Cisplatin

Brand Names: Platinol

Clinical Names: Cisplatin, Dichlorodiamine platinum

Summary

generic name: Cisplatin

synonym: Dichlorodiamine platinum

trade name: Platinol®

type of drug: Intravenous cytotoxic chemotherapeutic agent.

used to treat: Various forms of cancer.

overview of interactions:
• nutrient affected by drug: Magnesium

• nutrient affected by drug: Potassium

• nutrient affecting drug toxicity: Selenium

• nutrient affected by drug: Sodium

• nutrient affecting drug toxicity: Glutathione

• nutrient affecting drug performance and toxicity: Quercitin

• herb affecting drug toxicity: Silybum marianum (Milk Thistle)



Interactions

nutrient affected by drug: Magnesium

• mechanism: Cisplatin induces hypomagnesemia through its renal toxicity possibly by a direct injury to mechanisms of magnesium reabsorption in the ascending limb of the loop of Henle as well as the distal tubule. Consequently, cisplatin increases the urinary loss of magnesium. This drug-induced impairment of the renal tubules' ability to conserve magnesium may persist for months, or possibly years, after discontinuing use of the drug.
(Toffaletti J. Analyt Chem 1991 63(12):192R-194R; Lajer H, et al. Cancer Treat Rev. 1999 Feb;25(1):47-58; Koch Nogueira PC, et al. Pediatr Nephrol 1998 Sep;12(7):572-575.)

• nutritional support: One British study found higher serum magnesium concentration levels that children given intravenous magnesium before and after administration of cisplatin than in those give magnesium only after the cisplatin. The researchers concluded that magnesium supplements should be given to patients receiving cisplatin during the precisplatin hydration period to prevent hypomagnesemia.
(Kibirige MS, et al. Pediatr Hematol Oncol 1988;5(1):1-6.)

nutrient affected by drug: Potassium

• nutritional concerns: Individuals being treated with cisplatin often experience a decline in potassium levels that is unresponsive to potassium supplementation unless accompanied by supplemental magnesium. Magnesium is needed to maintain intracellular potassium.
(Rodriguez M, et al. Arch Intern Med 1989;149:2592-2594.).

• nutrient adverse effects due to drug: It is important to avoid supplementation, especially of potassium, if kidney failure is present. Supplementation of magnesium and potassium can pose a significant risk for an individual on cisplatin due to the kidney damage which frequently results from the drug and impairs the urinary excretion of both minerals.

• testing and nutritional support: Patients undergoing treatment with cisplatin need to have their doctor regularly monitor their kidney function along with magnesium and potassium status. Serum creatinine, BUN and creatinine clearance should be measured prior to initiating therapy and should be monitored throughout treatment. In this regard, many nutritionally-oriented practitioners find that a testing magnesium levels in red blood cells in far more reliable than testing serum magnesium. Only after such assessment should supplementation with magnesium or potassium be undertaken and then only under close supervision by the prescribing physician.

• nutritional concerns: Avoid supplementation, especially of Potassium, if kidney failure is present.

nutrient affecting drug toxicity: Selenium

• research: Recently, it has been reported that administration of sodium selenite reduces cisplatin toxicity without inhibiting the antitumor activity of cisplatin.
(Olas B, Wachowicz B. Postepy Hig Med Dosw 1997;51(1):95-108.)

nutrient affected by drug: Sodium

• mechanism: Cisplatin regimens can lead to a more or less pronounced hyponatremia in 4 to 10% of cases due to salt wasting with hypomagnesemia and normokalemia. Functional and renal failure and orthostatic hypotension can be observed.
(Peyrade F, et al. Presse Med 1997 Oct 25;26(32):1523-1525.)

• nutritional support: Cisplatin-induced hyponatremia requires specific management. Treatment is based on sodium intake which sometimes takes several months to replete stores.

nutrient affecting drug toxicity: Glutathione (GSH)

• research: Some human and animal studies have found that intravenous glutathione reduces the neurological toxicity of cisplatin and improves quality of life. More recently, Babu et al reported that administration of glutathione ester modulates the toxic side effect of cisplatin observed in kidney enzymes, and in blood parameters and concluded that glutathione ester plays an important role in protecting against the cisplatin induced nephrotoxicity by inhibiting the accumulation of platinum in kidneys. Even so, there is, as of yet, no conclusive evidence showing the effectiveness of oral glutathione.
(Jones MM, et al. Toxicology 1991;68(3):227-247; Cascinu S, et al. J Clin Oncol 1995;13:26-32; Smyth IF, et al. Ann Oncol 1997;8:569-573; Babu E, et al. Ren Fail 1999 Mar;21(2):209-217.)

• nutritional support: While research with glutathione in research settings appears promising there is, as of yet, no conclusive evidence showing the effectiveness of oral glutathione.

nutrient affecting drug performance and toxicity: Quercitin

• research: Several studies indicate that quercetin exerts cisplatin sensitizing properties in cancer cells. Subsequently Kuhlmann et al conducted research to investigate whether quercitin could reduce cisplatin toxicity in cultured renal tubular cells. In their in vitro experiments they found that pretreatment of cells with quercetin for three hours significantly reduced the extent of cell damage due to cisplatin and that this protective activity was concentration dependent. They proposed that this activity most likely derived from quercetin's scavenging of free oxygen radicals. In contrast, they also noted that other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations. However, they also cautioned that, at least under these experimental circumstances, quercetin itself showed some intrinsic cytotoxicity at very high concentrations.
(Scambia G, et al. Anticancer Drugs. 1990 Oct;1(1):45-48; Cross HJ, et al. Int J Cancer. 1996 May 3;66(3):404-408; Kuhlmann MK, et al. Arch Toxicol 1998 Jul-Aug;72(8):536-540.)

• nutritional support: As with other antioxidants, individuals being treated with cisplatin should consult with their prescribing physician and/or a healthcare professional trained in nutritional therapies before initiating use of quercitin. Quercitin is commonly used at dosage levels of 400-500 mg, two to three times per day. Bioflavanoids such as quercitin are often taken with vitamin C, which it potentiates and protects.

herb affecting drug toxicity: Silybum marianum (Milk Thistle)

mechanism: Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes and magnesium. Typical symptoms include decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes L-alanine-aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting.

• research: Silymarin is an extract of milk thistle, and silibinin is a key component of this plant extract. In studies using rats Bokemeyer et al concluded that Silibinin protects against cisplatin-induced nephrotoxicity without compromising anti-tumor activity. They found that infusion of silibinin before cisplatin resulted in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Likewise, Gaedeke et al found that the effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Both studies reported that Silibinin given alone had no effect on renal function.
(Bokemeyer C, et al. Br J Cancer 1996 Dec;74(12):2036-2041; Gaedeke J, et al. Nephrol Dial Transplant 1996 Jan;11(1):55-62.)

• herbal support: Individuals receiving cisplatin should consult with their prescribing physician and a healthcare professional trained in herbal medicine before introducing silymarin or derivative herbal products into their treatment regime.


Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Ariceta G, Rodriguez-Soriano J, Vallo A, Navajas A. Acute and chronic effects of cisplatin therapy on renal magnesium homeostasis. Med Pediatr Oncol 1997 Jan;28(1):35-40.
Abstract: Although the acute renal toxicity of cisplatin has been well documented, long-term follow-up studies in cisplatin-treated children are scanty. We have evaluated the incidence and characteristics of both acute and chronic nephrotoxicity in 22 children (median age 8 years) treated with cisplatin as part of different chemotherapeutic protocols. All patients exhibited a significant and progressive decrease in plasma magnesium (Mg) values soon after cisplatin administration. Magnesiuria also increased immediately after therapy. Hypomagnesemia (plasma Mg < 1.4 mg/dl) occurred in 10 patients and it was dose-dependent. Minimal and mean cumulated doses inducing hypomagnesemia were 300 and 500 mg/m2, respectively. In 18 children we followed renal function prospectively for a mean time of 2.3 years after arrest of cisplatin therapy. Chronic hypomagnesemia and moderate elevation of plasma creatinine were observed in 6 children, hypocalciuria in 5 children, and hypokalemia in 1 child. Presence of hypomagnesemia was unrelated to the total dose received or the time elapsed since cisplatin therapy. Renal function studies, performed in the 6 children with chronic hypomagnesemia, revealed different degrees of impairment in Mg reabsorption. The functional characteristics of chronic cisplatin nephrotoxicity found in the present series-contrary to prior reports-are not comparable to those present in the inherited Gitelman's syndrome.

Babu E, Ebrahim AS, Chandramohan N, Sakthisekaran D. Rehabilitating role of glutathione ester on cisplatin induced nephrotoxicity. Ren Fail 1999 Mar;21(2):209-217.
Abstract: Cisplatin caused differential toxic effects on blood glucose and plasma urea, uric acid and creatinine levels. Cisplatin also showed an inhibitory effect on kidney marker enzymes like alkaline phosphatase, acid phosphatase, aspartate aminotransferase and alanine aminotransferase. However, administration of glutathione ester modulates the toxic side effect of cisplatin observed in kidney enzymes, and in blood parameters. It seems that glutathione ester plays an important role in protecting against the cisplatin induced nephrotoxicity by inhibiting the accumulation of platinum in kidneys.

Bianchetti MG, Kanaka C, Ridolfi-Luthy A, Wagner HP, Hirt A, Paunier L, Peheim E, Oetliker OH. Chronic renal magnesium loss, hypocalciuria and mild hypokalaemic metabolic alkalosis after cisplatin. Pediatr Nephrol 1990 May;4(3):219-222.
Abstract: Renotubular handling of sodium, potassium (K) calcium (Ca), phosphate, hydrogen ions and glucose, and urinary concentrating ability were studied in three children (aged 8, 8.5, 11 years) with renal magnesium (Mg) loss, persisting for more than 2 years after discontinuation of cisplatin treatment for neuroblastoma. A group of healthy children served as controls. Besides renal Mg wasting, a clear-cut tendency towards reduced calciuria associated with normal or slightly elevated plasma Ca was observed. Plasma K tended to be low (3.4-3.7 mmol/l), and plasma chloride was normal. Plasma bicarbonate (HCO3) ranged from 24.9 to 27.8 mmol/l, and urinary pH was always less than 6.0, indicating a renal HCO3 threshold exceeding 24 mmol/l. Plasma creatinine levels, glucosuria and phosphaturia, and urinary concentrating capacity were adequate. Comparable features were found in three children (aged 4.5, 9, 13 years) with primary renotubular hypomagnesaemia-hypokalaemia and hypocalciuria. This study complements the picture of chronic cisplatin tubulopathy in childhood demonstrating that, apart from Mg wasting, a reduced Ca excretion, and a tendency to hypokalaemia and metabolic alkalosis exist. Thus cisplatin may induce renal functional damage identical to that found in primary renotubular hypomagnesaemia--hypokalaemia with hypocalciuria.

Bokemeyer C, Fels LM, Dunn T, Voigt W, Gaedeke J, Schmoll HJ, Stolte H, Lentzen H. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996 Dec;74(12):2036-2041.
Abstract: Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.

Buckley JE, Clark VL, Meyer TJ, Pearlman NW. Hypomagnesemia after cisplatin combination chemotherapy. Arch Intern Med 1984 Dec;144(12):2347-2348.
Abstract: Sixty-six patients receiving a five-drug combination chemotherapy regimen containing low-dose cisplatin were studied for the presence of hypomagnesemia. Thirty-eight (76%) of 50 patients receiving treatment every four weeks became hypomagnesemic during treatment. The incidence increased with the cumulative cisplatin dose, ranging from 41% after a single course to 100% of patients receiving six cycles of therapy. The incidence seemed lower in patients receiving the combination with a greater interval (eight weeks v four weeks) between cycles. We report the incidence and severity of hypomagnesemia to be dose dependent. The cause of the higher incidence of hypomagnesemia observed in this series compared with others is unknown but may be related to an interaction of cisplatin with another drug contained in this regimen.

Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G. Neuroprotective effect of reduced glutathione on cisplatin-based cheniotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. J Clin Oncol 1995 Jan;13(1):26-32.
Abstract: PURPOSE: We performed a randomized double-blind placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of cisplatin (CDDP)-induced neurotoxicity. PATIENTS AND METHODS: Fifty patients with advanced gastric cancer treated with a weekly CDDP-based regimen were included in this study. In patients randomized to receive GSH, GSH was given at a dose of 1.5 g/m2 in 100 mL of normal saline solution over a 15-minute period immediately before CDDP administration, and at a dose of 600 mg by intramuscular injection on days 2 to 5. Normal saline solution was administered to placebo-randomized patients. Clinical neurologic evaluation and electrophysiologic investigations have been performed at baseline and after 9 (CDDP dose, 360 mg/m2) and 15 (CDDP dose, 600 mg/m2) weeks of treatment. RESULTS: At the 9th week, no patients showed clinically evident neuropathy in the GSH arm, whereas 16 patients in the placebo arm did. After the 15th week, four of 24 assessable patients in the GSH arm suffered from neurotoxicity versus 16 of 18 in the placebo arm (P = .0001). In confirmation of this neuroprotective effect, the neurophisiologic investigations, based on the evaluation of the median, ulnar, and sural sensory nerve conduction, showed a statistically significant reduction of these values in the placebo arm but not in the GSH arm, above all considering potential amplitude. In this trial, GSH also reduced hemotransfusion requirements (32 v 62 hemotransfusions) and treatment delay (55 v 94 weeks). The response rate was 76% (20% complete response) in the GSH group and 52% (12% complete response) in the placebo arm, confirming preliminary reports about the lack of reduction in activity of cytotoxic drugs induced by GSH. CONCLUSION: This study provides evidence that GSH is a promising and effective new drug for the prevention of CDDP-induced neuropathy, and that it does not reduce the clinical activity of chemotherapeutic drugs.

Cohen L. Potassium replacement associated with the development of tetany in a patient with hypomagnesaemia. Magnes Res 1993 Mar;6(1):43-45.
Abstract: A case of hypomagnesaemia secondary to cisplatin therapy and diarrhoea had concomitant hypokalaemia. Increasing the serum potassium level from 2.8 to 3.4 mmol/litre by potassium supplementation induced tetany. Hypokalaemia in the face of hypomagnesaemia may have a membrane-stabilizing effect and preserve excitability.

Cross HJ, Tilby M, Chipman JK, Ferry DR, Gescher A. Effect of quercetin on the genotoxic potential of cisplatin. Int J Cancer. 1996 May 3;66(3):404-408.
Abstract: The natural product flavonoid quercetin has been shown to sensitise cells to the cytotoxic potential of cisplatin. Both cisplatin and quercetin are genotoxicants. As quercetin is currently in clinical trial as a cytotoxicant-sensitising agent, we wanted to elucidate whether it affects the genotoxicity associated with cisplatin. The genotoxic potential of both agents alone and in combination was studied in Salmonella typhimurium strains TA 98, TA 100 and TA 102 and by assessment of unscheduled DNA synthesis (UDS) in rat hepatocytes. Furthermore, effects of quercetin on levels of cisplatin-DNA adducts were studied in hepatocytes by ELISA. Cisplatin was mutagenic in all 3 bacterial strains and quercetin in strain TA 98. The number of revertant Salmonella colonies observed with the combination did not differ significantly from that caused by the drugs on their own. In the UDS assay, cisplatin was genotoxic but quercetin was not. In combination, quercetin decreased the nuclear grain count caused by cisplatin, but quercetin did not alter the level of cisplatin-DNA adduct formation in hepatocytes. Our results suggest that the mutagenic potential of the combination cisplatin-quercetin, as judged by the bacterial short-term test, does not exceed that associated with the individual components. However, in hepatocytes, quercetin appears to inhibit repair of cisplatin-induced DNA damage. Therefore, in patients who are to be treated with a combination of cisplatin and quercetin, the risk of genotoxicity in normal tissues will have to be taken into consideration.

Elisaf M, Milionis H, Siamopoulos KC. Hypomagnesemic hypokalemia and hypocalcemia: clinical and laboratory characteristics. Miner Electrolyte Metab 1997;23(2):105-112

Gaedeke J, Fels LM, Bokemeyer C, Mengs U, Stolte H, Lentzen H. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996 Jan;11(1):55-62.
Abstract: BACKGROUND. The anticancer drug cisplatin is know to have toxic side-effects on different segments of the nephron. The flavonoid silibinin has previously been shown to be protective in models of hepatotoxicity. The aim of the present study was to evaluate, whether silibinin can also ameliorate alterations in renal glomerular and tubular function and tubular morphology induced by cisplatin. METHODS. In a rat model renal damage was induced by a single injection of cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to the administration of cisplatin. Kidney function was monitored by analysing urinary markers of glomerular and tubular function over a period of 11 days. Animals of a second group, with identical treatment, were sacrificed 4 days after drug application for an evaluation of tubular morphology at the light-microscopical level. RESULTS. Administration of cisplatin caused a decline in kidney function within a day following treatment. Symptoms observed were for example decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Impairment of proximal tubular function was ameliorated, that is enzymuria and magnesium wasting was less pronounced. Silibinin alone had no effect on kidney function. Treatment with silibinin distinctly diminished morphological alterations observed in the S3-segment of the proximal tubule 4 days after cisplatin administration. CONCLUSION. The effects of cisplatin on glomerular and proximal tubular function as well as proximal tubular morphology could totally or partly be ameliorated by silibinin. It is concluded the silibinin can act as a nephroprotectant and it is suggested that it could have beneficial effects on the kidney in clinical settings.

Jones MM, Basinger MA, Holscher MA. Relative effectiveness of some compounds for the control of cisplatin-induced nephrotoxicity. Toxicology 1991;68(3):227-247.
Abstract: Several procedures which have been reported as effective for the control of cisplatin induced nephrotoxicity were compared in the Sprague-Dawley rat using the same dose of cisplatin. The treatments examined were based on the use of sodium thiosulfate, sodium diethyldithiocarbamate (DDTC), glutathione (GSH), sodium N-methyl-D-glucamine dithiocarbamate (NaG) and S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). The differences in the effectiveness of the procedures were assessed using BUN and serum creatinine values, histopathological examination, body weight changes, and renal platinum levels as indices. The effect of such treatments on the antineoplastic activity of cisplatin were examined with both the Walker 256 carcinosarcoma in the rat and the L1210 murine leukemia in mice. Under the conditions used, GSH was found to be more effective than the other nucleophiles in protecting against the nephrotoxicity of cisplatin while providing the least amount of interference with the antitumor activity as measured against the Walker 256 carcinosarcoma and the L1210 murine leukemia. Simultaneous i.v. administration of cisplatin and any of the sulfur-containing nucleophiles leads to a significant protection against the nephrotoxicity but reduced the anti-neoplastic activity of cisplatin when measured against the Walker 256 carcinosarcoma.

Kibirige MS, Morris-Jones PH, Addison GM. Prevention of cisplatin-induced hypomagnesemia. Pediatr Hematol Oncol 1988;5(1):1-6.
Abstract: Twenty-eight children were treated for various cancers with protocols that included dichlorodiamine platinum (cisplatin). Sixteen children were given intravenous magnesium after the administration of cisplatin, and 12 were given intravenous magnesium before and after administration of cisplatin. Serum magnesium concentration levels were monitored before, during, and after the full course of treatment and found to be lower in the first group of patients than in the second group. We recommend that magnesium supplements be given to patients receiving cisplatin during the precisplatin hydration period to prevent hypomagnesemia.

Koch Nogueira PC, Hadj-Aissa A, Schell M, Dubourg L, Brunat-Mentigny M, Cochat P. Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma. Pediatr Nephrol 1998 Sep;12(7):572-575.
Abstract: The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4+/-2.2 (+/-SD) years after chemotherapy (total cumulative dose: methotrexate 41+/-31 g/m2, ifosfamide 39+/-14 g/m2, cisplatin 674+/-188 mg/m2) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m2 in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications.

Kuhlmann MK, Horsch E, Burkhardt G, Wagner M, Kohler H. Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin. Arch Toxicol 1998 Jul-Aug;72(8):536-540.
Abstract: Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK1). Viability of LLC-PK1 cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100-400 microM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10-25 microM and reaching a plateau between 50 and 100 microM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100-500 microM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 microM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role.

Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt). 1999 Jul;13(7):1003-1008; discussion 1008, 1011-1012.
Abstract: Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies.

Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev. 1999 Feb;25(1):47-58. (Review)
Abstract: Hypomagnesemia is a well known side-effect in patients receiving cisplatin-containing chemotherapy. Cisplatin induces hypomagnesemia through its renal toxicity possibly by a direct injury to mechanisms of magnesium reabsorption in the ascending limb of the loop of Henle as well as the distal tubule. Since the magnesium reabsorption process still remains to be fully characterized, the effect by cisplatin on this process remains uncertain. Hypomagnesemia is a frequent complication to chemotherapy with cisplatin affecting up to 90% of patients if no corrective measures are initiated. The clinical importance of this hypomagnesemia remains uncertain. Possible symptoms of hypomagnesemia can be impossible to distinguish from symptoms related to the underlying disease or the treatment with chemotherapy. Existing studies on how to supplement magnesium during treatment with cisplatin have focused mainly on the effect on serum magnesium values and erythrocyte magnesium concentrations but both parameters are poor indicators of body magnesium stores. As long as the relationship between hypomagnesemia and possible complications thereof remains poorly elucidated, it seems reasonable to try to avoid hypomagnesemia. The best results seem to be provided by adding magnesium to the pre- and posthydration fluids.

Olas B, Wachowicz B. Modulation of cisplatin toxicity in blood platelets by glutathione depletion. Anticancer Drugs 1998 Jun;9(5):473-478.

Olas B, Wachowicz B. [Selenium in the cytotoxicity of cisplatin]. Postepy Hig Med Dosw 1997;51(1):95-108. [Article in Polish]
Abstract: Cisplatin is a widely used chemotherapeutic agent, highly effective in the treatment of various types of human malignancies. The antitumor activity of cisplatin is attributed mainly to its ability to form adducts with DNA. Cisplatin may react with proteins and also with glutathione forming complex GS-Pt. This agent causes haematological, neurological toxicity and changes function of different cells. Recently, is has been reported that administration of sodium selenite reduces cisplatin toxicity without inhibiting the antitumour activity of cisplatin. This review focuses on the mechanism of cisplatin-induced cytotoxicity and the protective role of selenium.

Peyrade F, Taillan B, Lebrun C, Bendini JC, Passerron C, Dujardin P. [Hyponatremia during treatment with cisplatin]. Presse Med 1997 Oct 25;26(32):1523-1525. [Article in French]
Abstract: BACKGROUND: Cisplatin is one of the most widely used agents in cancer treatment. Cisplatin regimens can lead to a more or less pronounced hyponatremia in 4 to 10% of cases due to salt wasting with hypomagnesemia and normokaliemia. Functional and renal failure and orthostatic hypotension can be observed. CASE REPORT: A 54-year-old woman with brain metastases of a non-small-cell lung cancer was given a chemotherapy regimen containing cisplatin. Hyponatremia with confusion occurred after each cisplatin perfusion. The diagnosis retained was cisplatin-induced salt wasting. The patient was given salt prolonged supplementation and carboplatin was substituted for cisplatin in the chemotherapy regimen. DISCUSSION: Hyponatremia frequently occurs in cancer patients. Cisplatin-induced hyponatremia requires specific management. Treatment is based on sodium intake which sometimes takes several months to replete stores. Carboplatin can be used instead of cisplatin in case of major hyponatremia.

Rodriguez M, Solanki DL, Whang R. Refractory potassium repletion due to cisplatin-induced magnesium depletion. Arch Intern Med 1989 Nov;149(11):2592-2594.
Abstract: Cisplatin is a common cause of hypomagnesemia and hypokalemia due to renal magnesium (Mg) and potassium (K) losses. Magnesium plays an important role in the maintenance of intracellular K. An unrecognized and untreated Mg depletion can lead to a refractory K repletion. We describe two patients with hypomagnesemia-associated refractory hypokalemia following cisplatin following cisplatin therapy. Potassium supplementation failed to replace the K deficit. Profound hypokalemia persisted until hypomagnesemia was recognized and corrected. In neither patient was the concurrent hypomagnesemia recognized until the 11th and 9th hospital days. These two cases demonstrated the association of a refractory K repletion and an Mg deficiency. Thus, both serum K ion and Mg levels should routinely be assessed in patients who require cisplatin therapy.

Scambia G, Ranelletti FO, Benedetti Panici P, Bonanno G, De Vincenzo R, Piantelli M, Mancuso S. Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth. Anticancer Drugs. 1990 Oct;1(1):45-48.
Abstract: It has been demonstrated that the flavonoid quercetin (3,3',4',5-7-pentahydroxyflavone) (Q) inhibits the growth of several cancer cell lines and that the antiproliferative activity of this substance is mediated by a so-called type II estrogen binding site (type II EBS). We investigated the effects of quercetin and cisplatin (CDDP) alone and in combination on the proliferation of the ovarian cancer cell line OVCA 433. Both drugs exhibited a dose-related growth inhibition in a range of concentrations between 0.01 and 2.5 microM and 0.01 and 2.5 micrograms/ml for Q and CDDP respectively. The combination of the two drugs resulted in a synergistic antiproliferative activity. Two other flavonoids tested, i.e., rutin (3-rhamnosylglucoside of quercetin) and hesperidin [7-b rutinoside of hesperetin (3'-5-3-hydroxy-4-methoxyflavone)] were ineffective both alone and in combination with CDDP. Since both rutin and hesperidin do not bind to type II EBS it can be hypothesized that Q synergizes with CDDP by acting through an interaction with these binding sites.

Shen F, Weber G. Synergistic action of quercetin and genistein in human ovarian carcinoma cells. Oncol Res. 1997;9(11-12):597-602.
Abstract: Ovarian carcinoma is the fourth most common cause of cancer death in women and there has been a steady increase in the age-adjusted cancer death rates in the past 25 years in the US. However, patients who become cisplatin resistant respond poorly to available cytotoxic agents; therefore, discovering novel targets for ovarian carcinoma is vital. Quercetin, an anticancer agent, arrests the cell cycle at G1 and S phase boundary. Genistein, a plant flavonoid, attacks the cell cycle at G2 and/or early M phases in most carcinoma cells. Quercetin and genistein block the phosphatidylinositol conversion to IP3 signal transduction pathway mainly by inhibiting 1-phosphatidylinositol 4-kinase (PI kinase, EC 2.7.1.67) and 1-phosphatidylinositol 4-phosphate 5-kinase (PIP kinase, EC 2.7.1.68), respectively. Because each drug attacks a different phase of the cell cycle and reduces IP3 concentration by attacking different signal transduction enzymes, we tested the hypothesis that the two drugs might be synergistic in human carcinoma cells. In human ovarian carcinoma OVCAR-5 cells in growth inhibition assay, the IC50S for quercetin and genistein were (mean +/- SE) 66 +/- 3.0 and 32 +/- 2.5 microM; in clonogenic assays they were 15 +/- 1.2 and 5 +/- 0.5 microM, respectively. When quercetin was added to the cultures of OVCAR-5 cells followed 8 h later by genistein, synergism was observed in growth inhibition and clonogenic assays. The synergistic action of quercetin and genistein may be of interest in clinical treatment of human ovarian carcinoma.

Smyth JF, Bowman A, Perren T, Wilkinson P, Prescott RJ, Quinn KJ, Tedeschi M. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomised trial. Ann Oncol 1997 Jun;8(6):569-573.
Abstract: BACKGROUND: Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. PATIENTS AND METHODS: One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. RESULTS: When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). CONCLUSIONS: The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.

Stewart DJ, Dulberg CS, Mikhael NZ, Redmond MD, Montpetit VA, Goel R. Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods. Cancer Chemother Pharmacol 1997;40(4):293-308.
Abstract: OBJECTIVE: To assess factors that affect cisplatin nephrotoxicity. METHODS: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. RESULTS: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2-5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. CONCLUSIONS: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes: (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

Toffaletti J. Electrolytes, divalent cations, and blood gases (magnesium). Analyt Chem 1991 63(12):192R-194R.

Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med 1992 Jan;152(1):40-45.
Abstract: Experimental and clinical observations support the view that uncorrected magnesium (Mg) deficiency impairs repletion of cellular potassium (K). This is consistent with the observed close association between K and Mg depletion. Concomitant Mg deficiency in K-depleted patients ranges from 38% to 42%. Refractory K repletion due to unrecognized concurrent Mg deficiency can be clinically perplexing. Refractory K repletion as a consequence of Mg deficiency may be operative in patients with congestive failure, digitalis toxicity, cisplatin therapy, and in patients receiving potent loop diuretics. Therefore, we recommend that: (1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.