- Email: [email protected]
Carboplatin-related hematuria and acute renal failure
CASE REPORT
Carboplatin-Related Hematuria and Acute Renal Failure Mahendra Agraharkar, MD, Stacy Nerenstone MD, Joseph Palmisano, MD, and Andre A. Kaplan, MD, FACP ● Cisplatin is a potent tubular toxin with a high incidence of nephrotoxicity. Carboplatin is considered less nephrotoxic but can still cause tubular injury and interstitial nephritis in patients who have been previously treated with cisplatin. The affected individuals usually have nonoliguric renal failure with a urine output of more than a liter per day. We present a 57-year-old white woman with no history of renal disease who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage IC ovarian carcinoma. One month later, she received chemotherapy with paclitaxel (Taxol) and carboplatin. On the following day, she developed frank hematuria and flank pain associated with a diminished urine output. Intravenous pyelogram (IVP) showed bilateral hydronephrosis with a total blockage of dye flow at the level of intraureteral lucencies consistent with bilateral blood clots. Her coagulation profile and uric acid was normal. Her acute renal failure (ARF) spontaneously resolved in the following 24 hours, with a brisk diuresis presumably due to clot lysis. The follow-up IVP showed a resolution of obstructive changes. A review of the literature shows a previous case in which high doses of carboplatin were implicated as the cause of hemorrhagic cystitis, presumably by toxicity to transitional epithelium of the bladder. We believe that the current case represents carboplatin-induced damage to the transitional epithelium in the renal pelvi and ureters causing gross hematuria and blood clots, resulting in bilateral ureteral obstruction and hydronephrosis. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Carboplatin; platinum-based chemotherapy; acute renal failure; hematuria; hemorrhagic ureteritis; transitional epithelium; hydronephrosis.
P
LATINUM-BASED compounds are potent chemotherapeutic agents effective in the treatment of ovarian, gonadal, lung, bladder, head and neck, and other cancers. Because of its serious nephrotoxic effects, cisplatin has often been replaced by carboplatin. Carboplatin was initially thought to be non-nephrotoxic but with similar anti-tumor activity. It is now known to be nephrotoxic but only at higher doses. Carboplatin is not commonly considered as a cause of frank hematuria, but there has been a report of two episodes in a single patient presumably as a result of hemorrhagic cystitis. CASE REPORT
A 57-year-old white woman with no history of renal disease was diagnosed with ovarian cancer for which she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The tumor was bilateral stage IC, with the left ovary showing surface involvement. The peritoneal fluid had positive cytology. All other biopsy specimens were negative except for an early-stage endometrial adenocarcinoma with superficial myometrial invasion. A month after surgery she was treated with 1,100 mg carboplatin in 250 mL of saline intravenously over 1 hour (753 mg/m2); AUC⫽7.5 mg/mL, with a calculated creatinine clearance of 123 mL/min) and 250 mg of paclitaxel (175 mg/m2). The following day, she developed frank hematuria and left flank pain and came to the emergency room. On examination, she was a well-developed, well-nourished woman weighing 47.3 kg. Her temperature was 98.4°F; blood pressure, 130/74 mm Hg; and heart rate, 70 beats/min.
Physical examination was unremarkable except for a slight left costovertebral tenderness. She was clinically euvolemic.
Investigations and Results Urinalysis showed a pH of 5, fewer than 50 red blood cells/ihgh-power field (HPF), 2 leukocytes/HPF, and no casts. Complete blood count (CBC) indicated white blood cell count, 10,000/µL; hemoglobin, 12.5 g/dL; hematocrit, 38%; and platelets of 245,000/µL. The prothrombin time was 11.4 seconds, and the partial thromboplastin time was 18.6 seconds. Serum chemistries were normal. A plain radiograph of the abdomen indicated no radiopaque stones. An intravenous pyelogram (IVP) showed early obstructive changes with caliectasis in both kidneys. There was bilateral blockage of dye flow and evidence of an intraureteral lucency compatible with an intraluminal blood clot (Fig 1A). In the emergency room, the patient voided an unmeasured amount of urine, but she remained anuric for more than 12 hours thereafter. On the next day, the blood urea nitrogen (BUN) and creatinine increased to 14 mg/dL and 1.8 mg/dL, respectively. A Foley catheter showed no urine in the blad-
From the University of Texas Medical Branch, Galveston, TX; Hartford Hospital, Hartford, CT; and the University of Connecticut Health Center, Farmington, CT. Received March 16, 1998; accepted in revised form July 14, 1998. Address reprint requests to Mahendra Agraharkar, MD, Assistant Professor of Medicine, Department of Medicine, Division of Nephrology, 4.200, John Sealy Annex, 301 University Boulevard, Galveston TX 77555-0562. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3205-0029$3.00/0
American Journal of Kidney Diseases, Vol 32, No 5 (November), 1998: E5
1
2
AGRAHARKAR ET AL
Fig 1. (A) IVP showing bilateral renal obstruction. The white arrow shows an intraluminal lucency corresponding to a possible clot in the left ureter. The exact level of obstruction for each ureter is not clear, but complete obstruction was presumed attributable to the bilateral caliectasis and the lack of any dye in the bladder. (B) IVP from the same patient 6 weeks later.
der. Because the patient was found to be euvolemic on physical examination but anuric for the preceding 12 hours, she was infused with 5% dextrose in 0.45% saline at a rate of 75 mL/hour. The following morning she had a brisk diuresis. She had not complained of flank pain or costovertebral tenderness. She did not receive fibrinolytics, heparin, or antiplatelet agents. There were no stones or gravel appreciated in the collected urine. The patient was discharged home on the following day, when the BUN was 7 mg/dL and the creatinine was 0.6 mg/dL. The patient refused any further chemotherapy. Six weeks later, follow-up IVP showed a complete resolution of the obstructive changes (Fig 1B).
DISCUSSION
Cisplatin is a complex of platinum atoms that are known to bind to DNA, thus blocking cell replication. Cisplatin toxicity is targeted mainly
towards mitochondrial DNA.1-8 Cisplatin causes a decrease in mitochondrial respiratory rate and mitochondrial swelling.9 Other changes include a decrease in glutathione peroxidase activity causing an increase in oxidized glutathione, suggesting that free radical formation may contribute to cisplatin-mediated nephrotoxicity.10-12 Use of cisplatin is limited by its potent nephrotoxicity. Carboplatin is considered to be less nephrotoxic and is rapidly removed from the blood, with a half-life of about 2.5 hours.13-15 More than 60% of carboplatin is excreted unchanged in the urine as compared with 25% to 40% of cisplatin. Both cisplatin and carboplatin undergo tubular reabsorption after glomerular filtration, but there is less renal retention of carboplatin.1 Early clinical studies established that, at doses of 400 mg/m2, carboplatin caused virtually no nephrotoxicity, ototoxicity, or peripheral neuropathy.13 The usual prescribed doses range from 300 to 360 mg/m2. Because the dose-limiting toxicity for carboplatin is myelosuppression, with little renal or neurological toxicity, Reed and Jacob16 administered high doses of 800 mg/m2 body surface area combined with granulocyte-macrophage colony-stimulating factor but without vigorous hydration. They noted a decrement in renal function in these patients. Subsequently, a protocol involving infusion of 250 mL of normal saline for three hours before and after carboplatin therapy resulted in no measurable reduction in creatinine clearance.3,16 Calvert et al have derived dosage adjustments for carboplatin in patients with varying degrees of renal function.17 Using the formula: dose (mg) ⫽ target AUC ⫻ (glomerular filtration rate [GFR]⫹25), they recommend a target AUC of 5 to 7 for single agent carboplatin therapy. Hematuria is not a well-recognized complication of carboplatin therapy, but Ettinger et al18 reported two episodes of gross hematuria in a single patient. On the first presentation, the patient was thrombocytopenic, but on the second occasion he had gross hematuria in the absence of thrombocytopenia. Details of the hematuria were not reported, and a cystoscopy was not performed, but the complication was reported as hemorrhagic cystitis. Our patient had received 1,100 mg carboplatin using the Calvert formula17 to obtain a free carboplatin plasma concentration versus time of 7.5 mg/mL. She also received 250 mg of pacli-
CARBOPLATIN-RELATED HEMATURIA AND RENAL FAILURE
taxel (175 mg/m2). She did not receive aggressive hydration. Carboplatin can cause thrombocytopenia in 7 to 10 days after the treatment, but our patient presented 1 day after receiving the drug, and her platelet count was normal. Our patient’s oligoanuria and the intravenous pyelogram showing bilateral hydronephrosis with blockage of the dye at the lower third of both ureters is strongly suggestive of bilateral ureteral obstruction (Fig 1A). An intraureteral lucency was compatible with an intraluminal blood clot. The most likely scenario is that she had bleeding into both ureters, with the clots causing bilateral obstruction and acute obstructive renal failure. The obstruction resolved spontaneously with a subsequent brisk diuresis and a rapid reversal of renal failure. The follow-up IVP showed resolution of the obstructive changes. (Fig 1B). This case represents an uncommon description of gross hematuria as a consequence of carboplatin therapy and may be the first case in which carboplatin is implicated as a cause of bilateral hydronephrosis. The earlier cited case of carboplatin-associated hematuria reported by Ettinger et al18 occurred in a patient receiving a higher total dose of carboplatin: 336 mg/m2 for 5 days (a total of 1,680 mg/m2). In comparison, our patient received less carboplatin: 1,100 mg (753 mg/m2), but the totality was given in a single dose. We believe that platinum analogs in general and carboplatin in particular can be toxic to transitional epithelium causing sloughing and bleeding. Although the mechanism of toxicity is unclear, it may be similar to that for the metabolites of cyclophosphamide, ifosphamide and related compounds, which also act by DNA linkage and are toxic to transitional epithelium, causing hemorrhagic ureteritis and cystitis. Our patient had not received aggressive hydration with carboplatin, a recommendation that is standard for cisplatin and cyclophosphamide. Whether that would have helped prevent or minimize the hematuria is not certain. This case report leads us to believe that aggressive hydration would be prudent when giving high doses of carboplatin. CONCLUSION
We present a case in which carboplatin toxicity is the most likely cause of gross hematuria leading to oliguric renal failure by bilateral ureteral obstruction with blood clots. Review of the
3
literature suggests that carboplatin may be toxic to transitional cell epithelium in a manner similar to that associated with the use of cyclophosphamide. We believe that aggressive hydration, as commonly recommended for cisplatin and cyclophosphamide, may be indicated as a means of avoiding this toxicity. ACKNOWLEDGMENT The authors thank Vishal Agraharkar for his typographic help in preparing the manuscript.
REFERENCES 1. Haskel CM: Antineoplastic agents. Chap 4, in Cancer Treatment (ed 4). Phildelphia, PA, Saunders, 1995, pp 78165 2. Ozols, RF, Young RC: High dose cisplatin therapy in ovarian cancer. Semin Oncol 12:21-30, 1985 3. Cornelison TL, Reed E: Nephrotoxicity and hydration management for cisplatin, Carboplatin, and ormaplatin. Gynecol Oncol 50:147-158, 1993 4. Salazar I, Tarrago-Litvak L, Gil L, Litvak S: The effect of benzo[a]pyrene on DNA synthesis and DNA polymerase activity of rat liver mitochondria. FEBS Lett 138:43-49, 1982 5. Clayton, DA: Replication of animal mitochondrial DNA. Cell 28:693-705, 1982 6. Clayton DA, Doda JN, Friedberg ED: The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A 71:2777-2781, 1974 7. Sharma RP, Edwards IR: Cisplatinum: Subcellular distribution and binding to cytosolic ligands, Biochem Pharmacol 32:2665-2669, 1983 8. Siddik ZH, Dible SE, Boxal FE, Harrap KR: Renal pharmacokinetics and toxicity of cisplatin and carboplatin in animals, in McBrien DCH, Slater TF (eds): Biochemical Mechanisms of Platinum Antitumor Drugs. Oxford, IRL, 1986, pp 171-198 9. Singh G: Cisplatin-Induced nephrotoxicity. Can Fed Biol Soc Letter 29:136, 1986 10. Bompart G: Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzyme activities in rat kidney cortex. Toxicol Lett 48:193199, 1989 11. Sugiyama S, Hayakawa M, Kato T, Hanaki Y, Shimizu K, Ozawa T: Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: Disturbances in glutathione peroxidase activity. Biochem Biophys Res Commun 159: 1121-1127, 1989 12. Nakano S, Gemba M: Potentiation of cisplatininduced lipid peroxidation in kidney cortical slices by glutathione depletion. Jpn J Pharmacol 50:87-92, 1989 13. Canetta R, Rozencweig M, Carter SK: Carboplatin: The clinical spectrum to date. Cancer Treat Rev 12:125-136, 1985 14. Bacha DM, Caparros-Sisson B, Allen JA, Walker R, Tan CTC: Phase I study of carboplatin (CBDCA) in children with cancer. Cancer Treat Rep 70:865-869, 1986 15. Gaynon PS, Ettinger LJ, Baum ES, Siegle SE, Krailo MD, Hammond GD: Carboplatin in childhood brain tumors:
4
A Children’s Cancer Study Group phase II trial. Cancer 66:2465-2469, 1990 16. Reed E, Jacob J: Carboplatin and renal dysfunction. Ann Intern Med 110:409, 1989 17. Calvert AH, Newel DR, Gumbrel LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME,
AGRAHARKAR ET AL
Wiltshaw E: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:17481756, 1989 18. Ettinger LJ, Krailo MD, Gaynon PS, Hammond GD: A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. Cancer 72:917-922, 1993
Carboplatin-Related Hematuria and Acute Renal Failure Mahendra Agraharkar, MD, Stacy Nerenstone MD, Joseph Palmisano, MD, and Andre A. Kaplan, MD, FACP ● Cisplatin is a potent tubular toxin with a high incidence of nephrotoxicity. Carboplatin is considered less nephrotoxic but can still cause tubular injury and interstitial nephritis in patients who have been previously treated with cisplatin. The affected individuals usually have nonoliguric renal failure with a urine output of more than a liter per day. We present a 57-year-old white woman with no history of renal disease who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage IC ovarian carcinoma. One month later, she received chemotherapy with paclitaxel (Taxol) and carboplatin. On the following day, she developed frank hematuria and flank pain associated with a diminished urine output. Intravenous pyelogram (IVP) showed bilateral hydronephrosis with a total blockage of dye flow at the level of intraureteral lucencies consistent with bilateral blood clots. Her coagulation profile and uric acid was normal. Her acute renal failure (ARF) spontaneously resolved in the following 24 hours, with a brisk diuresis presumably due to clot lysis. The follow-up IVP showed a resolution of obstructive changes. A review of the literature shows a previous case in which high doses of carboplatin were implicated as the cause of hemorrhagic cystitis, presumably by toxicity to transitional epithelium of the bladder. We believe that the current case represents carboplatin-induced damage to the transitional epithelium in the renal pelvi and ureters causing gross hematuria and blood clots, resulting in bilateral ureteral obstruction and hydronephrosis. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Carboplatin; platinum-based chemotherapy; acute renal failure; hematuria; hemorrhagic ureteritis; transitional epithelium; hydronephrosis.
P
LATINUM-BASED compounds are potent chemotherapeutic agents effective in the treatment of ovarian, gonadal, lung, bladder, head and neck, and other cancers. Because of its serious nephrotoxic effects, cisplatin has often been replaced by carboplatin. Carboplatin was initially thought to be non-nephrotoxic but with similar anti-tumor activity. It is now known to be nephrotoxic but only at higher doses. Carboplatin is not commonly considered as a cause of frank hematuria, but there has been a report of two episodes in a single patient presumably as a result of hemorrhagic cystitis. CASE REPORT
A 57-year-old white woman with no history of renal disease was diagnosed with ovarian cancer for which she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The tumor was bilateral stage IC, with the left ovary showing surface involvement. The peritoneal fluid had positive cytology. All other biopsy specimens were negative except for an early-stage endometrial adenocarcinoma with superficial myometrial invasion. A month after surgery she was treated with 1,100 mg carboplatin in 250 mL of saline intravenously over 1 hour (753 mg/m2); AUC⫽7.5 mg/mL, with a calculated creatinine clearance of 123 mL/min) and 250 mg of paclitaxel (175 mg/m2). The following day, she developed frank hematuria and left flank pain and came to the emergency room. On examination, she was a well-developed, well-nourished woman weighing 47.3 kg. Her temperature was 98.4°F; blood pressure, 130/74 mm Hg; and heart rate, 70 beats/min.
Physical examination was unremarkable except for a slight left costovertebral tenderness. She was clinically euvolemic.
Investigations and Results Urinalysis showed a pH of 5, fewer than 50 red blood cells/ihgh-power field (HPF), 2 leukocytes/HPF, and no casts. Complete blood count (CBC) indicated white blood cell count, 10,000/µL; hemoglobin, 12.5 g/dL; hematocrit, 38%; and platelets of 245,000/µL. The prothrombin time was 11.4 seconds, and the partial thromboplastin time was 18.6 seconds. Serum chemistries were normal. A plain radiograph of the abdomen indicated no radiopaque stones. An intravenous pyelogram (IVP) showed early obstructive changes with caliectasis in both kidneys. There was bilateral blockage of dye flow and evidence of an intraureteral lucency compatible with an intraluminal blood clot (Fig 1A). In the emergency room, the patient voided an unmeasured amount of urine, but she remained anuric for more than 12 hours thereafter. On the next day, the blood urea nitrogen (BUN) and creatinine increased to 14 mg/dL and 1.8 mg/dL, respectively. A Foley catheter showed no urine in the blad-
From the University of Texas Medical Branch, Galveston, TX; Hartford Hospital, Hartford, CT; and the University of Connecticut Health Center, Farmington, CT. Received March 16, 1998; accepted in revised form July 14, 1998. Address reprint requests to Mahendra Agraharkar, MD, Assistant Professor of Medicine, Department of Medicine, Division of Nephrology, 4.200, John Sealy Annex, 301 University Boulevard, Galveston TX 77555-0562. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3205-0029$3.00/0
American Journal of Kidney Diseases, Vol 32, No 5 (November), 1998: E5
1
2
AGRAHARKAR ET AL
Fig 1. (A) IVP showing bilateral renal obstruction. The white arrow shows an intraluminal lucency corresponding to a possible clot in the left ureter. The exact level of obstruction for each ureter is not clear, but complete obstruction was presumed attributable to the bilateral caliectasis and the lack of any dye in the bladder. (B) IVP from the same patient 6 weeks later.
der. Because the patient was found to be euvolemic on physical examination but anuric for the preceding 12 hours, she was infused with 5% dextrose in 0.45% saline at a rate of 75 mL/hour. The following morning she had a brisk diuresis. She had not complained of flank pain or costovertebral tenderness. She did not receive fibrinolytics, heparin, or antiplatelet agents. There were no stones or gravel appreciated in the collected urine. The patient was discharged home on the following day, when the BUN was 7 mg/dL and the creatinine was 0.6 mg/dL. The patient refused any further chemotherapy. Six weeks later, follow-up IVP showed a complete resolution of the obstructive changes (Fig 1B).
DISCUSSION
Cisplatin is a complex of platinum atoms that are known to bind to DNA, thus blocking cell replication. Cisplatin toxicity is targeted mainly
towards mitochondrial DNA.1-8 Cisplatin causes a decrease in mitochondrial respiratory rate and mitochondrial swelling.9 Other changes include a decrease in glutathione peroxidase activity causing an increase in oxidized glutathione, suggesting that free radical formation may contribute to cisplatin-mediated nephrotoxicity.10-12 Use of cisplatin is limited by its potent nephrotoxicity. Carboplatin is considered to be less nephrotoxic and is rapidly removed from the blood, with a half-life of about 2.5 hours.13-15 More than 60% of carboplatin is excreted unchanged in the urine as compared with 25% to 40% of cisplatin. Both cisplatin and carboplatin undergo tubular reabsorption after glomerular filtration, but there is less renal retention of carboplatin.1 Early clinical studies established that, at doses of 400 mg/m2, carboplatin caused virtually no nephrotoxicity, ototoxicity, or peripheral neuropathy.13 The usual prescribed doses range from 300 to 360 mg/m2. Because the dose-limiting toxicity for carboplatin is myelosuppression, with little renal or neurological toxicity, Reed and Jacob16 administered high doses of 800 mg/m2 body surface area combined with granulocyte-macrophage colony-stimulating factor but without vigorous hydration. They noted a decrement in renal function in these patients. Subsequently, a protocol involving infusion of 250 mL of normal saline for three hours before and after carboplatin therapy resulted in no measurable reduction in creatinine clearance.3,16 Calvert et al have derived dosage adjustments for carboplatin in patients with varying degrees of renal function.17 Using the formula: dose (mg) ⫽ target AUC ⫻ (glomerular filtration rate [GFR]⫹25), they recommend a target AUC of 5 to 7 for single agent carboplatin therapy. Hematuria is not a well-recognized complication of carboplatin therapy, but Ettinger et al18 reported two episodes of gross hematuria in a single patient. On the first presentation, the patient was thrombocytopenic, but on the second occasion he had gross hematuria in the absence of thrombocytopenia. Details of the hematuria were not reported, and a cystoscopy was not performed, but the complication was reported as hemorrhagic cystitis. Our patient had received 1,100 mg carboplatin using the Calvert formula17 to obtain a free carboplatin plasma concentration versus time of 7.5 mg/mL. She also received 250 mg of pacli-
CARBOPLATIN-RELATED HEMATURIA AND RENAL FAILURE
taxel (175 mg/m2). She did not receive aggressive hydration. Carboplatin can cause thrombocytopenia in 7 to 10 days after the treatment, but our patient presented 1 day after receiving the drug, and her platelet count was normal. Our patient’s oligoanuria and the intravenous pyelogram showing bilateral hydronephrosis with blockage of the dye at the lower third of both ureters is strongly suggestive of bilateral ureteral obstruction (Fig 1A). An intraureteral lucency was compatible with an intraluminal blood clot. The most likely scenario is that she had bleeding into both ureters, with the clots causing bilateral obstruction and acute obstructive renal failure. The obstruction resolved spontaneously with a subsequent brisk diuresis and a rapid reversal of renal failure. The follow-up IVP showed resolution of the obstructive changes. (Fig 1B). This case represents an uncommon description of gross hematuria as a consequence of carboplatin therapy and may be the first case in which carboplatin is implicated as a cause of bilateral hydronephrosis. The earlier cited case of carboplatin-associated hematuria reported by Ettinger et al18 occurred in a patient receiving a higher total dose of carboplatin: 336 mg/m2 for 5 days (a total of 1,680 mg/m2). In comparison, our patient received less carboplatin: 1,100 mg (753 mg/m2), but the totality was given in a single dose. We believe that platinum analogs in general and carboplatin in particular can be toxic to transitional epithelium causing sloughing and bleeding. Although the mechanism of toxicity is unclear, it may be similar to that for the metabolites of cyclophosphamide, ifosphamide and related compounds, which also act by DNA linkage and are toxic to transitional epithelium, causing hemorrhagic ureteritis and cystitis. Our patient had not received aggressive hydration with carboplatin, a recommendation that is standard for cisplatin and cyclophosphamide. Whether that would have helped prevent or minimize the hematuria is not certain. This case report leads us to believe that aggressive hydration would be prudent when giving high doses of carboplatin. CONCLUSION
We present a case in which carboplatin toxicity is the most likely cause of gross hematuria leading to oliguric renal failure by bilateral ureteral obstruction with blood clots. Review of the
3
literature suggests that carboplatin may be toxic to transitional cell epithelium in a manner similar to that associated with the use of cyclophosphamide. We believe that aggressive hydration, as commonly recommended for cisplatin and cyclophosphamide, may be indicated as a means of avoiding this toxicity. ACKNOWLEDGMENT The authors thank Vishal Agraharkar for his typographic help in preparing the manuscript.
REFERENCES 1. Haskel CM: Antineoplastic agents. Chap 4, in Cancer Treatment (ed 4). Phildelphia, PA, Saunders, 1995, pp 78165 2. Ozols, RF, Young RC: High dose cisplatin therapy in ovarian cancer. Semin Oncol 12:21-30, 1985 3. Cornelison TL, Reed E: Nephrotoxicity and hydration management for cisplatin, Carboplatin, and ormaplatin. Gynecol Oncol 50:147-158, 1993 4. Salazar I, Tarrago-Litvak L, Gil L, Litvak S: The effect of benzo[a]pyrene on DNA synthesis and DNA polymerase activity of rat liver mitochondria. FEBS Lett 138:43-49, 1982 5. Clayton, DA: Replication of animal mitochondrial DNA. Cell 28:693-705, 1982 6. Clayton DA, Doda JN, Friedberg ED: The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A 71:2777-2781, 1974 7. Sharma RP, Edwards IR: Cisplatinum: Subcellular distribution and binding to cytosolic ligands, Biochem Pharmacol 32:2665-2669, 1983 8. Siddik ZH, Dible SE, Boxal FE, Harrap KR: Renal pharmacokinetics and toxicity of cisplatin and carboplatin in animals, in McBrien DCH, Slater TF (eds): Biochemical Mechanisms of Platinum Antitumor Drugs. Oxford, IRL, 1986, pp 171-198 9. Singh G: Cisplatin-Induced nephrotoxicity. Can Fed Biol Soc Letter 29:136, 1986 10. Bompart G: Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drug-metabolizing enzyme activities in rat kidney cortex. Toxicol Lett 48:193199, 1989 11. Sugiyama S, Hayakawa M, Kato T, Hanaki Y, Shimizu K, Ozawa T: Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: Disturbances in glutathione peroxidase activity. Biochem Biophys Res Commun 159: 1121-1127, 1989 12. Nakano S, Gemba M: Potentiation of cisplatininduced lipid peroxidation in kidney cortical slices by glutathione depletion. Jpn J Pharmacol 50:87-92, 1989 13. Canetta R, Rozencweig M, Carter SK: Carboplatin: The clinical spectrum to date. Cancer Treat Rev 12:125-136, 1985 14. Bacha DM, Caparros-Sisson B, Allen JA, Walker R, Tan CTC: Phase I study of carboplatin (CBDCA) in children with cancer. Cancer Treat Rep 70:865-869, 1986 15. Gaynon PS, Ettinger LJ, Baum ES, Siegle SE, Krailo MD, Hammond GD: Carboplatin in childhood brain tumors:
4
A Children’s Cancer Study Group phase II trial. Cancer 66:2465-2469, 1990 16. Reed E, Jacob J: Carboplatin and renal dysfunction. Ann Intern Med 110:409, 1989 17. Calvert AH, Newel DR, Gumbrel LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME,
AGRAHARKAR ET AL
Wiltshaw E: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:17481756, 1989 18. Ettinger LJ, Krailo MD, Gaynon PS, Hammond GD: A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. Cancer 72:917-922, 1993