Relative differences (mean ± standard deviation) in gene expression of <i>GDF-15</i>, <i>ATF3</i>, <i>AREG</i> in HMEC-1 after “acute” exposure to bleomycin and cisplatin measured by qRT-PCR.

<p>Relative differences (mean ± standard deviation) in gene expression of <i>GDF-15</i>, <i>ATF3</i>, <i>AREG</i> in HMEC-1 after “acute” exposure to bleomycin and cisplatin measured by qRT-PCR.</p

Top 50 genes with largest difference in expression in the different exposition settings in HMEC-1.

<p>* Overlapping genes in the “acute” exposure setting for both drugs,</p><p>^† Overlapping genes in the “chronic” exposure setting for both drugs.</p><p>^‡ Overlapping genes in the “acute” and “chronic” exposure setting for bleomycin.</p><p>^§ Overlapping genes in the “acute” and “chronic” exposure setting for cisplatin.</p><p>Top 50 genes with largest difference in expression in the different exposition settings in HMEC-1.</p

Gene Set Enrichment Analysis on gene expression profiles from HMEC-1 following “acute” and “chronic” exposure to bleomycin and cisplatin, using pathway definitions from KEGG.

<p>No pathways were enriched according to these criteria after “chronic” exposure to bleomycin.</p><p>Gene Set Enrichment Analysis on gene expression profiles from HMEC-1 following “acute” and “chronic” exposure to bleomycin and cisplatin, using pathway definitions from KEGG.</p

Plasma levels of GDF-15 (pg/mL), vWF (%) and hsCRP (mg/L) in testicular cancer patients (n = 41) before, during and after completion of bleomycin- and cisplatin-based chemotherapy.

<p>* <i>P</i> < 0.01 compared to baseline, Wilcoxon signed rank test</p><p>^†<i>P</i> < 0.05 compared to baseline, Wilcoxon signed rank test</p><p>^‡<i>P</i> < 0.01 compared to one month after completion of chemotherapy, Wilcoxon signed rank test</p><p>^§<i>P</i> < 0.05 compared to one month after completion of chemotherapy, Wilcoxon signed rank test</p><p>Plasma levels of GDF-15 (pg/mL), vWF (%) and hsCRP (mg/L) in testicular cancer patients (n = 41) before, during and after completion of bleomycin- and cisplatin-based chemotherapy.</p

Characteristics of 41 patients with disseminated testicular cancer and treated with cisplatin containing combination chemotherapy.

<p>Abbreviations: International Germ Cell Cancer Collaborative Group (IGCCCG); bleomycin etoposide cisplatin chemotherapy (BEP).</p><p>Characteristics of 41 patients with disseminated testicular cancer and treated with cisplatin containing combination chemotherapy.</p

Lapatinib and 17AAG Reduce ⁸⁹Zr-Trastuzumab-F(ab′)₂ Uptake in SKBR3 Tumor Xenografts

Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with <i>in vivo</i> HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined <i>in vitro</i> using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied <i>in vitro</i> by ⁸⁹Zr-trastuzumab-F­(ab′)₂ internalization. For <i>in vivo</i> evaluation, ⁸⁹Zr-trastuzumab-F­(ab′)₂ μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second ⁸⁹Zr-trastuzumab-F­(ab′)₂ injection. Imaging data were compared with <i>ex vivo</i> biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (<i>P</i> = 0.016) and HER2 by 76% (<i>P</i> = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of ⁸⁹Zr-trastuzumab-F­(ab′)₂ with 25% (<i>P</i> = 0.0022). ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor to blood ratio was lowered 32% by lapatinib (<i>P</i> = 0.00004), 34% by 17AAG (<i>P</i> = 0.0022) and even 53% by the combination (<i>P</i> = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation

Lapatinib and 17AAG Reduce ⁸⁹Zr-Trastuzumab-F(ab′)₂ Uptake in SKBR3 Tumor Xenografts

Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with <i>in vivo</i> HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined <i>in vitro</i> using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied <i>in vitro</i> by ⁸⁹Zr-trastuzumab-F­(ab′)₂ internalization. For <i>in vivo</i> evaluation, ⁸⁹Zr-trastuzumab-F­(ab′)₂ μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second ⁸⁹Zr-trastuzumab-F­(ab′)₂ injection. Imaging data were compared with <i>ex vivo</i> biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (<i>P</i> = 0.016) and HER2 by 76% (<i>P</i> = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of ⁸⁹Zr-trastuzumab-F­(ab′)₂ with 25% (<i>P</i> = 0.0022). ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor to blood ratio was lowered 32% by lapatinib (<i>P</i> = 0.00004), 34% by 17AAG (<i>P</i> = 0.0022) and even 53% by the combination (<i>P</i> = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation

Lapatinib and 17AAG Reduce ⁸⁹Zr-Trastuzumab-F(ab′)₂ Uptake in SKBR3 Tumor Xenografts

Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with in vivo HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined in vitro using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied in vitro by 89Zr-trastuzumab-F­(ab′)2 internalization. For in vivo evaluation, 89Zr-trastuzumab-F­(ab′)2 μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second 89Zr-trastuzumab-F­(ab′)2 injection. Imaging data were compared with ex vivo biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (P = 0.016) and HER2 by 76% (P = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of 89Zr-trastuzumab-F­(ab′)2 with 25% (P = 0.0022). 89Zr-trastuzumab-F­(ab′)2 tumor to blood ratio was lowered 32% by lapatinib (P = 0.00004), 34% by 17AAG (P = 0.0022) and even 53% by the combination (P = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce 89Zr-trastuzumab-F­(ab′)2 tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation

Lapatinib and 17AAG Reduce ⁸⁹Zr-Trastuzumab-F(ab′)₂ Uptake in SKBR3 Tumor Xenografts

Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with <i>in vivo</i> HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined <i>in vitro</i> using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied <i>in vitro</i> by ⁸⁹Zr-trastuzumab-F­(ab′)₂ internalization. For <i>in vivo</i> evaluation, ⁸⁹Zr-trastuzumab-F­(ab′)₂ μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second ⁸⁹Zr-trastuzumab-F­(ab′)₂ injection. Imaging data were compared with <i>ex vivo</i> biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (<i>P</i> = 0.016) and HER2 by 76% (<i>P</i> = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of ⁸⁹Zr-trastuzumab-F­(ab′)₂ with 25% (<i>P</i> = 0.0022). ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor to blood ratio was lowered 32% by lapatinib (<i>P</i> = 0.00004), 34% by 17AAG (<i>P</i> = 0.0022) and even 53% by the combination (<i>P</i> = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation

Lapatinib and 17AAG Reduce ⁸⁹Zr-Trastuzumab-F(ab′)₂ Uptake in SKBR3 Tumor Xenografts

Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with <i>in vivo</i> HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined <i>in vitro</i> using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied <i>in vitro</i> by ⁸⁹Zr-trastuzumab-F­(ab′)₂ internalization. For <i>in vivo</i> evaluation, ⁸⁹Zr-trastuzumab-F­(ab′)₂ μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second ⁸⁹Zr-trastuzumab-F­(ab′)₂ injection. Imaging data were compared with <i>ex vivo</i> biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (<i>P</i> = 0.016) and HER2 by 76% (<i>P</i> = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of ⁸⁹Zr-trastuzumab-F­(ab′)₂ with 25% (<i>P</i> = 0.0022). ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor to blood ratio was lowered 32% by lapatinib (<i>P</i> = 0.00004), 34% by 17AAG (<i>P</i> = 0.0022) and even 53% by the combination (<i>P</i> = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce ⁸⁹Zr-trastuzumab-F­(ab′)₂ tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation