Doxorubicin (DOX) is one of the primary chemotherapeutic agents used to treat soft tissue sarcoma (STS). However, it only shows a 30% overall response rate and contributes to a disappointing 50% STS comprehensive survival rate that has not improved in the last 50 years. Doxorubicin use also induces significant side effects, such as drug-related cardiotoxicity and irreversible congestive heart failure. In order to improve drug efficacy and reduce cardiotoxicity, three Doxorubicin derivatives (P-DOX, GPX-150, GPX-160) were synthesized and their inhibitory concentration at half maxima (IC50) values were studied. Based on preliminary data, P-DOX showed potent activity against the HT1080 fibrosarcoma cell line (IC50 0.1 nM – 1.0 nM). In contrast, Doxorubicin was a thousand-fold less potent (IC50 0.1 μM - 1 μM). According to the in vitro cell viability data, P-DOX could be a better chemotherapeutic agent to treat STS, with a decreased cumulative dose than DOX. Drug transportation studies were conducted on Caco-2, colorectal adenocarcinoma, to investigate the permeability of the anticancer agents, and to explain pharmacokinetics of the novel drugs. Moreover, mouse tumor xenograft models of STS and images were collected to study tumor regression under the treatment of DOX derivatives against HT1080. The result indicates GPX-150 and -160 was effective to halt tumor growth, however, DOX was the most active agent against tumor xenografts based on tumor weights and volumes. Mice treated with GPX-150 and -160 were sacrificed 5 days prior to mice treated with DOX due to aggressive tumor development under the test groups.

In vitro cell viability and mice tumor xenograft effect of doxorubicin analogs on soft tissue sarcomas

251st National Meeting (2016)

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