Therapy of human pancreatic carcinoma implants by irinotecan and the oral immunomodulator JBT 3002 is associated with enhanced expression of inducible nitric oxide synthase in tumor-infiltrating macrophages

Christiane J. Bruns, Hisashi Shinohara, Matthew T. Harbison, Darren W. Davis, Gina Nelkin, Jerald J. Killion, David McConkey, Zhongyun Dong, Isaiah J. Fidler

Research output: Contribution to journalArticle

Abstract

We determined the therapeutic effect of irinotecan (CPT-11) combined with the immunomodulator JBT 3002, a synthetic bacterial lipopeptide (N- acylated derivative of ψ-amino-C1-C3-alkane-sulfonic acid), against highly metastatic human pancreatic carcinoma cells injected into the pancreas of athymic nude mice. Mice received four courses consisting of three daily oral doses of JBT 3002, followed by once weekly i.p. injection of CPT-11. Control mice were treated with CPT-11 alone, JBT 3002 alone, or saline. Tumor growth and metastasis were assessed by gross pathology and confirmed by histological examination. Treatment with CPT-11 alone significantly decreased the median volume of pancreatic tumors and the incidence of metastasis, whereas treatment with only JBT 3002 did not. The combination therapy of CPT-11 plus JBT 3002 decreased tumor volume and incidence of metastasis significantly more than CPT-11 alone. The number of apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), the number of scavenger-receptor-positive macrophages, and expression level of inducible nitric oxide synthase (iNOS) within lesions directly correlated with therapeutic effects. Indeed, the in vitro incubation of tumor cells with macrophages activated by JBT 3002 plus IFN-γ produced a significant lysis of tumor cells that could be blocked by a specific inhibitor of iNOS. Collectively, these data demonstrate that the oral administration of the immunomodulator JBT 3002 combined with i.p. injection of CPT-11 can decrease the growth of human pancreatic carcinoma and the incidence of metastasis in nude mice by both a direct antitumor effect and the activation of iNOS in infiltrating macrophages.

Original languageEnglish (US)
Pages (from-to)2-7
Number of pages6
JournalCancer Research
Volume60
Issue number1
StatePublished - Jan 1 2000
Externally publishedYes

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irinotecan
Immunologic Factors
Nitric Oxide Synthase Type II
Macrophages
Neoplasms
Nude Mice
Neoplasm Metastasis
Therapeutic Uses
Therapeutics
Tumor Burden
Incidence
Lipopeptides
Scavenger Receptors
Injections
Alkanes
Sulfonic Acids
DNA Nucleotidylexotransferase
Pancreatic Carcinoma
JBT-3002
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Therapy of human pancreatic carcinoma implants by irinotecan and the oral immunomodulator JBT 3002 is associated with enhanced expression of inducible nitric oxide synthase in tumor-infiltrating macrophages. / Bruns, Christiane J.; Shinohara, Hisashi; Harbison, Matthew T.; Davis, Darren W.; Nelkin, Gina; Killion, Jerald J.; McConkey, David; Dong, Zhongyun; Fidler, Isaiah J.

In: Cancer Research, Vol. 60, No. 1, 01.01.2000, p. 2-7.

Research output: Contribution to journalArticle

Bruns, Christiane J. ; Shinohara, Hisashi ; Harbison, Matthew T. ; Davis, Darren W. ; Nelkin, Gina ; Killion, Jerald J. ; McConkey, David ; Dong, Zhongyun ; Fidler, Isaiah J. / Therapy of human pancreatic carcinoma implants by irinotecan and the oral immunomodulator JBT 3002 is associated with enhanced expression of inducible nitric oxide synthase in tumor-infiltrating macrophages. In: Cancer Research. 2000 ; Vol. 60, No. 1. pp. 2-7.
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abstract = "We determined the therapeutic effect of irinotecan (CPT-11) combined with the immunomodulator JBT 3002, a synthetic bacterial lipopeptide (N- acylated derivative of ψ-amino-C1-C3-alkane-sulfonic acid), against highly metastatic human pancreatic carcinoma cells injected into the pancreas of athymic nude mice. Mice received four courses consisting of three daily oral doses of JBT 3002, followed by once weekly i.p. injection of CPT-11. Control mice were treated with CPT-11 alone, JBT 3002 alone, or saline. Tumor growth and metastasis were assessed by gross pathology and confirmed by histological examination. Treatment with CPT-11 alone significantly decreased the median volume of pancreatic tumors and the incidence of metastasis, whereas treatment with only JBT 3002 did not. The combination therapy of CPT-11 plus JBT 3002 decreased tumor volume and incidence of metastasis significantly more than CPT-11 alone. The number of apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), the number of scavenger-receptor-positive macrophages, and expression level of inducible nitric oxide synthase (iNOS) within lesions directly correlated with therapeutic effects. Indeed, the in vitro incubation of tumor cells with macrophages activated by JBT 3002 plus IFN-γ produced a significant lysis of tumor cells that could be blocked by a specific inhibitor of iNOS. Collectively, these data demonstrate that the oral administration of the immunomodulator JBT 3002 combined with i.p. injection of CPT-11 can decrease the growth of human pancreatic carcinoma and the incidence of metastasis in nude mice by both a direct antitumor effect and the activation of iNOS in infiltrating macrophages.",
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AU - Nelkin, Gina

AU - Killion, Jerald J.

AU - McConkey, David

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AU - Fidler, Isaiah J.

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