Irinotecan is widely used to treat colorectal and lung cancers but causes severe, occasionally fatal toxicity in the form of leukopenia and diarrhea. Earlier research led Dr. Ando and colleagues to hypothesize that polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A7 gene would reduce its enzymatic activity and affect toxicity in patients treated with irinotecan. UGT is involved in the glucuronidation of SN-38, the active metabolite of irinotecan.

Dr. Ando's group had previously reported that UGT1A1*28 was a significant risk factor for these side effects. Subsequently, the researchers focused on polymorphisms of UGT1A7, a gene that has been recently reported to glucuronidate SN-38 at a more than 9-fold higher level than that associated with UGT1A1 and that is expressed strongly in gastrointestinal tissues. They speculated that investigating these polymorphisms might help predict severe irinotecan toxicity, especially diarrhea.

Gene sequencing analysis produced three variants of the reference allele UGT1A7*1, namely, UGT1A7*2, UGT1A7*3, and UGT1A7*4. Next, the researchers established the genotype of the UGT1A7 gene in 118 cancer patients and in 108 healthy subjects. The patients had been previously diagnosed with small cell lung cancer (n=21), non-small cell lung cancer (n=65), colorectal cancer (n=21), or others (n=11). Twenty-six of the patients experienced grade 4 leukopenia and/or grade 3 or 4 diarrhea following treatment with irinotecan.

Both univariate and multivariate analysis found no significant association between the variant alleles and the occurrence of severe toxicity. These results suggest that determination of UGT1A7 genotype status is not helpful as a predictor of severe, irinotecan-associated toxicity. The distribution of UGT1A7 genotypes was similar in both healthy subjects and cancer patients.

In addition, Dr. Ando noted that the frequencies of UGT1A7 variant alleles are significantly lower in the Japanese population that she studied than in Caucasian populations, as had been reported earlier by others.