Summary We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. (Dalton, 1990). In such patients, clinical drug resistance (failure to respond to drugs which were initially effective) is a common phenomenon. Clinical drug resistance is likely due to a number of factors such as tumour growth kinetics, development of pharmacologic sanctuaries due to loss of vascular supply, development of hypoxia in large tumours, and development of structural and metabolic changes in individual tumour cells. Doxorubicin (DOX) is the most active single agent currently available for the treatment of breast cancer (Tormey, 1975). For previously treated and untreated patients the response to DOX as a single agent varies between 28 and 43% respectively. In addition, DOX is an integral component of many combination chemotherapy regimens for breast cancer.
Summary The EVI-I gene was originally detected as an ectopic viral insertion site and encodes a nuclear zinc finger DNA-binding protein. Previous studies showed restricted EVI-1 RNA or protein expression during ontogeny; in a kidney and an edometrial carcinoma cell line; and in normal murine oocytes and kidney cells. EVI-1 expression was also detected in a subset of acute myeloid leukaemias (AMLs) and myelodysplasia. Because EVI-1 is expressed in the urogenital tract during development, we examined ovarian cancers and normal ovaries for EVI-1 RNA expression using reverse transcription-polymerase chain reaction (RT-PCR) and RNAase protection. Chromosome abnormalities were examined using karyotypes and whole chromosome 3 and 3q26 fluorescence in situ hybridisation (FISH). RNA from six primary ovarian tumours, five normal ovaries and 47 tumour cell lines (25 ovarian, seven melanoma, three prostate, seven breast and one each of bladder, endometrial, lung, epidermoid and histiocytic lymphoma) was studied. Five of six primary ovarian tumours, three of five normal ovaries and 22 of 25 ovarian cell lines expressed EVI-1 RNA. A variety of other non-haematological cancers also expressed EVI-1 RNA. Immunostaining of ovarian cancer cell lines revealed nuclear EVI-1 protein. In contrast, normal ovary stained primarily within oocytes and faintly in stroma. Primary ovarian tumours showed nuclear and intense, diffuse cytoplasmic staining. Quantitation of EVI-1 RNA, performed using RNAase protection, showed ovarian carcinoma cells expressed 0 to 40 times the EVI-I RNA in normal ovary, and 0 -6 times the levels in leukaemia cell lines. Southern analyses of ovarian carcinoma cell lines showed no amplification or rearrangements involving EVI-1. In some acute leukaemias, activation of EVI-1 transcription is associated with translocations involving 3q26, the site of the EVI-I gene. Ovarian carcinoma karyotypes showed one line with quadruplication 3(q24q27), but no other clonal structural rearrangements involving 3q26. However, whole chromsome 3 and 3q26 FISH performed on lines with high EVI-1 expression showed translocations involving chromosome 3q26. EVI-1 is overexpressed in ovarian cancer compared with normal ovaries, suggesting a role for EVI-1 in solid tumour carcinogenesis or progression. Mechanisms underlying EVI-1 overexpression remain unclear, but may include rearrangements involving chromosome 3q26.
As a prelude to assessing the relationship of chromosome alterations to clinical outcome in ovarian carcinoma, we report on the cytogenetic analysis on short-term cultures from 54 patients. All patients had histopathologically confirmed malignancy, with the majority of cases demonstrating serous ovarian adenocarcinomas. Structural alterations were evident in 52 cases, whereas numeric changes were identified in 13 cases. The most notable numeric abnormalities were loss of the X-chromosome (9/13 total cases) and +7 (3/9 diploid cases). Structural alterations most frequently involved chromosomes 1, 3, 6, 7, 11, and 12. Chromosomal breakpoints were shown to cluster in several chromosomal banding regions, including 1p36, 1p11-q21, 3p23-p10, 7p (especially 7p22), 11p, 11q, 12p13-q12, and 12q24. The frequency of structural alterations involving the following chromosome arms was found to be significantly increased: 1p (p < 0.01), 7p (p < 0.01), 11p (p < 0.01), 11q (p < 0.05), and 12p (p < 0.05). An analysis of the net gain or loss of chromosome segments was also performed, with the most consistent tendency observed being over-representation of 1q and chromosome 7, deletion of 1p, and loss of the X chromosome.
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