129 research outputs found

    OncoLog Volume 46, Number 03, March 2001

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    Researchers Examine Link Between Stress and Response to Cancer Treatment Emotional Side Effects: Section of Behavioral Medicine in Department of Pediatrics Helps Patients and Their Families Cope with Cancer House Call: Getting the Facts About Clinical Trials DiaLog: Where Patient Care and Research Meet, by Leonard A. Zwelling, MD, MBA, Vice President for Research Administration Moving Toward Recovery: Exercise Video Features Adolescents with Cancerhttps://openworks.mdanderson.org/oncolog/1095/thumbnail.jp

    Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

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    Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material. Tumour cells isolated from 50 ovarian cancer patients were treated ex vivo with 100 μM cisplatin for 1 h and crosslink formation and repair (unhooking) measured. No significant difference in the peak level of crosslinking in tumour cells was observed between patients who were either newly diagnosed or previously treated with platinum-based therapy, or between tumour and mesothelial cells from an individual patient. This indicates no difference in cellular mechanisms such as drug transport or detoxification. In contrast, the percentage repair (unhooking) of DNA interstrand crosslinks was much greater in the group of treated patients. At 24 h in the 36 newly diagnosed patient tumour samples, only one gave >50% repair and 23 gave <10% repair; however, 19 out of 22 treated patient samples gave >10% repair and 14 showed >50% repair. The estimated median difference (newly diagnosed minus treated) was −52 (95% CI −67 to −28), and the P-value from a Mann–Whitney test was <0.001. In eight patients, it was possible to obtain tumour samples prior to any chemotherapy, and also on relapse or at interval debulking surgery following platinum-based chemotherapy. In these patients, the mean % repair prior to therapy was 2.85 rising to 71.23 following treatment. These data demonstrate increased repair of DNA interstrand crosslinks in ovarian tumour cells following platinum therapy which may contribute to clinical acquired resistance

    The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents.

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    Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR-ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC(50) on day 5 of 4.6 microg ml(-1) and 3.4 microg ml(-1) for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 microg ml(-1): 55.5+/-8.7 vs 96.4+/-3.7%). STI571 also appeared to specifically target bcr-abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34(+) chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+/-11.3 vs 44.5+/-8.7 and 17.8+/-7.0% in cultures with STI571 and etoposide alone respectively; P<0.001). This study confirms the central oncogenic role of BCR-ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease
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