Repair and restitution in the gastrointestinal tract after exposure to a cancer chemotherapy drug.

Chemotherapy and radiotherapy target neoplastic cells. However, they also adversely affect progenitor cells throughout the healthy alimentary tract, resulting in severe ulceration and pain. This affects around 500,000 patients annually. The aims of the present research were to identify the main cellular changes triggered in the small intestine by chemotherapy and to evaluate the efficacy of a possible palliative, a lectin. Rats were given 5-nuorouracil. This caused loss of rapidly dividing cells from the intestinal crypts and collapse of crypt / villus structure. By 2 days, few progenitor cells were evident. Nonetheless, cell division re-started thereafter and the stem cell population re-established. This did not, as expected, result in restoration of the crypt-villus axis. It remained disorganised. Persistent disruption of the intestinal sub-epithelial myofibroblast sheath, caused by 5-fluorouracil, impaired repair. Regulatory signals from myofibroblasts are essential for proper crypt development. In their absence, crypt regrowth would be disorganised, as seen after 5-fluorouracil. Chemotherapy-linked affects on myofibroblasts have not been reported before. Oral administration of lectin caused adaptational change in the small intestine. It induced crypt cell proliferation in a cyclooxygenase 2-dependent manner. Lectin also caused an expansion in the oligomucous cell population of the crypt. This was modulated through bioactive factors from mucosal mast cells and cyclooxygenase 2. Sub-epithelial myofibroblast function was also modified, possibly via angiotensin II. Pre-treatment of rats with lectin ameliorated the effects of 5-fluorouracil on the gut. This was due to a novel protective mechanism. Although cell loss occurred, as with 5-fluorouiracil alone, there was rapid appearance of mature goblet-and Paneth-like cells within damaged crypts. These probably protected the remaining stem cells. At two days post-chemotherapy, micro-crypts (consisting of clusters of dividing cells, goblet and Paneth cells surrounded by a myofibroblast sheath) were evident. These formed the launch platform for regrowth of the gut. Overall, 5-fluorouracil caused disruption of the small intestine sub-epithelium, as well as triggering death of epithelial stem cells. Pre-treatment with lectin adapted the gut and enabled micro-crypts to be preserved after chemotherapy. Regrowth of the epithelium from these micro-crypts was rapid and organised. Key words: chemotherapy, 5-fluorouracil, mucositis, intestine, mucosal damage, crypt epithelium, sub-epithelial myofibroblasts, palliative treatment, lectin.

Grantor dc:publisher.institution

Robert Gordon University

Year dc:date.issued

2006

Author dc:creator

• Duncan, Michelle

Advisor dc:contributor.advisor

• G. Grant and R. Lea

• Chemotherapy
• 5-fluorouracil
• Mucositis
• Intestine
• Mucosal damage
• Crypt epithelium
• Sub-epithelial myofibroblasts
• Palliative treatment
• Lectin

Language dc:language

en

Identifier

oai:rgu-repository.worktribe.com:2807369
https://doi.org/10.48526/rgu-wt-2807369

OAI identifier oai:identifier

oai:rgu-repository.worktribe.com:2807369