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Basic Sciences

Enhanced Therapeutic Efficacy of an Immunotoxin in Combination with Chemotherapy against an Intraperitoneal Human Tumor Xenograft in Athymic Mice

John W. Pearson, Gowsala Sivam, Ron Manger, Robert H. Wiltrout, A. C. Morgan Jr. and Dan L. Longo
John W. Pearson
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Gowsala Sivam
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Ron Manger
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Robert H. Wiltrout
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A. C. Morgan Jr.
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Dan L. Longo
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DOI:  Published September 1989
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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 ≥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 µg 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 µg NR-Lu-10/PE exhibited significantly increased MSTs (P = 0.002) of 50 and 60 days, respectively. Coinjection of unconjugated NR-LU-10 (20 µg) and 0.5 µg 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/kg 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.

Footnotes

  • ↵1 To whom requests for reprints should be addressed.

  • Received February 23, 1989.
  • Revision received May 22, 1989.
  • Accepted June 20, 1989.
  • ©1989 American Association for Cancer Research.
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September 1989
Volume 49, Issue 18
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Enhanced Therapeutic Efficacy of an Immunotoxin in Combination with Chemotherapy against an Intraperitoneal Human Tumor Xenograft in Athymic Mice
John W. Pearson, Gowsala Sivam, Ron Manger, Robert H. Wiltrout, A. C. Morgan Jr. and Dan L. Longo
Cancer Res September 15 1989 (49) (18) 4990-4995;

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Enhanced Therapeutic Efficacy of an Immunotoxin in Combination with Chemotherapy against an Intraperitoneal Human Tumor Xenograft in Athymic Mice
John W. Pearson, Gowsala Sivam, Ron Manger, Robert H. Wiltrout, A. C. Morgan Jr. and Dan L. Longo
Cancer Res September 15 1989 (49) (18) 4990-4995;
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