Gilbert's syndrome, Side effects of CPT-11 [UGT1A1 Test];

Oncoscreen GmbH
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Scientific background

The chemotherapeutical drug CPT-11 is transformed mainly in the liver into the actual cytotoxic substance SN-38. SN-38 is distributed in the blood-stream of the body and inhibits the enzyme Topoisomerase I, which itself plays an important role in DNA synthesis. Once Topoisomerase I is inhibited, especially fast-growing cells are not able to replicate their DNA before cell division and they die. The chemotherapeutical effect and the outbreak of most side effects are based on this specific cell death mechanism.

SN-38 is transformed into SN-38G mainly by the enzyme Uridin-Glucuronosyl-Transferase 1A1 (UGT1A1). SN-38G is removed from the liver via the gall-bladder through the intestines. UGT1A1 is therefore a very important factor for detoxicating CPT-11. The number of UGT1A1 enzymes in a cell depends on the genotype of the so-called TATA-Box in the promoter of the UGT1A1 gene. If this TATA-Box has the genotype 7/7 (homozygous for 7 TA-repetitions), little UGT1A1 is produced; if the TATA-Box has the genotype 6/7 (heterozygous), medium amounts of the enzyme are produced; and if the genotype is 6/6 (homozygous for 6 TA-repetitions), higher amounts of UGT1A1 are produced. About 11% of all Europeans have the genotype 7/7, 55% have the genotype 6/7, and 34% have the genotype 6/6 (promoter polymorphism, Beutler et al., PNAS 95:8170-4). Oncoscreen has shown the same results in its own study with 34 patients.

he correlation between the side effects of the CPT-11 and the promoter polymorphism of the UGT1A1 was confirmed in two internationally published studies. In a retrospective study Ando et al. showed that 118 patients who have the promoter structure 6/6 suffer significantly less from toxicities than do patients with other promoter structures:

These results show that more than half of all the patients of the genotype 7/7 suffer from severe to life-threatening side effects after Irinotecan treatment, while only 15% of the genotype 6/6 are affected by strong side effects.

Preliminary prospective data of another team support this conclusion:

Iyer et al. therefore recommend a pre-therapeutic check-up of the UGT1A1 promoter region.

Gilbert’s Syndrome, Meulengracht Syndrome

The Gilbert’s syndrome (Meulengracht syndrome, familiar non-haemolytic icterus, functional hyperbilirubinemia) was identified by Nicolas Augustin Gilbert and Pierre Lereboullet in 1900 and later by Jens Einar Meulengracht. A hereditary disorder of the bilirubinemia metabolism in the liver, it does not indicate a serious liver disorder; mostly it appears as a mild form of sclerenicterus (yellow coloring of the eye's sclera).

It was recently discovered that this syndrome is linked to the promoter polymorphism in the UGT1A1 gene. This rather harmless metabolic anomaly has clinical significance only when drugs are administered whose metabolism requires the UGT1A1 enzyme, for example, the drug CPT-11/Irinotecan. In the case of an additional liver disorder, the metabolic anomaly may result in jaundice. In the case of a patient with jaundice, Oncoscreen can test whether Gilbert's syndrome is present.

Neonatal Icterus (Jaundice)

A mild form of neonatal icterus occurs in 90% of all newborn babies within the first days of life. However, there are cases of distinctive icterus that have many different causes, some of which are dangerous for the child. One cause is the UGT1A1 promoter polymorphism (J Pediatr 1999; 134: 441-446, Semin Neonatol 2002; 7: 121-128). Oncoscreen´s test is suitable for newborn babies with icterus to see if a UGT 1A1 Promotor Polymorphimism exists. We require only 0.1 to 0.2ml EDTA, Citrate or Heparin blood for a test.