Ioflubenzamide I-131

External beam radiotherapy (EBRT) with carbon ions and endoradiotherapy using radiolabeled tumor targeting agents are emerging concepts in precision cancer therapy. We report on combination effects of these two promising strategies. Tumor targeting ¹³¹I-labelled anti-EGFR-antibody (Cetuximab) was used in the prototypic EGFR-expressing A431 human squamous cell carcinoma xenograft model. A ¹³¹I-labelled melanin-binding benzamide derivative was utilized targeting B16F10 melanoma in an orthotopic syngeneic C57bl6 model. Fractionated EBRT was performed using carbon ions in direct comparison with conventional photon irradiation. Tumor uptake of ¹³¹I-Cetuximab and ¹³¹I-Benzamide was enhanced by fractionated EBRT as determined by biodistribution studies. This effect was independent of radiation quality and significant for the small molecule ¹³¹I-Benzamide, i.e., >30% more uptake in irradiated vs. non-irradiated melanoma was found (p<0.05). Compared to each monotherapy, dual combination with ¹³¹I-Cetuximab and EBRT was most effective in inhibiting A431 tumor growth. A similar trend was seen for ¹³¹I-Benzamide and EBRT in B16F10 melanoma model. Addition of ¹³¹I-Benzamide endoradiotherapy to EBRT altered expression of genes related to DNA-repair, cell cycle and cell death. In contrast, immune-response related pathways such as type 1 interferon response genes (ISG15, MX1) were predominantly upregulated after combined ¹³¹I-Cetuximab and EBRT. The beneficial effects of combined 131I-Cetuximab and EBRT was further attributed to a reduced microvascular density (CD31) and decreased proliferation index (Ki-67). Fractionated EBRT could be favorably combined with endoradiotherapy. ¹³¹I-Benzamide endoradiotherapy accelerated EBRT induced cytotoxic effects. Activation of immune-response by carbon ions markedly enhanced anti-EGFR based endoradiotherapy suggesting further evaluation of this novel and promising radioimmunotherapy concept.

This study investigated the changes in establishment rates during the time course of a 6 week trickle infection of chickens with Ascaridia galli at two different dose levels, using a molecular marker. To differentiate early and late infection, two different egg cohorts (haplotype a and haplotype b, genetically identified using PCR-linked restriction fragment length polymorphism on the cox1 gene of the mitochondrial DNA) were used. Cohort-specific egg batches were produced by harvesting eggs from the uteri of female worms of the specific cohort. Fifty-six 8 week old Lohmann Brown Lite chickens were divided into seven groups and the infectivity of the egg batches was compared between two groups of chickens (P=0.6). The remaining chickens were allocated to four infection regimes and one control group. Group ab100 was trickle infected for 3 weeks with 100 eggs of haplotype a (twice weekly) followed by the same dose of eggs of haplotype b for another 3 weeks. Group ba100 was treated similarly but in the opposite order (haplotype b preceding a). A similar infection regime was applied for groups ab25 and ba25 but with a lower inoculation dose (25 eggs). All of the birds in these five groups (four infected and one control) were euthanased 2 weeks after the last inoculation. It was found that in the low-dose groups both the early and late infections established equally well, whereas in the high-dose groups the early infection was recovered in a significantly (P<0.001) higher proportion of chickens than the late infection, irrespective of genetic cohorts. Moreover, relatively higher proportions of the larvae from both the early and late infections were found in the posterior section of the small intestine. This result indicates the presence of dose-dependent resistance against reinfection and this resistance seems to act by reducing the establishment of late infection and by relocating the larvae from early infection.