title: Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants.
abstract: Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America.
authors.forename: Sharath P
authors.initials: SP
authors.lastname: Sasi
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America; Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Sanggyu
authors.initials: S
authors.lastname: Bae
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Song
authors.affiliation: Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Perepletchikov
authors.affiliation: Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Schneider
authors.affiliation: Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Carrozza
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yan
authors.affiliation: Feinberg Cardiovascular Institute, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Heiko
authors.initials: H
authors.lastname: Enderling
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008954:Models, Biological; D009336:Necrosis / Q000139:chemically induced; D034741:RNA, Small Interfering / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D034741:RNA, Small Interfering; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha