Alex Sparreboom

Significance: Acute kidney injury (AKI) is a common clinical condition caused by loss of kidney function. Lack of therapeutic options has contributed to high mortality rates in AKI patients. Drug-induced AKI, as observed during cisplatin-based anticancer therapy, is responsible for about 20% of renal failure cases. The initial injury triggers a proliferative response in renal tubular cells, which in the presence of cellular damage can further accelerate renal injury. Our study provides evidence that the small-molecule cell-cycle inhibitors palbociclib and LEE011 can prevent cisplatin-induced AKI by inhibiting two relevant targets: renal cell-cycle progression and organic cation transporter 2, a renal uptake transporter of cisplatin. The future development of cyclin-dependent kinase 4/6 inhibitors as renal protective agents could have significant clinical benefits.

In a landmark article published in the May 1, 2001, issue of Clinical Cancer Research, Lee and colleagues reported the original preclinical studies demonstrating anticancer activity of BMS-247550 (ixabepilone) against taxane-sensitive and taxane-resistant cancers. Subsequent clinical trials established the clinical efficacy of ixabepilone, leading to its regulatory approval for the treatment of drug-resistant metastatic or locally advanced breast cancers. Clin Cancer Res; 21(6); 1237–9. ©2015 AACR. See related article by Lee et al., Clin Cancer Res 2001;7(5) May 2001;1429–37

Although kinetic phenotypes of drugs often show considerable variability between different laboratories and/or within the same laboratory when experiments are performed over time, even in a genetically uniform mouse strain, the extent to which our original data differ from more recent findings (>10-fold) seems to be greater than what could have been expected from related literature on this topic. We have not been able to attribute these discrepancies to any particular reason (either biologic, environmental, and/or analytic), and have not identified any calculation errors. Although the pharmacokinetic differences in question are of a quantitative nature and do not affect the posited conclusions of our original article in a qualitative manner, based on the collective evidence now available, the original report likely overestimated the individual contribution of Oatp1b2 to the clearance of docetaxel in mice. This conclusion is consistent with recently reported by two other groups (4,5), and is in better agreement with published studies on the related drug paclitaxel (6, 7).

Purpose: Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 (Oct1/2^−/−mice), and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2^−/−mice, we hypothesized that alternate pathways are involved in the observed injury. Experimental Design: Studies were done in wild-type, Oct1/2^−/−, or p53-deficient animals, all on an FVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays. Results: KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wild-type (P = 2.40 × 10⁻¹¹) and Oct1/2^−/−mice (P = 1.92 × 10⁻⁸). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, whereas loss of p53 in Oct1/2^−/−mice (p53^−/−/Oct1/2^−/−) completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53^−/−/Oct1/2^−/−mice. Conclusions: These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized. Clin Cancer Res; 20(15); 4026–35. ©2014 AACR.

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P = 0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P < 0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug–drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. Cancer Res; 74(11); 3137–45. ©2014 AACR.

Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field.

Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1. The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice. All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics. These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI–chemotherapy interactions involving transporters.