Abstract
BackgroundThe aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT) in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate 227Th-DOTA-p-benzyl-trastuzumab.Methodology/Principal FindingsNude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg 227Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4–5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01) and survival with tumor diameter less than 16 mm was prolonged (p<0.05) in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4–5 days interval groups (p<0.001) and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05). Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4–5 days interval groups (p<0.05). No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05) for SKOV-3 animals and in 2 weeks interval group compared with the 4–5 days interval groups (p<0.05) for SKBR-3 animals.Conclusions/SignificanceThe same concentration of radioactivity split into several fractions may improve toxicity of 227Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose to tumor with acceptable toxicity by fractionation of the dosage.
Highlights
Breast and ovarian cancer caused an estimated 590 000 cancer deaths worldwide in 2008 [1]
A pilot study was done in mice xenografted with SKBR-3 tumor by administration of 1000 kBq/kg 227Th-trastuzumab as single injection or as 4 injections of 250 kBq/kg 227Thtrastuzumab separated by 4–5 days (Figure 2A)
SKOV-3 tumor growth was initially more delayed in the group receiving a single dosage of 1000 kBq/kg body weight of 227Thtrastuzumab than in the groups given 250 kBq/kg body weight at intervals of 2 and 4 weeks, which seemed to follow the growth of the control groups (Figure 2B and 3A)
Summary
Breast and ovarian cancer caused an estimated 590 000 cancer deaths worldwide in 2008 [1]. Overall survival rates for patients with disseminated cancers are poor despite improvements in therapy methods [2,3]. The human epidermal growth factor receptor 2 (HER2, known as ErbB2/c-erbB2/HER2-neu), a transmembrane receptor tyrosine kinase, is overexpressed in 25– 30% of breast cancers [4] and 6–50% of epithelial ovarian cancers [5]. The humanized monoclonal antibody (mAb) trastuzumab (HerceptinH, Roche) targets HER2 and gained FDA approval in 2008 for treatment of HER2-overexpressing metastatic breast cancer. Resistance often develops despite sustained HER2 expression [7]. The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT) in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate 227Th-DOTA-p-benzyl-trastuzumab
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