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Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer.

Bull-Hansen B, Berstad MB, Berg K, Cao Y, Skarpen E, Fremstedal AS, Rosenblum MG, Peng Q, Weyergang A - Oncotarget (2015)

Bottom Line: Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells.The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts.Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

ABSTRACT
HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus

Tumor size after PCI of MH3-B1/rGel in SKOV-3 xenograftsThe bars show the measured tumor size at day 16 for each animal in the four treatment groups (A) and the percent change in tumor size at day 16 calculated from the measured tumor size at treatment day (day 0) for each animal in the four treatment groups (B). Calculated p-values representing statistical differences in tumor size between the treatment groups at day 16 post treatment (C).
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Figure 5: Tumor size after PCI of MH3-B1/rGel in SKOV-3 xenograftsThe bars show the measured tumor size at day 16 for each animal in the four treatment groups (A) and the percent change in tumor size at day 16 calculated from the measured tumor size at treatment day (day 0) for each animal in the four treatment groups (B). Calculated p-values representing statistical differences in tumor size between the treatment groups at day 16 post treatment (C).

Mentions: The high efficacy of PCI of MH3-B1/rGel in the MH3-B1/rGel resistant SKOV-3 cells was further evaluated on SKOV-3 subcutaneous xenografts in athymic mice. This is a relatively slow growing tumor model and the mean time to reach the endpoint of 800 mm3 from a treatment volume of ~100 mm3 was 43.4 days (Fig. 6D). The photochemical treatment induced edema and accurate measurements of tumors were therefore difficult to obtain the first ~2 weeks after treatment. Early effects on tumor growth following the different treatments were assessed on day 16 since this was the first day without any detectable edema in any of the animals. Comparing the size of all tumors at day 16 revealed significantly smaller tumors in the PCI group compared to the control groups receiving either MH3-B1/rGel, photochemical treatment or no treatment (Fig. 5A and 5C). No significant difference was found between the no treatment group and the groups receiving MH3-B1/rGel or photochemical treatment as monotherapies. Neither was there any difference in tumor size between the group receiving MH3-B1/rGel and the photochemical treatment group at day 16 (Fig. 5A and 5C).


Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer.

Bull-Hansen B, Berstad MB, Berg K, Cao Y, Skarpen E, Fremstedal AS, Rosenblum MG, Peng Q, Weyergang A - Oncotarget (2015)

Tumor size after PCI of MH3-B1/rGel in SKOV-3 xenograftsThe bars show the measured tumor size at day 16 for each animal in the four treatment groups (A) and the percent change in tumor size at day 16 calculated from the measured tumor size at treatment day (day 0) for each animal in the four treatment groups (B). Calculated p-values representing statistical differences in tumor size between the treatment groups at day 16 post treatment (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494949&req=5

Figure 5: Tumor size after PCI of MH3-B1/rGel in SKOV-3 xenograftsThe bars show the measured tumor size at day 16 for each animal in the four treatment groups (A) and the percent change in tumor size at day 16 calculated from the measured tumor size at treatment day (day 0) for each animal in the four treatment groups (B). Calculated p-values representing statistical differences in tumor size between the treatment groups at day 16 post treatment (C).
Mentions: The high efficacy of PCI of MH3-B1/rGel in the MH3-B1/rGel resistant SKOV-3 cells was further evaluated on SKOV-3 subcutaneous xenografts in athymic mice. This is a relatively slow growing tumor model and the mean time to reach the endpoint of 800 mm3 from a treatment volume of ~100 mm3 was 43.4 days (Fig. 6D). The photochemical treatment induced edema and accurate measurements of tumors were therefore difficult to obtain the first ~2 weeks after treatment. Early effects on tumor growth following the different treatments were assessed on day 16 since this was the first day without any detectable edema in any of the animals. Comparing the size of all tumors at day 16 revealed significantly smaller tumors in the PCI group compared to the control groups receiving either MH3-B1/rGel, photochemical treatment or no treatment (Fig. 5A and 5C). No significant difference was found between the no treatment group and the groups receiving MH3-B1/rGel or photochemical treatment as monotherapies. Neither was there any difference in tumor size between the group receiving MH3-B1/rGel and the photochemical treatment group at day 16 (Fig. 5A and 5C).

Bottom Line: Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells.The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts.Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

ABSTRACT
HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus