Pre-clinical evaluation of the Gastrimmune immunogen alone and in combination with 5-fluorouracil/leucovorin in a rat colorectal cancer model

Watson, Susan A.; Michael, Dov; Justin, Timothy A.; Grimes, Stephen; Morris, Teresa; Robinson, Graham; Clarke, Paula J.; Hardcastle, J. D.

doi:10.1002/(sici)1097-0215(19980316)75:6<873::aid-ijc9>3.0.co;2-s

Cited by 25 publications

(11 citation statements)

References 10 publications

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“…Colorectal carcinomas have been found to produce progastrin related peptides and to express CCK 2 /gastrin receptors (Nemeth et al, 1993; Baldwin and Shulkes, 1998; McWilliams et al, 1998) and/or a constitutively active splice variant of this receptor (Hellmich et al, 2000). In vivo animal models for colorectal cancer have shown inhibition of tumor growth by antibodies against gastrin (Watson et al, 1996, 1998).…”

mentioning

confidence: 99%

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Slice

Hodikian

Zhukova

2003

Journal Cellular Physiology

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Over-expression of cyclooxygenase-2 (COX-2) has been demonstrated to be tumorigenic in transgenic mice. Chronic treatment with NSAIDs is chemoprotective for colorectal cancer. Gastrin is a growth factor for gastric mucosa and has been shown to promote proliferation of colorectal cells. Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin. Here, we report that gastrin increased PGE2 secretion in Swiss 3T3 cells expressing the CCK2 receptor. Gastrin dose dependently induced COX-2 protein levels in a time dependent manner. COX-2 mRNA levels were rapidly induced by a dose dependent increase in gastrin. Prior treatment of the cells with the CCK2 receptor specific antagonist, L365,260, inhibited gastrin-induced COX-2 protein and mRNA expression. Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin. Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin. Also, gastrin-dependent COX-2 expression did not require PKC activity, activation of ERK, or transactivation of EGFR. However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion. Measurements of COX-2 mRNA stability and COX-2 gene transcription reveal that EGF significantly increased the half-life of COX-2 mRNA with only a slight increase in the COX-2 transcription rate. Conversely, gastrin significantly increased COX-2 gene transcription rates but did not enhance COX-2 mRNA stability.

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mentioning

confidence: 99%

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Slice

Hodikian

Zhukova

2003

Journal Cellular Physiology

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“…Its action is to enhance both humoral [27] GMK: GM2-ganglioside conjugated to keyhole limpet haemocyanin used in conjunction with QS-21…”

Section: Qs-21 (Stimulon™)mentioning

confidence: 99%

“…Similarly, it was shown that neutralising gastrin inhibited cell growth. Gastrimmune™ is a multi-component formulation composed of a monomer peptide identical to a portion of gastrin-17, fused to a carrier protein (diphtheria toxin) and mixed with an oil-in-water emulsion [27,28].…”

Section: Synthetic Vaccinesmentioning

confidence: 99%

Cancer vaccines entering Phase III clinical trials

Durrant¹,

Spendlove²

2003

Expert Opinion on Emerging Drugs

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The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.

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“…In vivo G17DT generates antibodies that block gastrin interaction with the CCK-2 receptor and also produces active as well as passive immunization. G17DT (Gastrimmune) has been shown to be active against colorectal cancer in a rat model (83). A pivotal phase III trial in the USA compared G17DT in combination with gemcitabine with gemcitabine alone and a second trial in Europe compared G17DT directly with gemcitabine.…”

Section: Immunotherapymentioning

confidence: 99%

New Techniques and Agents in the Adjuvant Therapy of Pancreatic Cancer

et al. 2002

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Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.

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Pre-clinical evaluation of the Gastrimmune immunogen alone and in combination with 5-fluorouracil/leucovorin in a rat colorectal cancer model

Cited by 25 publications

References 10 publications

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Cancer vaccines entering Phase III clinical trials

New Techniques and Agents in the Adjuvant Therapy of Pancreatic Cancer

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Pre-clinical evaluation of the Gastrimmune immunogen alone and in combination with 5-fluorouracil/leucovorin in a rat colorectal cancer model

Cited by 25 publications

References 10 publications

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor

Cancer vaccines entering Phase III clinical trials

New Techniques and Agents in the Adjuvant Therapy of Pancreatic Cancer

Contact Info

Product

Resources

About

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor

Gastrin and EGF synergistically induce cyclooxygenase‐2 expression in Swiss 3T3 fibroblasts that express the CCK₂ receptor