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Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer
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| Zeitschriftentitel: | Journal of Clinical Oncology |
|---|---|
| Personen und Körperschaften: | , , , , |
| In: | Journal of Clinical Oncology, 27, 2009, 15_suppl, S. e16026-e16026 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
|
| Schlagwörter: |
| author_facet |
Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. |
|---|---|
| author |
Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. |
| spellingShingle |
Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. Journal of Clinical Oncology Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer Cancer Research Oncology |
| author_sort |
fabbri, f. |
| spelling |
Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16026 <jats:p> e16026 </jats:p><jats:p> Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m<jats:sup>2</jats:sup>) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. </jats:p><jats:p> No significant financial relationships to disclose. </jats:p> Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer Journal of Clinical Oncology |
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| title |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_unstemmed |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_full |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_fullStr |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_full_unstemmed |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_short |
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_sort |
translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16026 |
| publishDate |
2009 |
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e16026-e16026 |
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<jats:p> e16026 </jats:p><jats:p> Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m<jats:sup>2</jats:sup>) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. </jats:p><jats:p> No significant financial relationships to disclose. </jats:p> |
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| author_facet | Fabbri, F., Montanari, M., Cruciani, G., Amadori, D., Zoli, W., Fabbri, F., Montanari, M., Cruciani, G., Amadori, D., Zoli, W. |
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| description | <jats:p> e16026 </jats:p><jats:p> Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m<jats:sup>2</jats:sup>) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. </jats:p><jats:p> No significant financial relationships to disclose. </jats:p> |
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| spelling | Fabbri, F. Montanari, M. Cruciani, G. Amadori, D. Zoli, W. 0732-183X 1527-7755 American Society of Clinical Oncology (ASCO) Cancer Research Oncology http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16026 <jats:p> e16026 </jats:p><jats:p> Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m<jats:sup>2</jats:sup>) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. </jats:p><jats:p> No significant financial relationships to disclose. </jats:p> Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer Journal of Clinical Oncology |
| spellingShingle | Fabbri, F., Montanari, M., Cruciani, G., Amadori, D., Zoli, W., Journal of Clinical Oncology, Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer, Cancer Research, Oncology |
| title | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_full | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_fullStr | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_full_unstemmed | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_short | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_sort | translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| title_unstemmed | Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16026 |