Antonelli
A
A
D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001260:Ataxia Telangiectasia / Q000235:genetics*; D001761:Bleomycin / Q000494:pharmacology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D012854:Sister Chromatid Exchange; D013601:T-Lymphocytes / Q000187:drug effects*; D014178:Translocation, Genetic / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001761:Bleomycin; D005047:Etoposide