Effects of the combination of camptothecin and doxorubicin or etoposide on rat glioma cells and camptothecin-resistant variants

From the rat C6 glioma cell line in culture, we selected camptothecin-resistant variants by growth in the presence of increasing amounts of this drug (C6CPT10, C6CPT50 and C6CPT100, growing respectively with 10, 50 and 100 ng ml–1camptothecin). The degree of resistance to camptothecin ranged between 15-fold (C6CPT10) and 30-fold (C6CPT50and C6CPT100). The C6CPT10cell line presented a collateral sensitivity to etoposide (3.6-fold), while the C6CPT50 and C6CPT100 cell lines were cross-resistant to etoposide (1.8-fold) The resistant lines were characterised by a two-fold reduced content and catalytic activity of topoisomerase I, and C6CPT50 and C6CPT100 presented a significant increase in topoisomerase IIα content and catalytic activity and a marked overexpression of P-glycoprotein. We explored the cytotoxicity of combinations of a topoisomerase I inhibitor (camptothecin) and a topoisomerase II inhibitor (doxorubicin or etoposide) at several molar ratios, allowing the evaluation of their synergistic or antagonistic effects on cell survival using the median effect principle. The simultaneous combination of camptothecin and doxorubicin or etoposide was additive or antagonistic in C6 cells, slightly synergistic in the C6CPT10 line and never more than additive in the C6CPT50 and C6CPT100 cell lines. The sequential combination of doxorubicin and camptothecin gave additivity in the order camptothecin → doxorubicin and antagonism in the order doxorubicin → camptothecin. Clinical protocols combining a topoisomerase I and a topoisomerase II inhibitor should be considered with caution because antagonistic effects have been observed with combinations of camptothecin and doxorubicin.© 2001 Cancer Research Campaign http://www.bjcancer.co

J Pediatr

OBJECTIVE: To describe four subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia (cITP). STUDY DESIGN: Selection of patients with cITP from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine or rituximab as a first second-line treatment. RESULTS: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival (EFS) was 62% (95%CI: 55; 71). It was 85% (95%CI: 77; 95) for the 56 splenectomized patients, 60% (95%: 44; 84) for the 23 patients treated with rituximab, 46% (95%CI: 30; 71) for the 24 patients treated with azathioprine and 37% (95%CI: 24; 59) for the 34 patients treated with hydroxychloroquine (Log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve EFS (p = 0.05). Female teenagers with ANA positivity benefited from hydroxychloroquine therapy. CONCLUSION: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months