Antiproliferative effects of 111In- or 177Lu-DOTATOC on cells exposed to low multiplicity-of-infection double-deleted vaccinia virus encoding somatostatin subtype-2 receptor.
Oncolytic viruses may be limited in their ability to infect and lyse tumor cells because of penetration barriers and viral elimination by the immune system. Combining virotherapy with targeted radiotherapy that uses (111)In- or (177)Lu-DOTATOC may address such issues by spatially enhancing antitumor effects through bystander and/or cross-fire phenomena. In this study, a double-deleted vaccinia virus (vvDD) encoding the gene for somatostatin subtype-2 receptor (sstr-2) infected MC-38 murine colon adenocarcinoma cells and increased their sstr-2 expression by 2-fold. A low multiplicity-of-infection (MOI = 0.1) of vvDD and short exposure time (48 hours) preserved MC-38 viability (>80%-90%) for up to 3 days, permitting targeting of sstr-2 by (111)In- or (177)Lu-DOTATOC. (111)In-DOTATOC, alone or in combination with vvDD, was less effective than (177)Lu-DOTATOC at decreasing the growth of sstr-2-gene-transfected human embryonic kidney (HEK)-293 cells or MC-38 cells in monolayer. However, (111)In- or (177)Lu-DOTATOC combined with vvDD provided equivalent growth inhibition of HEK-293 or MC-38 cells as spheroids, suggesting a bystander effect from (111)In-DOTATOC. Growth of the cells was reduced 4-fold (from 20% to <5%) at 8 days in this case. Further evaluation of low-MOI vvDD in combination with (111)In- or (177)Lu-DOTATOC for the treatment of MC-38 tumors in mice is planned.
Akinlolu
Olayinka
O
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Ottolino-Perry
Kathryn
K
McCart
Judith Andrea
JA
Reilly
Raymond M
RM
D000230:Adenocarcinoma; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects*; D003110:Colonic Neoplasms; D003131:Combined Modality Therapy / Q000379:methods; D003593:Cytoplasm / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D050130:Oncolytic Virotherapy / Q000379:methods*; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014616:Vaccinia virus / Q000235:genetics* / Q000502:physiology
C507387:111In-DOTA-TOC; C504257:177Lu-octreotide, DOTA(0)-Tyr(3)-; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D015282:Octreotide