Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
AHS Cancer Control Alberta
ClinicalTrials.gov Identifier:
NCT00131586
First received: August 17, 2005
Last updated: April 4, 2012
Last verified: April 2012

August 17, 2005
April 4, 2012
April 2003
February 2009   (final data collection date for primary outcome measure)
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Complete list of historical versions of study NCT00131586 on ClinicalTrials.gov Archive Site
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Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins
Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins

Cisplatin is a widely used anti-tumor agent for the treatment of testicular and ovarian cancers. Carboplatin is used extensively for small cell, non small cell lung cancer and ovarian cancer. Oxaliplatin has recently been approved in the United States (US) for treatment of colorectal cancer. A large portion (in the range of 65% to 98%) of cisplatin in the blood plasma was bound to protein within a day after intravenous administration. The binding of cisplatin and other analogues to proteins and enzymes is generally believed to be the cause of several severe side effects such as ototoxicity and nephrotoxicity. The interactions between platinum based chemotherapy drugs and proteins is proposed to play important roles in both drug activity and toxicity. Therefore, a better understanding of the molecular mechanism of platinum-protein interactions may have an impact on optimization of strategies for treatment. The objective is to develop novel approaches and techniques to provide detailed mechanistic, kinetic and high-resolution structural information on the binding of platinum analogues to blood proteins, and to improve treatment efficacy and reduce side effects.

Cisplatin, cis-[Pt(NH3)2Cl2], is a widely used antitumor agent for the treatment of testicular and ovarian cancers. Carboplatin is used extensively for small cell, non small cell lung cancer and ovarian cancer. Oxaliplatin has recently been approved in the US for treatment of colorectal cancer. All of these analogues are administered by intravenous injection, and within one day, 65-98% of the platinum in the blood plasma is bound to protein. Binding of cisplatin to proteins reduces urinary excretion of platinum, and causes deposition of platinum in tissues. Binding of cisplatin to proteins and enzymes is generally believed to be the cause of several severe side effects exhibited by these drugs, especially ototoxicity and nephrotoxicity.

Despite numerous studies of platinum-protein binding in the last few decades, the roles of platinum-protein adducts in drug action, and in toxicity of these drugs are not known. Although cisplatin-protein adducts are widely believed to cause the drug's side effects, there are also claims that platinum-protein adducts are important for the drug's activity. Therefore, a better understanding of the molecular mechanism of platinum-protein interactions may have an impact on the optimization of strategies for platinum treatment. It is important to understand basic principles that govern formation and reactivity of platinum-protein adducts because these adducts may be important in defining the therapeutic profile of these drugs. In this quest, the first goal is to develop a reliable technique for these studies. To date, ultraviolet/visible (UV-Vis), fourier transform infrared (FT-IR), and nuclear magnetic resonance (NMR) studies of cisplatin-protein interactions have provided only low-resolution information on the mechanism of the binding or on the nature of the adducts. The researchers propose to investigate the role of platinum-protein adducts in the mechanisms of the drug action and their contributions towards the toxicity of these drug. The short-term objective is to investigate platinum interaction with serum proteins using both nanoelectrospray mass spectrometry (nanoESI-MS) and a combination of size exclusion high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICP-MS). The long-term objective of this research is to develop biomarkers based on platinum-protein adducts for clinical monitoring.

Initially, metallothionein and human hemoglobin were used as model proteins to develop nESI/MS and HPLC/ICP-MS techniques for studying cisplatin-protein interactions in vitro. The researchers have demonstrated that the combination of size exclusion HPLC/ICP-MS and nanoESI/MS provided new information on the adduct formation and potential reaction mechanism. The size exclusion HPLC with ICP-MS enables monitoring of cisplatin-protein binding under physiological conditions. Nanospray tandem MS offers information on formation of specific complexes and on characteristics of binding. This information is useful for a better understanding of drug toxicity and treatment resistance. The information on platinum-protein interactions allows us to evaluate the utility of both nanoESI/MS and size exclusion HPLC/ICP-MS techniques in providing mechanistic, kinetic and structural information on the binding of platinum to other proteins. The methodology will be further validated by studying the platinum-blood protein adducts in cancer patients undergoing chemotherapeutic treatments. The correlation between the levels of platinum-protein adducts and clinical outcomes will be studied.

The successful completion of this research program should provide the researchers with a better understanding of mechanisms of the drug action and toxicity. This knowledge will be of great importance in clinical monitoring of cancer patients to assist doctors to improve cancer chemotherapy.

Observational
Observational Model: Case-Only
Time Perspective: Prospective
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Non-Probability Sample

community sample

  • Lung Cancer
  • Colorectal Cancer
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
100
February 2009
February 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • To have lung or colorectal cancer and be treated with either oxaliplatin, carboplatin or cisplatin
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Canada
 
NCT00131586
SP-11-0033/ethics 17173
No
AHS Cancer Control Alberta
AHS Cancer Control Alberta
Not Provided
Principal Investigator: Michael Sawyer, MD AHS Cancer Control Alberta
AHS Cancer Control Alberta
April 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP