The effect of surgically induced ischaemia on gene expression in a colorectal cancer xenograft model

Delays in tissue fixation following tumour vascular clamping and extirpation may adversely affect subsequent protein and mRNA analysis. This study investigated the effect of surgically induced ischaemia in a xenograft model of a colorectal cancer on the expression of a range of prognostic, predictive, and hypoxic markers, with a particular emphasis on thymidylate synthase. Vascular occlusion of human tumour xenografts by D-shaped metal clamps permitted defined periods of tumour ischaemia. Alterations in protein expression were measured by immunohistochemistry and spectral imaging, and changes in mRNA were measured by reverse transcriptase–polymerase chain reaction. Thymidylate synthase expression decreased following vascular occlusion, and this correlated with cyclin A expression. A similar reduction in dihydropyrimidine dehydrogenase was also seen. There were significant changes in the expression of several hypoxic markers, with carbonic anhydrase-9 showing the greatest response. Gene transcriptional levels were also noted to change following tumour clamping. In this xenograft model, surgically induced tumour ischaemia considerably altered the gene expression profiles of several prognostic and hypoxic markers, suggesting that the degree of tumour ischaemia should be minimised prior to tissue fixation

Phase I trial of zalutumumab and irinotecan in metastatic colorectal cancer patients who have failed irinotecan- and cetuximab-based therapy

[Background:] Zalutumumab is a novel human IgG1 anti-EGFR mAb. We investigated the safety of zalutumumab and irinotecan in heavily pretreated mCRC patients. [Methods:] Metastatic CRC patients with documented progression (PD) during or within 6 months of stopping cetuximab and irinotecan based therapy were eligible. No prior treatment with anti-EGFR antibodies other than cetuximab was allowed. Patients received weekly doses of zalutumumab 8mg/kg and 16 mg/kg respectively in combination with irinotecan (180 mg/m2) every second week until PD or unacceptable toxicity. [Results:] The maximum tolerated dose was not reached and no patients experienced any dose limiting toxicity. At data cut-off (18-Dec-08) 4 patients had died (no cases of death were considered related to zalutumumab), 4 were off study due to PD and 1 was still ongoing (Table 1). In total, 6 patients experienced one or more grade 3/4 toxicities (diarrhea 2; neutropenia 2; leucopenia 1; abdominal pain 1; pulmonary embolism 1; alopecia 1). [Conclusions:] Zalutumumab can be safely administrated in doses up to 16mg/kg in combination with irinotecan in mCRC patients failing cetuximab and irinotecan based therapy. Zalutumumab and irinotecan resulted in durable stable disease warranting further investigation of this regimen