3-AP is a novel small-molecule inhibitor of RR that acts by destroying the tyrosyl radical of the R2 subunit. It belongs to a class of iron chelators known as heterocyclic carboxaldehyde thiosemicarbazones, and its activity depends on the formation of a ferrous-3-AP complex (17
). In preclinical studies 3-AP was shown to have an increased affinity for RR, up to 1000-fold potent than HU, with a broad spectrum of antitumor activity in leukemia and solid tumors (5
. In addition to direct inhibition of tumor growth, it is postulated that 3-AP enhances the cytotoxic effect of other chemotherapeutic drugs by disrupting DNA repair. Indeed, in preclinical experiments 3-AP potentiated several agents, including cisplatin, etoposide, and doxorubicin (5
. Here, we report a phase I trial of combining 3-AP with irinotecan, including pharmacokinetic and pharmacogenomic data with regards to ABCB1 and UGT1A1.
In our study, the MTD of 3-AP was significantly lower than previously reported. Other phase I studies with single-agent 3-AP demonstrated safety with single 2-hour IV infusions of up to 105 mg/m2
every 4 weeks (18
); daily 2-hour infusions up to 96 mg/m2
for 5 days every two weeks (13
); and continuous 96-hour infusions up to 120 mg/m2
/day every two weeks (19
). Similarly, the MTD of irinotecan was lower than the standard dose, which in most studies is between 300-350 mg/m2
every 3 weeks. The lower MTDs suggest that 3-AP and irinotecan are at least additive in terms of toxicity, if not synergistic. The most frequent grade 3 or 4 side effects of this regimen were nausea, vomiting, diarrhea, and myelosuppression, all of which are typical of irinotecan. 3-AP infusions were generally well-tolerated, with only 2 patients developing grade 3 hypoxia.
Partial response to treatment was seen in only 1 patient with non-small cell lung cancer, who remained on therapy for about 6 months. The duration of stable disease was generally short, with only 1 patient receiving more than 4 cycles of therapy. The paucity of response is not surprising given this group was heavily pre-treated, and most of whom had tumor types that are not known to be sensitive to irinotecan. Considering the modest antitumor activity and substantial dose-reduction of irinotecan, further study of this particular regimen is not being pursued.
The gene ABCB1, also known as MDR1, encodes for the ubiquitous efflux pump P-glycoprotein (P-gp). Single-nucleotide polymorphisms of this gene can affect not only drug resistance but also drug exposure and disease susceptibility, although the precise role of ABCB1 remains controversial (20
). Analysis of the ABCB1 haplotype in our study indicates that polymorphisms of this gene do in fact influence drug exposure and toxicity from 3-AP, with wild-type patients experiencing higher plasma concentrations and being more likely to experience a DLT when compared to the variants. Emerging evidence suggests that the ABCB1 haplotype (C1236T, G2677T, C3435T) may contribute to subtle changes in protein folding and function that lead to altered substrate binding, specificity and drug effect (21
). In general wild-type individuals have more P-gp and may be able to pump more drug out of the cell, resulting in higher plasma concentrations, increased toxicity and less activity. This is consistent with our previous work, where variants had a longer progression free survival compared to wild-type individuals (22
). In addition to substrate specificity, dose may contribute to pharmacokinetic variability with variant genotypes, as our previous work using a lower dose of 3-AP did not show a correlation between genotype and plasma concentrations (23