INTRODUCTION
CISPLATIN
Cisplatin is used in chemotherapy but with nephrotoxicity as the most common side effect. Thus, cancer patients treated with cisplatin can suffer from acute renal failure (ARF) which is fatal.
Cisplatin is a chemotherapy drug and contains platinum that is complexed. It is an anti-cancer drug. It is also known as platinol or Platin. It has a half life of 300-100 hours and is excreted via the kidneys. Cisplatin is used to induce ARF in mice. Cisplatin inhibits fatty acid oxidation, and fatty acids accumulate in affected cells. Cisplatin induces nephrotoxicity (toxic to the renal cells). The platinum complex reacts in vivo, binding to and causing crosslinking of DNA (DNA cease to function), which ultimately triggers apoptosis (programmed cell death). Cisplatin causes necrosis. It is used for treatment of solid malignancies. It is used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. Cisplatin is particularly effective against testicular cancer; the cure rate was improved from 10% to 85%. In addition, Cisplatin is used in Auger therapy (to breakup herpes genes with ionising radiation from platinum).
PPARalpha
Fibrate treatment (with PPARalpha) ameliorates (relieves, improves) renal function by preventing the inhibition of fatty acid oxidation and proximal tubule cell death. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor protein. It serves to overcome the effects of cisplatin in renal cells.
Function
PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through ligand binding. Endogenous ligands include fatty acids and various fatty acid-derived compounds. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia. Insecticides, herbicides, plasticizers, and organic solvents also bind to PPAR-alpha, and are collectively referred to as peroxisome proliferators.
Tissue distribution
Expression of PPAR-alpha is highest in tissues that oxidize fatty acids at a rapid rate. In rodents, highest mRNA expression levels of PPAR-alpha are found in liver and brown adipose tissue, followed by heart and kidney. Lower PPAR-alpha expression levels are found in small and large intestine, skeletal muscle and adrenal gland. Human PPAR-alpha seems to be expressed more equally among various tissues, with high expression in liver, intestine, heart, and kidney.
METABOLIC ABNORMALITIES IN ARF
There are several systemic metabolic abnormalities which occur prior to and coexist with the development of ARF. They are responsible for the accumulation of free fatty acids in ischaemic ARF. They include:
CREATININE
In the past, creatinine was often measured to determine creatinine clearance and hence assess renal function. However, creatinine levels change slowly in blood and alterations in creatinine often go undetected. So we research on ARF, cisplatin and PPARalpha in live mice models instead.
METHODOLOGY
1. Lab animals: Mice
ARF is studied in live laboratory mice models.
Urine samples of mice treated with single injection of cisplatin (20 mg/kg body weight) were collected for 3 days and analyzed by 1H—nuclear magnetic resonance (NMR) spectroscopy.
2. Test drugs
Two drugs are used - cisplatin and PPARalpha.
3. Investigations
There are many ways to study the effects of cisplatin and PPARalpha on kidneys:
Biochemical analysis of endogenous metabolites was performed in serum, urine, and kidney tissue.
Principal component analysis demonstrated the presence of glucose, amino acids, and trichloacetic acid cycle (TCA cycle) metabolites in the urine after 48 h of cisplatin administration. These metabolic alterations precede changes in serum creatinine.
Urine metabolite concentrations are measured by 1H NMR spectroscopy:
Alanine --> amino acid (Ala)
Glucose --> glucosuria (sweet urine)
Lactate --> organic acid; end product from anaerobic glycolysis
Leucine --> amino acid (Leu)
Methionine --> amino acid (Met)
1-Methylnicotinamide --> methylated NADH produced by glycolysis
2-Oxoglutarate --> TCA cycle intermediate
Proline --> amino acid (Pro)
Pyruvate --> organic acid; end product from aerobic glycolysis
Trimethylamine --> internal standard for 1H NMR
Tyrosine --> amino acid (Tyr)
Valine --> amino acid (Val)
The urine metabolite concentrations are normalised to the concentration of creatinine in urine. Values are expressed as mg metabolite/mg creatinine.
Electron microscopy
Electron microscopic studies were carried out to examine the effects of PPARalpha ligand and cisplatin.
Electron microscopic analysis confirmed the protective effect of the fibrate on preventing cisplatin-mediated necrosis of the S3 segment of the proximal tubule.
RESULTS
CONCLUSION
The study shows that cisplatin-induced a unique NMR metabolic profile in urine of mice that developed ARF, and confirmed the protective effect of a fibrate class of PPARalpha ligands.
BIOMARKER PROPOSAL
The researchers proposed that the injury-induced metabolic profile may be used as a biomarker of cisplatin-induced nephrotoxicity.
External links:
http://www.nature.com/ki/journal/v69/n12/full/5000433a.html
http://en.wikipedia.org/wiki/Cisplatin
http://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_alpha
http://en.wikipedia.org/wiki/Auger_therapy
CISPLATIN
Cisplatin is used in chemotherapy but with nephrotoxicity as the most common side effect. Thus, cancer patients treated with cisplatin can suffer from acute renal failure (ARF) which is fatal.
Cisplatin is a chemotherapy drug and contains platinum that is complexed. It is an anti-cancer drug. It is also known as platinol or Platin. It has a half life of 300-100 hours and is excreted via the kidneys. Cisplatin is used to induce ARF in mice. Cisplatin inhibits fatty acid oxidation, and fatty acids accumulate in affected cells. Cisplatin induces nephrotoxicity (toxic to the renal cells). The platinum complex reacts in vivo, binding to and causing crosslinking of DNA (DNA cease to function), which ultimately triggers apoptosis (programmed cell death). Cisplatin causes necrosis. It is used for treatment of solid malignancies. It is used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. Cisplatin is particularly effective against testicular cancer; the cure rate was improved from 10% to 85%. In addition, Cisplatin is used in Auger therapy (to breakup herpes genes with ionising radiation from platinum).
 |
| From Wikipedia |
Fibrate treatment (with PPARalpha) ameliorates (relieves, improves) renal function by preventing the inhibition of fatty acid oxidation and proximal tubule cell death. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor protein. It serves to overcome the effects of cisplatin in renal cells.
Function
PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through ligand binding. Endogenous ligands include fatty acids and various fatty acid-derived compounds. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia. Insecticides, herbicides, plasticizers, and organic solvents also bind to PPAR-alpha, and are collectively referred to as peroxisome proliferators.
Tissue distribution
Expression of PPAR-alpha is highest in tissues that oxidize fatty acids at a rapid rate. In rodents, highest mRNA expression levels of PPAR-alpha are found in liver and brown adipose tissue, followed by heart and kidney. Lower PPAR-alpha expression levels are found in small and large intestine, skeletal muscle and adrenal gland. Human PPAR-alpha seems to be expressed more equally among various tissues, with high expression in liver, intestine, heart, and kidney.
 |
| From Wikipedia |
METABOLIC ABNORMALITIES IN ARF
There are several systemic metabolic abnormalities which occur prior to and coexist with the development of ARF. They are responsible for the accumulation of free fatty acids in ischaemic ARF. They include:
- glucose intolerance
- insulin resistance
- accumulation of fatty acids (accumulation of free fatty acids and toxic long chain fatty acid metabolites in freshly isolated proximal tubules subjected to hypoxic injury, and in kidney tissue of animals subjected to ischemia/reperfusion injury)
- activation of intracellular calcium-independent phospholipase A2
- inhibition of mitochondrial fatty acid oxidation
CREATININE
In the past, creatinine was often measured to determine creatinine clearance and hence assess renal function. However, creatinine levels change slowly in blood and alterations in creatinine often go undetected. So we research on ARF, cisplatin and PPARalpha in live mice models instead.
METHODOLOGY
1. Lab animals: Mice
ARF is studied in live laboratory mice models.
Urine samples of mice treated with single injection of cisplatin (20 mg/kg body weight) were collected for 3 days and analyzed by 1H—nuclear magnetic resonance (NMR) spectroscopy.
2. Test drugs
Two drugs are used - cisplatin and PPARalpha.
3. Investigations
There are many ways to study the effects of cisplatin and PPARalpha on kidneys:
- Biochemical analyses (chemicals in urine; urine metabolites)
- Electron microscopy (tissue specific changes; cytopathology)
Biochemical analysis of endogenous metabolites was performed in serum, urine, and kidney tissue.
Principal component analysis demonstrated the presence of glucose, amino acids, and trichloacetic acid cycle (TCA cycle) metabolites in the urine after 48 h of cisplatin administration. These metabolic alterations precede changes in serum creatinine.
Urine metabolite concentrations are measured by 1H NMR spectroscopy:
Alanine --> amino acid (Ala)
Glucose --> glucosuria (sweet urine)
Lactate --> organic acid; end product from anaerobic glycolysis
Leucine --> amino acid (Leu)
Methionine --> amino acid (Met)
1-Methylnicotinamide --> methylated NADH produced by glycolysis
2-Oxoglutarate --> TCA cycle intermediate
Proline --> amino acid (Pro)
Pyruvate --> organic acid; end product from aerobic glycolysis
Trimethylamine --> internal standard for 1H NMR
Tyrosine --> amino acid (Tyr)
Valine --> amino acid (Val)
The urine metabolite concentrations are normalised to the concentration of creatinine in urine. Values are expressed as mg metabolite/mg creatinine.
Electron microscopy
Electron microscopic studies were carried out to examine the effects of PPARalpha ligand and cisplatin.
Electron microscopic analysis confirmed the protective effect of the fibrate on preventing cisplatin-mediated necrosis of the S3 segment of the proximal tubule.
RESULTS
- Biochemical studies confirmed the presence of glucosuria, but also demonstrated the accumulation of nonesterified fatty acids, and triglycerides in serum, urine, and kidney tissue, in spite of increased levels of plasma insulin.
- These metabolic alterations were ameliorated by the use of PPARalpha ligand.
- When cisplatin is administered into mice, there are metabolites found in urine - they appear with time.
CONCLUSION
The study shows that cisplatin-induced a unique NMR metabolic profile in urine of mice that developed ARF, and confirmed the protective effect of a fibrate class of PPARalpha ligands.
BIOMARKER PROPOSAL
The researchers proposed that the injury-induced metabolic profile may be used as a biomarker of cisplatin-induced nephrotoxicity.
External links:
http://www.nature.com/ki/journal/v69/n12/full/5000433a.html
http://en.wikipedia.org/wiki/Cisplatin
http://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_alpha
http://en.wikipedia.org/wiki/Auger_therapy
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