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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2010)

ABSTRACT

TARGETING DRUG TRANSPORTERS AS A NOVEL APPROACH FOR PLATINUM-BASED ANTICANCER THERAPY

Shuanglian Li

Tissue specific targeting by design and development of influx transporter targeted compounds represents one effective approach for increasing efficacy and reducing toxicity of drugs. The overall goal of this dissertation research was to test the hypothesis that organic cation transporter 1 (OCT1) can be used as a target to deliver platinum-based chemotherapeutics to tumors with the goal of enhancing the efficacy and reducing the toxicity of these agents.

As a first step in evaluating the potential of OCT1 as a valid drug delivery target we determined the effect of OCT1 on the disposition of pyroplatin (a potent OCT1 substrate) under normal physiological OCT1 expression level in vitro and in vivo. Studies in primary hepatocytes and Oct1 knockout mice demonstrated that Oct1 plays a role in mediating the transport of pyroplatin into the Oct1 expressing tissues and accordingly its pharmacokinetics.

The goal of the second part of this dissertation was to determine the role of OCT1 in response to pyroplatin. In particular the role of OCT1 in the toxicity and antitumor effect of pyroplatin was intensively investigated using genetically modified mice. The data supported the concept that by targeting drug influx transporters, off-target toxicities can be greatly spared. Although OCT1 mediated the accumulation of pyroplatin in hepatocellular carcinoma, a benefit on overall survival of the mice was not observed. Further investigation is needed to elucidate the mechanisms of resistance of hepatocellular carcinoma to pyroplatin and other platinum based chemotherapies.

In the final part of this dissertation, the role of OCT1 in the disposition and drug action of oxaliplatin (a moderate substrate of OCT1) was explored. The minor effects of OCT1 on the pharmacokinetics and tissue accumulation suggested that the Oct1-mediated transport of oxaliplatin is not sufficiently high to remarkably affect its disposition in vivo. The increased hepatic platinum levels after multiple dosing in Oct1+/+ mice did not result in obvious liver toxicity, indicating that the hepatic toxicity of oxaliplatin observed in humans was not observed under the conditions used in this study and a clear role for Oct1 in oxaliplatin-induced hepatotoxicity could not be established.

    Cover page: TARGETING DRUG TRANSPORTERS AS A NOVEL APPROACH FOR PLATINUM-BASED ANTICANCER THERAPY
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2011)

    Purpose

    The goal of this study was to test the hypothesis that by controlling intracellular uptake, organic cation transporter 1, Oct1 is a key determinant of the disposition and toxicity of cis-diammine(pyridine)chloroplatinum(II)(CDPCP) and oxaliplatin.

    Methods

    Pharmacokinetics, tissue accumulation and toxicity of CDPCP and oxaliplatin were compared between Oct1-/- and wild-type mice.

    Results

    After intravenous administration, hepatic and intestinal accumulation of CDPCP was 2.7-fold and 3.9-fold greater in Oct1 wild-type mice (p < 0.001). Deletion of Oct1 resulted in a significantly decreased clearance (0.444 ± 0.0391 ml/min*kg versus 0.649 ± 0.0807 ml/min*kg in wild-type mice, p < 0.05) and volume distribution (1.90 ± 0.161 L/kg versus 3.37 ± 0.196 L/kg in wild-type mice, p < 0.001). Moreover, Oct1 deletion resulted in more severe off-target toxicities in CDPCP-treated mice. Histologic examination of the liver and measurements of liver function indicated that the level of hepatic toxicity was mild and reversible, but was more apparent in the wild-type mice. In contrast, the effect of Oct1 on the pharmacokinetics and toxicity of oxaliplatin in the mice was minimal.

    Conclusions

    Our study suggests that Oct1 plays an important role in the pharmacokinetics, tissue distribution and toxicity of CDPCP, but not oxaliplatin.
      Cover page: Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis-Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2014)
      Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function.
        Cover page: OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2021)
        Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.
          Cover page: Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial
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