Tags

Type your tag names separated by a space and hit enter

Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin.
Clin Cancer Res. 2000 Jul; 6(7):2891-902.CC

Abstract

Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment levels during the course of subsequent ODN administration, which suggested the development of resistance to continued Bcl-2 ODN treatment. The antitumor activity of ODN given in conjunction with either F-DOX or SL-DOX was also examined. The combination of G3139 and F-DOX was able to suppress the growth of MDA435/LCC6 cells beyond that obtained with either of the treatments given alone, indicative of synergistic action. Examination of the pharmacokinetics of F-DOX with systemic G3139 administration revealed that elevated tumor drug DOX levels were obtained compared with DOX treatment in the absence of G3139. This effect was sequence-specific and plasma DOX levels were unaffected by G3139 treatment, which indicated possible positive ODN-drug interactions at the tumor site. Combining G3139 with SL-DOX further increased the degree of antitumor activity. The improved efficacy of this combination was attributed to increased tumor drug levels that arise from the ability of SL-DOX to passively accumulate in solid tumors. These results suggest that additional benefits of Bcl-2 antisense ODN may be obtained when it is combined with liposomal formulations of anticancer drugs such as DOX.

Authors+Show Affiliations

Department of Advanced Therapeutics, British Columbia Cancer Research Centre, Vancouver, Canada.No 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

10914739

Citation

Lopes de Menezes, D E., et al. "Molecular and Pharmacokinetic Properties Associated With the Therapeutics of Bcl-2 Antisense Oligonucleotide G3139 Combined With Free and Liposomal Doxorubicin." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 6, no. 7, 2000, pp. 2891-902.
Lopes de Menezes DE, Hudon N, McIntosh N, et al. Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin. Clin Cancer Res. 2000;6(7):2891-902.
Lopes de Menezes, D. E., Hudon, N., McIntosh, N., & Mayer, L. D. (2000). Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 6(7), 2891-902.
Lopes de Menezes DE, et al. Molecular and Pharmacokinetic Properties Associated With the Therapeutics of Bcl-2 Antisense Oligonucleotide G3139 Combined With Free and Liposomal Doxorubicin. Clin Cancer Res. 2000;6(7):2891-902. PubMed PMID: 10914739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin. AU - Lopes de Menezes,D E, AU - Hudon,N, AU - McIntosh,N, AU - Mayer,L D, PY - 2000/7/29/pubmed PY - 2001/2/28/medline PY - 2000/7/29/entrez SP - 2891 EP - 902 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 6 IS - 7 N2 - Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment levels during the course of subsequent ODN administration, which suggested the development of resistance to continued Bcl-2 ODN treatment. The antitumor activity of ODN given in conjunction with either F-DOX or SL-DOX was also examined. The combination of G3139 and F-DOX was able to suppress the growth of MDA435/LCC6 cells beyond that obtained with either of the treatments given alone, indicative of synergistic action. Examination of the pharmacokinetics of F-DOX with systemic G3139 administration revealed that elevated tumor drug DOX levels were obtained compared with DOX treatment in the absence of G3139. This effect was sequence-specific and plasma DOX levels were unaffected by G3139 treatment, which indicated possible positive ODN-drug interactions at the tumor site. Combining G3139 with SL-DOX further increased the degree of antitumor activity. The improved efficacy of this combination was attributed to increased tumor drug levels that arise from the ability of SL-DOX to passively accumulate in solid tumors. These results suggest that additional benefits of Bcl-2 antisense ODN may be obtained when it is combined with liposomal formulations of anticancer drugs such as DOX. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/10914739/Molecular_and_pharmacokinetic_properties_associated_with_the_therapeutics_of_bcl_2_antisense_oligonucleotide_G3139_combined_with_free_and_liposomal_doxorubicin_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10914739 DB - PRIME DP - Unbound Medicine ER -