In vivo antitumoral efficacy of PhAc-ALGP-doxorubicin, an enzyme-activated doxorubicin prodrug, in patient-derived soft tissue sarcoma xenograft models

Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind.

We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models. Sixty-eight mice were engrafted bilaterally with human DDLPS or SynSa and randomized to control, doxo or ALGP-doxo treatment, which were administered using an intraperitoneal minipump. Tumor volume measurement, histopathology and Western blotting were used to assess treatment efficacy. Tumor regrowth was evaluated in a subset of mice over a period of two weeks after treatment cessation.

While tumor volume in the control and doxo groups increased steadily, ALGP-doxo caused tumor volume stabilization in the DDLPS xenografts and significant tumor shrinkage in the SynSa model, continuing after treatment cessation. A significant decrease in proliferation and increase in apoptosis compared to control and doxo was observed during and after treatment with ALGP-doxo in all models.

In conclusion, ALGP-doxo shows considerably higher antitumoral efficacy compared to doxo in all patient-derived xenograft models tested. Administration of a 30-40 fold higher dose of ALGP-doxo than doxo is tolerated without significant adverse events. These results warrant further testing of this prodrug in anthracycline-sensitive and -resistant models of soft tissue sarcoma.

Publication year:2017

BOF-keylabel:yes

IOF-keylabel:yes

BOF-publication weight:2

CSS-citation score:1

Authors from:Private, Higher Education

Accessibility:Open