title: Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from (177)Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts.
abstract: Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β(-)-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes (177)Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with (177)Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with (177)Lu-trastuzumab comparatively to animals treated with a non-specific control, (177)Lu-HuIgG, and then to prior published results obtained using (212)Pb-trastuzumab, an α-particle RIT agent. (177)Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein (212)Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. (177)Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β(-)- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β(-)-particle RIT for the management of intraperitoneal disease.
authors.affiliation: Radioimmune &amp; Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive MSC-1002, Bethesda, MD 20892, USA. halroya@gmail.com.
authors.forename: Kwon Joong
authors.initials: KJ
authors.lastname: Yong
authors.affiliation: Radioimmune &amp; Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive MSC-1002, Bethesda, MD 20892, USA. milenic.dm71q@nih.gov.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.affiliation: Radioimmune &amp; Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive MSC-1002, Bethesda, MD 20892, USA. kwamena.baidoo@nih.gov.
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.affiliation: Radioimmune &amp; Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive MSC-1002, Bethesda, MD 20892, USA. martinwb@mail.nih.gov.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D015151:Immunoblotting; D018796:Immunoconjugates / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D018499:Linear Energy Transfer; D008187:Lutetium / Q000494:pharmacology*; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D051135:Rad51 Recombinase / Q000378:metabolism; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates; D011868:Radioisotopes; D008187:Lutetium; D051135:Rad51 Recombinase; D000068878:Trastuzumab
keywords: 177Lu-Radioimmunotherapy (RIT); DNA double strand breaks; DNA repair; apoptosis; micrometastatic disease