Tags

Type your tag names separated by a space and hit enter

A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts.
Cancer Res. 1999 Mar 01; 59(5):1036-40.CR

Abstract

Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition >70%; log10 cell kill >1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance.

Authors+Show Affiliations

Division of Experimental Oncology B, Istituto Nazionale Tumori, Milan, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10070960

Citation

Polizzi, D, et al. "A Novel Taxane With Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts." Cancer Research, vol. 59, no. 5, 1999, pp. 1036-40.
Polizzi D, Pratesi G, Tortoreto M, et al. A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Res. 1999;59(5):1036-40.
Polizzi, D., Pratesi, G., Tortoreto, M., Supino, R., Riva, A., Bombardelli, E., & Zunino, F. (1999). A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Research, 59(5), 1036-40.
Polizzi D, et al. A Novel Taxane With Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts. Cancer Res. 1999 Mar 1;59(5):1036-40. PubMed PMID: 10070960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. AU - Polizzi,D, AU - Pratesi,G, AU - Tortoreto,M, AU - Supino,R, AU - Riva,A, AU - Bombardelli,E, AU - Zunino,F, PY - 1999/3/10/pubmed PY - 1999/3/10/medline PY - 1999/3/10/entrez SP - 1036 EP - 40 JF - Cancer research JO - Cancer Res. VL - 59 IS - 5 N2 - Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition >70%; log10 cell kill >1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10070960/A_novel_taxane_with_improved_tolerability_and_therapeutic_activity_in_a_panel_of_human_tumor_xenografts_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10070960 DB - PRIME DP - Unbound Medicine ER -