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Haruyo Hirota

Publications and source records attributed to Haruyo Hirota.

2 recordsLinked to original sources

Multi-institutional study on the correlation between chromosomal abnormalities and epilepsy.

While there is an abundance of literature describing the association of chromosome aberrations with epilepsy, only a few refer to the detailed features of epilepsy. It is important to investigate the associations between specific chromosome abnormalities and features of epilepsy to identify genes involved in epilepsy and treat them more effectively. We investigated the correlation between specific chromosome aberrations and epilepsy by sending questionnaires to the members of Kyoto Multi-institutional Study Group of Pediatric Neurology. Seventy-six patients were collected from 10 institutions. Chromosome abnormalities included: Down syndrome (n = 19); Angelman syndrome (n = 8); Prader-Willi syndrome (n = 4); 4p- syndrome (n = 3); 1q- syndrome (n = 2); 5p- syndrome (n = 2); Miller-Dieker syndrome (n = 2); 18q- syndrome; (n = 2); Klinefelter syndrome; (n = 2); and 32 other individual chromosomal aberrations. Overall, the severity of mental retardation correlated with the severity of epilepsy. We could abstract characteristic features of epilepsy in some syndromes. In Angelman and Prader-Willi syndromes, febrile seizures occurred frequently, the onset of epilepsy was in early childhood and seizure phenotype was multiple. Paroxysmal discharge of the occipital region and diffuse high voltage slow wave on electroencephalography were characteristic in Angelman syndrome. In Down syndrome, West syndrome and focal epilepsy were common and the prognosis of epilepsy in West syndrome with Down syndrome was good. In 4p- syndrome, febrile seizures were often seen, and unilateral or generalized clonic or tonic-clonic status epilepticus were characteristic. For the other chromosomal aberrations investigated here, the patient numbers were too small to abstract common features of epilepsy.

Adolescent↗

Interference with topoisomerase IIalpha potentiates melphalan cytotoxicity.

We studied the consequences of interfering with DNA topoisomerase IIalpha (topo IIalpha) activity on melphalan-induced cytotoxicity. In order to accomplish our goal we used three different approaches to interfere with topo IIalpha. These include: i) use of three V79 Chinese hamster lung fibroblast-derived mutant cell lines, V507, V511, and V513 that are dysfunctional in topo IIalpha activity; ii) treatment of cells with etoposide (VP-16) which inhibits topo IIalpha through the formation of DNA-enzyme cleavable complex; and iii) exposure of cells to merbarone or ICRF-187 (Zinecard) that inhibits the activity of topo IIalpha by restricting its access to DNA. Based on clonogenic survival assays, all three approaches resulted in a significant potentiation of cytotoxicity of melphalan suggesting that topo IIalpha plays an important role in processing of DNA damage induced by melphalan. Furthermore, using alkaline elution assay, we show that melphalan-induced DNA cross-link formation and its repair is faster in V511 cells compared to the parental V79 cells. However, melphalan-induced sister chromatid exchanges (SCE) are found to be significantly higher in V511 cells compared to V79 cells. In addition, we find an excellent correlation between melphalan-induced SCE and cytotoxicity. These results could be explained on the assumption that topo IIalpha plays an important role in damage processing through excision repair of melphalan-induced DNA cross-links. However, in the absence of topo IIalpha the damages are primarily processed by recombination repair which may be prone to deleterious genetic alterations resulting in increased lethality as the frequency of recombination increases. In summary, our results demonstrate that: i) topo IIalpha deficiency is associated with increased sensitivity to melphalan; ii) deficiency of topo IIalpha is associated with an increase in melphalan-induced SCE; iii) increase in melphalan-induced SCE is associated with an increase in cytotoxicity; and iv) downregulation of topo IIalpha may be a useful approach to modulate the cytotoxicity of melphalan in combination chemotherapy regimens. These results have several important clinical implications. First, interference with topo IIalpha using agents such as VP-16 or ICRF-187 may provide a useful approach to enhance the efficacy of melphalan in combination chemotherapy regimens. Second, tumors which develop resistance to topo IIalpha-directed drugs due to quantitative or qualitative alterations in topo IIalpha may show increased susceptibility to a chemotherapy regimen containing melphalan.

Animals↗