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Enhanced therapeutic efficacy of an immunotoxin in combination with chemotherapy against an intraperitoneal human tumor xenograft in athymic mice.

Abstract
A mouse IgG2b anti-pan carcinoma monoclonal antibody, NR-LU-10, was shown to bind homogeneously to ascites xenografts of both ovarian and colon carcinoma. Following linkage to a highly potent holotoxin, Pseudomonas exotoxin A (PE), NR-LU-10 demonstrated high potency and selectivity in vitro (ID50 = 100 pg/ml; elimination of greater than or equal to 4.5 logs of cells). The conjugate was evaluated for therapeutic efficacy against a human colon tumor (HT-29) transplantable in the peritoneal cavity of nude mice. Beginning 3 days after HT-29 injection, mice received either three or six i.p. injections of 0.5 micrograms of unconjugated NR-LU-10 or immunotoxin conjugate (NR-LU-10/PE) every other day. Mice that received three or six treatments of NR-LU-10 alone had median survival times (MSTs) of 39 and 40 days, respectively, which did not differ significantly from the MST observed for the untreated control groups (MST = 35 days). In contrast, treatment with three or six injections of 0.5 micrograms NR-LU-10/PE exhibited significantly increased MSTs (P = 0.002) of 50 and 60 days, respectively. Coinjection of unconjugated NR-LU-10 (20 micrograms) and 0.5 micrograms of NR-LU-10/PE blocked the therapeutic effect of the immunotoxin (MST = 33 days). The therapeutic efficacy of NR-LU-10/PE was further enhanced against HT-29 when administered i.p. during and after cytoreductive chemotherapy. The i.p. administration of 300 mg/lg of cyclophosphamide plus 100 mg/kg of the chemoprotective drug, WR-2721, 10 and 17 days posttumor cell inoculation induced a significant increase in MST from 36 days to 59 days (P = 0.002). Interestingly, groups of mice that received either two, four, or seven treatments of NR-LU-10/PE following cytoreductive therapy exhibited a further significant increase (P = 0.001) in MSTs of 89, 97, and 105 days, respectively. Therefore, the use of immunotoxin therapy following cytoreductive chemotherapy significantly prolonged survival time of mice bearing the HT-29 colon tumor over that observed with chemotherapy or NR-LU-10/PE alone.
AuthorsJ W Pearson, G Sivam, R Manger, R H Wiltrout, A C Morgan Jr, D L Longo
JournalCancer research (Cancer Res) Vol. 49 Issue 18 Pg. 4990-5 (Sep 15 1989) ISSN: 0008-5472 [Print] United States
PMID2504482 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Bacterial Toxins
  • Exotoxins
  • Immunotoxins
  • Virulence Factors
  • ADP Ribose Transferases
  • Pseudomonas aeruginosa exotoxin A
Topics
  • ADP Ribose Transferases
  • Animals
  • Antibodies, Monoclonal (therapeutic use)
  • Antigens, Neoplasm (analysis)
  • Bacterial Toxins
  • Cell Line
  • Colonic Neoplasms (therapy)
  • Exotoxins
  • Flow Cytometry
  • Humans
  • Immunotoxins (therapeutic use)
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Pseudomonas aeruginosa
  • Transplantation, Heterologous
  • Tumor Stem Cell Assay
  • Virulence Factors

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