Resistance mechanisms of gastrointestinal cancers: why does conventional chemotherapy fail?
BACKGROUND
Gastrointestinal cancers belong to the most important causes of cancer death in the Western world. Because cure can be achieved only by complete surgical removal of the tumor, and most patients have metastasis at the time point of diagnosis, the majority of patients receive chemotherapy.


CONCLUSIONS
Indications for chemotherapy are either the prevention of recurrence after tumor resection (neoadjuvant or adjuvant) or palliative treatment if the tumor is already widespread at diagnosis. Although gastrointestinal cancers often respond to primary treatment, the long-term results are disappointing. This is attributable to a variety of cellular resistance mechanisms, namely: (a) kinetic resistance due to slow growth rates that preclude the use of topoisomerase IIalpha inhibitors and related drugs; (b) genetic resistance due to mutations, for example, in the p53 gene, which impede the sensing of DNA damage and obstruct apoptotic pathways; (d) pharmacokinetic resistance, due to an excess of target proteins, inadequate drug metabolism, administration period, time or drug interactions; and (d) biological resistance due to tumor-induced environmental changes. These factors interfere specifically with the molecular mode of action of standard drugs used in the therapy of gastrointestinal cancers.


CONCLUSIONS
Awareness of the various causes of drug resistance may help to devise individual tumor-adapted treatment designs. Notably, nonsteroidal antiphogistics may delay carcinogenesis, anticoagulants may increase the vulnerability of circulating tumor cells and reduce the nesting abilities of single tumor cells, inhibitors of angiogenesis may quell the growth of micrometastases, and kinase inhibitors may be administered as sensitizers to cytotoxic treatment.
Gieseler
F
F
Department of Internal Medicine, University Hospital of Kiel, Schittenhelmstrasse 12, 24105, Kiel, Germany. gieseler@email.uni-kiel.de
Rudolph
P
P
Kloeppel
G
G
Foelsch
U R
UR
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II