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.
Inclusion Criteria:

 -  To have lung or colorectal cancer and be treated with either oxaliplatin, carboplatin
 or cisplatin