Tumor growth and response to chemotherapeutic and chemoprotective agents in SHR/SST-2 animals.

<p><i>A,</i> SHRs were implanted with SST-2 cells and 24 h later were administered either doxorubicin (10 mg/kg), dexrazoxane (50 mg/kg), Mito-T (4) (5 or 25 mg/kg), a combination of doxorubicin and dexrazoxane, or a combination of doxorubicin and Mito-T (4). Each treatment group consisted of 10 animals. The mean tumor volumes (mm³) measured 14 days after drug treatment are shown for each treatment group. The two <i>inset</i> images show representative excised tumors from saline and doxorubicin-treated SHR/SST-2 animals. <i>B</i>, DNA damage by doxorubicin and chemoprotective agents was measured in tumor cells by confocal microscopic detection of γ-H2AX foci. Average foci intensity was measured in at least 100 cells per drug treatment observed from at least 10 representative fields. The data are represented as fold increase over no treatment tumor cells (Control). <i>C</i>, Active caspase-3 levels were assessed as a marker of apoptosis induction. Average fold increase is shown over saline control tumor tissue samples. * = statistically significant compared to saline and ** = statistically significant compared to doxorubicin (A–C). <i>D,</i> Transmission electron microscopy analysis of tumor samples from rats exposed to doxorubicin showing the formation of autophagic vacuoles (Autophagy panel), or nuclear condensation and membrane blebbing (Apoptosis panel), and membrane breakdown (Necrosis panel). Saline treated (Tumor/Control panels) are shown as controls. Representative low- and high-magnification images for the control and autophagic samples are shown for clarity. Mitochondria (labeled M), nucleus (N), and fat bodies (FB) are labeled within the images. <i>E,</i> Swollen mitochondria following doxorubicin treatment (right) are indicated with yellow arrows in comparison to mitochondria from saline-treated animals (left) indicated with white arrows. Scale bars and magnification are indicated on each panel. Quantification of the mitochondrial cross-section areas is provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070575#pone.0070575.s002" target="_blank">Figure S2</a>.