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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Effects of platinum-based anticancer drugs on the trace element profile of liver and kidney tissue from mice
John T Sloop1, Jake A Carter1, Ulrich Bierbach2
1Department of Chemistry, Wake Forest University, Salem Hall, Box 7486, Winston-Salem, NC, 27109, USA.
Background:
Platinum-based anticancer drugs are relatively successful chemotherapeutic agents, which can cause significant elemental changes in key organs and are known for undesirable side effects, such as nephrotoxicity (damage to the kidneys).
Objectives And Methods:
Inductively coupled plasma mass spectrometry (ICP-MS) and traditional statistical tools such as two-sample Student's t-test and Pearson's correlation analysis are used to evaluate the effects of different investigational Pt-based anticancer drugs on the elemental constitution of kidneys and liver of mice. Principal component analysis is used to uncover relationships in element concentration and potential correlations between those and clinical effects. Random forest importance is used to identify elements most associated with the drug's maximum tolerated doses (MTDs).
Results:
Strong negative correlations between Pt and both Cu (-0.814) and Zn (-0.784) in kidneys were observed for one of the Pt-acridine anticancer agents evaluated (Drug C). Strong positive correlations were observed between Cu in both kidneys (0.834) and liver (0.756) with Zn in liver for the same compound. Cisplatin administration correlates to higher concentrations of Ca, Cu, Rb and Zn in liver. Calcium and Mo in kidneys and Pt and Zn in liver are the features most associated with MTDs.
Conclusions:
The results indicate that the Pt-based agents investigated are major modulators of ion homeostasis in excretory organs, which most likely contributes to their systemic toxicity and limits their efficacy. A better understanding of subtle patterns and correlations among elements in key organs may provide deeper insights into the mechanisms of action and ultimately contribute for better, safer drugs. To achieve this goal, researchers involved in cancer drug development may leverage the high sensitivity and high sample throughput of ICP-MS, and the capabilities of modern statistical tools to extract relevant information from a large dataset.
Insights
Platinum-based anticancer drugs alter essential element levels in mouse kidneys and liver, impacting toxicity and efficacy. Understanding these elemental changes is key to developing safer cancer therapies.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Platinum-based anticancer drugs are vital chemotherapeutics but cause significant elemental shifts in organs.
- Nephrotoxicity and other side effects limit the clinical utility of these drugs.
- Investigating drug-induced elemental changes is crucial for understanding toxicity and improving drug safety.
Purpose of the Study:
- To evaluate the impact of investigational platinum-based anticancer drugs on the elemental composition of mouse kidneys and liver.
- To identify correlations between elemental concentrations and clinical effects, including maximum tolerated doses (MTDs).
- To explore the utility of ICP-MS and advanced statistical methods in cancer drug research.
Main Methods:
- Inductively coupled plasma mass spectrometry (ICP-MS) was used for elemental analysis.
- Statistical tools including two-sample Student's t-test, Pearson's correlation, principal component analysis, and random forest importance were employed.
- Elemental concentrations in kidneys and liver of mice treated with platinum-based drugs were analyzed.
Main Results:
- A Pt-acridine drug (Drug C) showed strong negative correlations between platinum (Pt) and copper (Cu) and zinc (Zn) in kidneys.
- Significant positive correlations were found between Cu and Zn in kidneys and liver for Drug C.
- Cisplatin treatment led to increased concentrations of calcium (Ca), Cu, rubidium (Rb), and Zn in the liver.
Conclusions:
- Platinum-based agents significantly disrupt ion homeostasis in excretory organs, contributing to toxicity and reduced efficacy.
- Detailed analysis of elemental patterns in organs can reveal drug mechanisms and inform the development of safer anticancer agents.
- ICP-MS and modern statistical analysis offer powerful tools for extracting critical information in cancer drug development.
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