Evaluation of bioreductively-activated Tirapazamine (TPZ) prodrugs for the management of hypoxic solid tumors

• Author / Creator

  Pattabhi Raman, Sindhuja

• Solid tumors often have large areas with low levels of oxygen (termed hypoxic regions), which are associated with poor prognosis and treatment response. Tirapazamine (TPZ), a hypoxia targeting anticancer drug, started as a promising candidate to deal with this issue. However, it was withdrawn from the clinic due to severe neurotoxic side effects and poor target delivery. -Hypoxic cells overexpress glucose transporters (GLUT) - a key feature during hypoxic tumor progression. Our project aims at conjugating TPZ with glucose to exploit the upregulated GLUTs for its delivery, and thereby facilitate the therapeutic management of hypoxic tumors. We hypothesized that glucose-conjugated TPZ (G6-TPZ) would be selectively recruited to these receptors, facilitating its entrapment in poorly oxygenated cells only, with minimal damage to their oxygenated counterparts. However, our results reveal that the addition of the glucose moiety to TPZ was counterproductive since G6-TPZ displayed selective hypoxic cytotoxicity only at very high concentrations of the compound. We speculate that the reduced cytotoxicity of G6-TPZ might be due to the fact that the compound was not taken up by the cells. In order to monitor the cellular uptake of TPZ, we developed a click chemistry-based approach by incorporating an azido (N3) group to our parent compound (N3-TPZ). We observed that the azido-conjugated TPZ was highly hypoxia selective and the compound successfully tracks cellular hypoxia. Using a similar methodology, we went on to isolate and identify the proteins that are modified by N3-TPZ under hypoxia in order to obtain a better understanding of the potential underlying molecular mechanism of TPZ cytotoxicity. In addition, we exploited the property of monitoring TPZ uptake by N3-TPZ to study the uptake and localization of G6-TPZ by synthesizing a new derivative of TPZ, which incorporated both glucose and azido moieties. Overall, we carried out the above specified structural modifications on TPZ as an attempt to overcome the limitations of TPZ therapy.

• Subjects / Keywords

  • Tirapazamine
  • Glucose transporters
  • Tumor hypoxia

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-kq9e-2928

• License

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