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Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics.

Nagourney RA, Sommers BL, Harper SM, Radecki S, Evans SS - Br. J. Cancer (2003)

Bottom Line: The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed.Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s.Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.

View Article: PubMed Central - PubMed

Affiliation: Rational Therapeutics, Inc., 750 East 29th Street, Long Beach, CA 90806, USA. robert.nagourney@rationaltherapeutics.com

ABSTRACT
Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose-response curves were interpolated to provide 50% lethal concentrations (LC(50)). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC(50) value (0.26+/-0.06 microg ml(-1); P=0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.

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Related in: MedlinePlus

LC50 values for single-agent topotecan in tumour biopsies taken from untreated and previously treated patients in the master database. Tumour biopsies from patients with breast cancer, colon cancer, NSCLC, or prostate cancer were incubated with various concentrations of topotecan, and the LC50 values were calculated. The numbers in parentheses indicate the number of samples for the indicated drug combination.
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fig1: LC50 values for single-agent topotecan in tumour biopsies taken from untreated and previously treated patients in the master database. Tumour biopsies from patients with breast cancer, colon cancer, NSCLC, or prostate cancer were incubated with various concentrations of topotecan, and the LC50 values were calculated. The numbers in parentheses indicate the number of samples for the indicated drug combination.

Mentions: To assess the effect of prior chemotherapy exposure on the activity of topotecan, the LC50 values of topotecan in cells obtained from previously treated specimens were compared with those from untreated specimens (Figure 1Figure 1


Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics.

Nagourney RA, Sommers BL, Harper SM, Radecki S, Evans SS - Br. J. Cancer (2003)

LC50 values for single-agent topotecan in tumour biopsies taken from untreated and previously treated patients in the master database. Tumour biopsies from patients with breast cancer, colon cancer, NSCLC, or prostate cancer were incubated with various concentrations of topotecan, and the LC50 values were calculated. The numbers in parentheses indicate the number of samples for the indicated drug combination.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394409&req=5

fig1: LC50 values for single-agent topotecan in tumour biopsies taken from untreated and previously treated patients in the master database. Tumour biopsies from patients with breast cancer, colon cancer, NSCLC, or prostate cancer were incubated with various concentrations of topotecan, and the LC50 values were calculated. The numbers in parentheses indicate the number of samples for the indicated drug combination.
Mentions: To assess the effect of prior chemotherapy exposure on the activity of topotecan, the LC50 values of topotecan in cells obtained from previously treated specimens were compared with those from untreated specimens (Figure 1Figure 1

Bottom Line: The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed.Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s.Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.

View Article: PubMed Central - PubMed

Affiliation: Rational Therapeutics, Inc., 750 East 29th Street, Long Beach, CA 90806, USA. robert.nagourney@rationaltherapeutics.com

ABSTRACT
Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose-response curves were interpolated to provide 50% lethal concentrations (LC(50)). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC(50) value (0.26+/-0.06 microg ml(-1); P=0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.

Show MeSH
Related in: MedlinePlus