Adriamycin

Brand Names: Adriamycin

Clinical Names: Doxorubicin

Summary

generic name: Doxorubicin

trade name: Adriamycin®

type of drug: Cytotoxic chemotherapy.

used to treat: Cancer, especially late stage breast cancer, and rheumatoid arthritis.

nutritional need: Antioxidant nutrients can reduce cardiac toxicity, i.e., damage to the heart.

overview of interactions:
• nutrient affected by drug: Vitamin B2 (Riboflavin)

• nutrient affecting drug toxicity: Vitamin C

• nutrient affecting drug performance and toxicity: Vitamin E

• nutrient affecting drug toxicity: N-acetyl Cysteine (NAC)

• nutrient affecting drug toxicity: Coenzyme Q10 (Ubiquinone)




Interactions

nutrient affected by drug: Vitamin B2 (Riboflavin)

• mechanism: Doxorubicin can interfere with the normal metabolism and function of vitamin B2 and increase it urinary excretion. Doxorubicin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins.
(Pinto J, et al. Cancer 1986 Oct 15;58(8 Suppl):1911-1914.)

• research: Research with rats has demonstrated riboflavin deficiency due to doxorubicin, even when dietary sources of riboflavin have been sufficient. Studies by Pinto et al has demonstrated that the increased levels in aldosterone associated with doxorubicin are the result of the drug's inhibition of flavin coenzyme biosynthesis. They concluded that their findings with rat studies suggest that flavins play a decisive role in regulating the levels of aldosterone and raise the possibility that the doxorubicin-induced increase in serum aldosterone may be part of the pathogenetic mechanisms of cardiovascular toxicity and overall muscular weakness. Research looking at adverse effects, especially doxorubicin-induced mortality, has indicated that supplementation with riboflavin may reduce adverse side effects and enhance survival rates.
(Ogura R, et al. J Nutr Sci Vitaminol (Tokyo). 1991 Oct;37(5):473-477; Raiczyk GB, et al. Proc Soc Exp Biol Med 1988 Sep;188(4):495-499; Pinto JT, et al. Endocrinology 1990 Sep;127(3):1495-1501.)

• nutritional support: Individuals taking doxorubicin may benefit from supplementation with vitamin B2. A daily dosage of 20-25 mg of vitamin B2, the amounts found in many multi-vitamin supplements, is most likely sufficient to compensate for doxorubicin-induced deficiency. Riboflavin is non-toxic, even in high amount. Even so, individuals taking doxorubicin should consult their prescribing physician and/or a nutritionally trained healthcare professional about nutritional deficiencies related to the drug and dietary or supplemental means of protecting against adverse effects.

nutrient affecting drug toxicity: Vitamin C

• mechanism: Antioxidant action reduces cardiac toxicity. However, as a strong antioxiidant and as an effective promoter of glutathione activity, vitamin C could potentially inhibit the therapeutic mechanism of doxorubicin which relies upon the cytotoxic effect of free radical formation.
(Labriola D, Livingston R. Oncology (Huntingt). 1999 Jul;13(7):1003-1008.)

• research: Animal studies, using mice and guinea pigs, indicated that vitamin C significantly increased life expectancy by reducing the cardiotoxicity of doxorubicin; this positive effect was gained without interfering with the drug's anticancer effects. However, the relationship between these findings based on animal studies and human clinical cardiac toxicity is uncertain.
(Fujita, K, et al. Cancer Res 1982;42:309-316; Shimpo K, et al. Am J Clin Nutr 1991 Dec;54(6 Suppl):1298S-1301S; Ellison, NM, Londer H. 1981.)

• nutritional support: Supplementation of vitamin C at doses of one or more grams per day is prescribed by some practitioners as nutritional support for patients taking doxorubicin, even though the practice lacks conclusive data based on human studies.

nutrient affecting drug performance and toxicity: Vitamin E

• mechanism: Antioxidant action reduces cardiac toxicity.

• research: Initial research by Prasad et al suggested that supplementation with vitamin E might reduce cardiac and skin toxicity due to doxorubicin. Research studies with animals have found that vitamin E's potent antioxidant activity can protect against Adriamycin-induced cardiotoxicity; hence reducing the risk of heart failure which is a serious side effect associated with doxorubicin.
(Prasad KN, et al. Proc Soc Exp Biol Med 1980 Jun;164(2):158-163; Ellison NM. Cancer Bull 1985;37(3):112-113; Am Heart J 1986;lll:95; Myers C, et al. Cancer Treat Rep 1976;60:961-962; Sonneveld P. Cancer 1978;62:1033-1036.)

However, no conclusive evidence has come forth confirming the cardioprotective effect of vitamin E in human trials. Nevertheless, some evidence suggests that supplementation with vitamin E may allow use of higher doses of doxorubicin without correspondingly increasing toxicity.
(Ellison, NM, Londer H. 1981; Weiji NI, et al. Cancer Treatment Rev 1997,23:209-210.)

Anecdotal reports indicate that very high doses of vitamin E (1600 IU) may reduce the amount of alopecia (hair loss) resulting from use of doxorubicin. (Wood LA. N Engl J Med 1985;312:1060 ) As of yet, no research on humans has duplicated the protective effect against hair loss found in one study with rabbits. (Weiji NI, et al. Cancer Treatment Rev 1997;23:209-240.)

• nutritional support: Supplementation of vitamin E at doses of 800 IU or more is prescribed by some practitioners as nutritional support for patients taking doxorubicin, even though no decisive evidence has emerged showing that the vitamin reduces drug toxicity or protects against hair loss.

• nutritional synergy: In vitro evidence suggests that vitamin E enhances the growth inhibitory effect of doxorubicin, at least in a test tube.
(Ripoll EAP, et al. J Urol 1986;136:529-531.)

nutrient affecting drug toxicity: N-acetyl Cysteine (NAC), a precursor to Glutathione

• mechanism: Antioxidant action reduces cardiac toxicity of doxorubicin.

• research: Research has found that N-acetyl cysteine (NAC) exerts a protective effect from the cardiotoxicity of doxorubicin, at least in animals; no research with human has yet confirmed these results.
(Schmitt-Graff A, et al. Pathol Res Pract. 1986 May;181(2):168-74; Martinez E, Domingo P. Lancet 1991;338:249; Doroshow JH, et al. J Clin Invest 1981;68:1053-1064; Meyers C, et al. Semin Oncol 1983;10:53-55.)

• nutritional support: The prescription of oral NAC for individuals receiving doxorubicin therapy is not a common practice among nutritionally-oriented physicians.

nutrient affecting drug toxicity: Coenzyme Q10 (Ubiquinone)

• mechanism: Coenzyme Q10 reduces free radical formation induced by doxorubicin.
(Folkers K. 1985; Gaby, AR. 1987; Anonymous. Nutr Rev 1988;46:1367; Beyer RE. Biochem Cell Biol 1992 70(6):390-403.)

• research: Studies with both animals and humans have found that pretreating with coenzyme Q10, at levels of 100 mg per day, reduces cardiac toxicity caused by doxorubicin.
(Gaby, AR.1987; Judy WV, et al. 1984,231-241; Ogura R, et al. J Appl Biochem 1979,1:325; Shinozawa S, et al. Gan To Kagaku Ryoho. 1996 Jan;23(1):93-98; Shinozawa S, et al. Biol Pharm Bull. 1993 Nov;16(11):1114-1117; Shinozawa S, et al. Acta Med Okayama. 1991 Jun;45(3):195-199; Shinozawa S, et al. Acta Med Okayama. 1987 Feb;41(1):11-17; Shinozawa S, et al. Acta Med Okayama. 1984 Feb;38(1):57-63; Labriola D, Livingston R. Oncology (Huntingt). 1999 Jul;13(7):1003-1008.)

• nutritional concern: Individuals taking doxorubicin (Adriamycin) may benefit from supplementation with coenzyme Q10 at some point in their treatment protocol. However, such supplementation should only be started after consultation with and under the close supervision of the prescribing physician and/or a nutritionally trained healthcare professional. Nutrients with antioxidant potential should generally be avoided during the course of treatment with doxorubicin as there is concern that the effectiveness of the medication might be diminished since it relies upon free radical formation for its cytotoxic effect. Should use of coenzyme Q10 be agreed upon a dosage in the range of 50-100 mg three times daily would be in the range many nutritionally oriented healthcare professionals would use.


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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

Anonymous. Vitamin E and cell injury. Nutr Rev 1988;46:1367. (Review)

Beyer RE. An analysis of the role of coenzyme Q in free radical generation, and as an antioxidant. Biochem Cell Biol 1992 70(6):390-403. (Review)
Abstract: The vital role of coenzyme Q in mitochondrial electron transfer and its regulation, and in energy conservation, is well established. However, the role of coenzyme Q in free oxyradical formation and as an antioxidant remains controversial. Demonstration of the existence of the semiquinone form of coenzyme Q during electron transport, coupled with recent evidence that hydrogen peroxide (but not molecular oxygen) may act as an oxidant of the semiquinone, suggests that the highly reactive OH. radical may be formed from the semiquinone. On the other hand, data exist implicating the Fe-S species as the source of electron transfer chain, free radical production. Additional data exist suggesting instead that the unpaired electron of the coenzyme Q semiquinone most likely dismutases superoxide radicals. These concepts and those arising from observations at several levels of organization including subcellular systems, intact animals, and human subjects in the clinical setting, supporting the concept of reduced coenzyme Q as an antioxidant, will be presented. The results of recent studies on the interaction between the two-electron quinone reductase--DT diaphorase and coenzyme Q10 will be presented. The possibility that superoxide dismutase may interact with reduced coenzyme Q, in conjunction with DT diaphorase inhibiting its autoxidation, will be described. The regulation of cellular coenzyme Q concentrations during oxidative stress accompanying aerobic exercise, resulting in increased protection from free radical damage, will also be presented.

Beyer RE. The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q. J Bioenerg Biomembr. 1994 Aug;26(4):349-358. (Review)
Abstract: One of the vital roles of ascorbic acid (vitamin C) is to act as an antioxidant to protect cellular components from free radical damage. Ascorbic acid has been shown to scavenge free radicals directly in the aqueous phases of cells and the circulatory system. Ascorbic acid has also been proven to protect membrane and other hydrophobic compartments from such damage by regenerating the antioxidant form of vitamin E. In addition, reduced coenzyme Q, also a resident of hydrophobic compartments, interacts with vitamin E to regenerate its antioxidant form. The mechanism of vitamin C antioxidant function, the myriad of pathologies resulting from its clinical deficiency, and the many health benefits it provides, are reviewed.

Doroshow JH, Locker GY, Ifrim I, Myers CE. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J Clin Invest 1981 Oct;68(4):1053-1064.
Abstract: This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

Ellison, NM. Relationship between vitamin E and cancer - facts, not fancy. Cancer Bull 1985;37(3):112-113.

Ellison, NM, Londer H. Vitamin E and C and their relatiuonship to cancer. In: Newell GR, Ellison NM, eds. Nutrition and Cancer: Etiology and Treatment. New York: Raven Press, 1981.

Folkers K. Basic chemical research on coenzyme Q10 and integrated clinical research on therapy of diseases. In: Lenaz G, ed. Coenzyme Q. John Wiley and Sons, 1985.

Fujita K, Shinpo K, Yamada K, Sato T, Niimi H, Shamoto M, Nagatsu T, Takeuchi T, Umezawa H. Reduction of Adriamycin toxicity by ascorbate in mice and guinea pigs. Cancer Res 1982 Jan;42(1):309-316.
Abstract: The effect of ascorbate in reducing Adriamycin toxicity has been examined in mice and guinea pigs. Ascorbate had no effect on the antitumor activity of Adriamycin in mice inoculated with leukemia L1210, but it significantly prolonged the life of mice and guinea pigs treated with Adriamycin. Adriamycin elevated lipid peroxide levels in serum and liver, and ascorbate prevented the elevation. The significant prevention of Adriamycin-induced cardiomyopathy by ascorbate was proved by means of electron microscopy. The earliest alterations of dilation of the sarcoplasmic reticulum and transverse tubular system and the appearance of a large number of cytoplasmic fat droplets, which were seen in cardiac tissue from guinea pigs receiving Adriamycin, were apparently reduced in animals that were treated with ascorbate.

Judy, WV, Hall, JH, Dugan, W, et al. Coenzyme Q10 reduction of Adriamycin cardiotoxicity. In Biomedical and Clinical Aspects of Coenzyme Q, vol.4, ed. Folkers, K, Yamamura, Y. Amsterdam: Elsevier/North Holland Biomedical Press, 1984,231-241.

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.

Martinez, E, Domingo, P. N-acetylcysteine as chemoprotectant in cancer chemotherapy. Lancet 1991 Jul 27;338(8761):249. (Letter)

Myers C, Bonow R, Palmeri S, Jenkins J, Corden B, Locker G, Doroshow J, Epstein S. A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983 Mar;10(1 Suppl 1):53-55.

Myers, C, McQuire, W, Young, R. Adriamycin amelioration of toxicity by alpha-tocopherol. Cancer Treat Rep 1976 Jul;60(7):961-962.

Ogura R, Ueta H, Hino Y, Hidaka T, Sugiyama M. Riboflavin deficiency caused by treatment with adriamycin. J Nutr Sci Vitaminol (Tokyo). 1991 Oct;37(5):473-477.
Abstract: The present study was undertaken to determine whether administration of adriamycin causes the depletion of riboflavin content. Rats received intraperitoneal injections of adriamycin (4 mg per kg body weight) for 6 consecutive days. Urinary riboflavin excretion began to increase after 2 days of treatment with adriamycin. Erythrocyte FAD levels decreased gradually and plasma lipid peroxide contents increased markedly at the 6th day. The activity coefficient of erythrocyte glutathione reductase showed a significant increase before the decrease of flavin content and the elevation of lipid peroxide level. Therefore, the value of this coefficient obtained from erythrocyte appears to be a reliable index of riboflavin deficiency, particularly during the early stage.

Ogura R, Toyama H, Shimada T, Murakami M. The role of ubiquinone (Coenzyme Q10) in preventing Adriamycin-induced mitochondrial disorders in rat heart. J Appl Biochem 1979,1:325.
Abstract: The combined use of CoQ10 with adriamycin has been recommended for reduction of the cardiotoxicity that occurs during cancer chemotherapy. Vitamin B2-butyrate was also investigated in order to determine anti-oxidative effects on adriamycin cardiotoxicity. This vitamin analysis prevented enhanced lipid peroxidation and rectified the respiratory disorders of heart mitochondria induced by adriamycin, however, the deficiency of the CoQ10-pool was not rectified. The combined approach of using CoQ10 for rectifying the deficiency of this component and of using B2-butyrate for reducing lipid peroxidation was indicated for adriamycin cancer chemotherapy.

Okamoto K, Ogura R. Effects of vitamins on lipid peroxidation and suppression of DNA synthesis induced by adriamycin in Ehrlich cells. J Nutr Sci Vitaminol (Tokyo) 1985 Apr;31(2):129-137.
Abstract: The effects of various vitamins on lipid peroxidation and the suppression of DNA synthesis induced by adriamycin (ADR) in vitro using Ehrlich ascites carcinoma (EAC) cells were studied. ADR produced a concentration-dependent stimulation of lipid peroxidation in EAC cells. alpha-Tocopherol and coenzyme Q10 inhibited ADR-induced lipid peroxidation to about the same extent and these effects were the greatest for all antioxidants added. The inhibitory effect of riboflavin 2',3',4',5'-tetrabutyrate was greater than that of riboflavin 5'-phosphate. On measuring incorporation of [3H]thymidine into EAC cells, these vitamins did not alter appreciably the magnitude of the ADR-induced suppression of DNA synthesis in EAC cells.

Pinto JT, Delman BN, Dutta P, Nisselbaum J. Adriamycin-induced increase in serum aldosterone levels: effects in riboflavin-sufficient and riboflavin-deficient rats. Endocrinology 1990 Sep;127(3):1495-1501.
Abstract: Previous studies in rats have demonstrated that 1) aldosterone enhances biosynthesis of renal flavin coenzymes; 2) riboflavin analogs inhibit the synthesis of aldosterone; and 3) adriamycin inhibits flavin coenzyme biosynthesis. In their entirety, these findings suggest that both diminished flavin coenzyme biosynthesis induced by adriamycin and a dietary riboflavin deficiency would result in decreased formation of aldosterone. The present study examined the effects of adriamycin treatment on serum aldosterone in rats consuming either a diet adequate in riboflavin or a riboflavin-deficient diet. Groups of rats fed specially prepared diets were injected for 3 days with adriamycin (cumulative dose range, 6-24 mg/kg BW). Pair-fed controls were given saline. After death, adrenal glands were excised, and blood samples were analyzed for aldosterone levels. No changes in adrenal weights or protein and potassium concentrations were observed after adriamycin treatment. In contrast to initial predictions, in riboflavin-sufficient rats, serum aldosterone levels were markedly enhanced by adriamycin in a dose-related manner. Riboflavin-deficient animals had lower basal aldosterone levels and markedly attenuated responses to adriamycin than did riboflavin-sufficient rats. In separate groups of adriamycin-treated rats fed a normal chow diet, serum aldosterone levels increased, and serum corticosterone levels showed a small but significant decline. In addition, adriamycin treatment caused an increase in urinary potassium excretion and a decrease in sodium excretion. These results suggest that flavins play a decisive role in regulating the levels of aldosterone and raise the possibility that the adriamycin-induced increase in serum aldosterone may be part of the pathogenetic mechanisms of cardiovascular toxicity and overall muscular weakness.

Pinto J, Raiczyk GB, Huang YP, Rivlin RS. New approaches to the possible prevention of side effects of chemotherapy by nutrition. Cancer 1986 Oct 15;58(8 Suppl):1911-1914.
Abstract: In an effort to develop new methods for preventing side effects of chemotherapy, the authors initiated studies to determine whether Adriamycin (doxorubicin) inhibits the metabolism of riboflavin (vitamin B2). Adriamycin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins. Adult rats treated with Adriamycin in clinically relevant doses were compared to control animals in ability to convert riboflavin into flavin adenine dinucleotide (FAD), the active flavin coenzyme derivative, in heart, skeletal muscle, liver, and kidney. Rats treated with Adriamycin exhibited diminished formation of carbon 14 (14C)FAD in skeletal muscle to nearly 50% that of controls, and in heart to about 70% to 80% of controls. Under these conditions, (14C)FAD formation in liver and kidney was largely unaffected by Adriamycin. In preliminary studies, riboflavin-deficient animals treated with Adriamycin had accelerated mortality rates compared to those of food restricted controls treated with similar doses of Adriamycin. The data as a whole suggest a potential mechanism for Adriamycin-induced cardiac and skeletal myopathy, i.e., inhibition of synthesis of FAD, a flavin coenzyme which is involved in electron transport, lipid metabolism, and energy generation. These findings in an animal model raise the possibility that defects of riboflavin nutriture, either dietary or drug-induced, may be a determinant of Adriamycin toxicity. Further studies are required to explore the potential for preventing side effects due to Adriamycin by administration of this vitamin.

Prasad KN, Edwards-Prasad J, Ramanujam S, Sakamoto A. Vitamin E increases the growth inhibitory and differentiating effects of tumor therapeutic agents on neuroblastoma and glioma cells in culture. Proc Soc Exp Biol Med 1980 Jun;164(2):158-163.

Ripoll, EAP, Rama, BN, Webber, MM. Vitamin E enhances the chemotherapeutic effects of Adriamycin on human prostatic carcinoma cells in vitro. J Urol 1986 Aug;136(2):529-531.
Abstract: Vitamin E (tocopherol) enhances the growth inhibitory effects of adriamycin (ADR) on a variety of cancer cells in vitro. The role of vitamin E (d-alpha-tocopheryl) acid succinate in adjuvant chemotherapy with ADR was assessed in DU-145 human prostatic carcinoma cells in culture. Adriamycin produced a dose-dependent growth inhibition of DU-145 cells. The ID50 of DU-145 cells on the criteria: of clonal assay was 13 ng./ml. and of cell count assay was 14 ng./ml. Vitamin E succinate also inhibited the growth of DU-145 human prostatic carcinoma cells in a dose-dependent manner. 4.4 micrograms./ml. and 5.4 micrograms./ml. vitamin E succinate in the culture medium produced inhibition of growth to 50 per cent of control (ID50) in the clonal and the cell count assays respectively. When adriamycin and vitamin E succinate were used in combination, both additive and synergistic effects were observed, depending on the concentration of vitamin E succinate used. Doses of vitamin E succinate greater than its ID50 had a synergistic effect while doses smaller than its ID50 had an additive effect. In either case, the presence of vitamin E succinate caused an enhancement of tumor cell cytotoxicity of adriamycin while decreasing its ID50. Equivalent concentrations of sodium succinate and ethanol used to dissolve vitamin E succinate did not have any effect on DU-145 cells. Thus, it is concluded that the effect of vitamin E succinate is due to vitamin E and not due to succinate or ethanol. These results suggest that vitamin E may have a role in the treatment of human prostatic cancer as an adjuvant agent to adriamycin.

Raiczyk GB, Rivlin RS, Pinto J. Enhancement of adriamycin-induced mortality during riboflavin administration and riboflavin deficiency in rats. Proc Soc Exp Biol Med 1988 Sep;188(4):495-499.
Abstract: Adriamycin-treated rats were monitored for survivorship while consuming a normal diet adequate in riboflavin, a normal diet and receiving daily high-dose injections of riboflavin-5'-phosphate (flavin mononucleotide, FMN), or a riboflavin-deficient diet. Each animal was compared to a corresponding pair-fed, saline-treated control. In Adriamycin-treated rats fed the normal chow diet alone, survivorship declined within 7 days and remained constant after 12 days to about 50%. Adriamycin-treated rats consuming the normal diet and injected with FMN initially showed similar survivorship; however, after 20 days survival fell to 14%. Adriamycin-treated, riboflavin-deficient rats showed within 5 days a precipitous decline in survivorship which leveled to 5%. These results suggest that during Adriamycin treatment, proper riboflavin nutriture may be a crucial determinant of survival.

Shinozawa S, Kawasaki H, Gomita Y. [Effect of biological membrane stabilizing drugs (coenzyme Q10, dextran sulfate and reduced glutathione) on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice]. Gan To Kagaku Ryoho. 1996 Jan;23(1):93-98. [Article in Japanese]
Abstract: The protective effects of the biological membrane stabilizing drugs, coenzyme Q10 (CoQ), dextran sulfate (DS) and reduced glutathione (GSH), on doxorubicin (adriamycin, ADM)-induced toxicity and microsomal lipid peroxidation were studied in mice. The mice administered ADM with combined treatment of CoQ, DS or GSH showed a significantly longer survival time than the ADM control group (which were injected with 15 mg/kg of ADM twice). The optimum protective doses of these drugs against ADM-induced toxicity were 10 mg/kg/day (p.o.) for CoQ, 100 mg/kg/day (s.c.) for DS and 100 mg/kg/day (i.p.) for GSH. The survival times of the mice (expressed as a percent of the treated group per control group) were 224.1% for CoQ, 220.7% for DS and 213.7% for GSH. The groups treated with these drugs showed a significant decrease in mouse liver and heart microsomal lipid peroxidation in comparison to that of the ADM control group. These results suggest that the heart microsomal lipid peroxidation levels may be one of the indications of ADM-induced cardiac toxicity. These drugs tested in the present study may stabilize the heart microsomal membrane lipid or may improve the myocardiac mitochondrial functions over those in ADM-treated mouse.

Shinozawa S, Gomita Y, Araki Y. Protective effects of various drugs on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice and rats. Biol Pharm Bull. 1993 Nov;16(11):1114-1117.
Abstract: The protective effects of clinically used drugs on the toxicity and microsomal lipid peroxidation induced by doxorubicin (adriamycin, ADM), an anthracycline type antitumor agent, were studied in mice and rats. Regarding the effects of anthracyclines (aclarubicin, ACL; daunorubicin, DAU; ADM; epirubicin, EPI; pirarubicin, PIR) on rat liver microsomal lipid peroxidation, ACL had the smallest effect, and effectiveness increased in the order of PIR, ADM, DAU and EPI. The increasing effect of lipid peroxidation induced by these drugs was closely correlated with the decrease in the body weight of mice administered intraperitoneally at a dose of 20 mg/kg and in rats at LD50 of the drugs. The survival times of ADM-administered mice (which were injected 15 mg/kg of ADM twice) treated with the following drugs, expressed as a percent of that of the control group, were 236% for adenosine triphosphate, 224% for coenzyme Q10 (Co Q), 235% for dextran sulfate (DS), 123% for dipyridamole, 121% for flavin adenine dinucleotide, 213% for reduced glutathion, 155% for inositol nicotinate, 157% for nicardipin and 297% for nicomol. The rat heart microsomal lipid peroxidation levels in vivo may be one of the indications of ADM-induced toxicity. The levels treated with DS correlated well with the development of ADM-induced toxicity: mouse survival time, change of body weight and tissue wet weight loss. Another type of drug, such as Co Q, may improve the myocardiac mitochondrial functions compared to those of ADM-administered mice.

Shinozawa S, Gomita Y, Araki Y. Tissue concentration of doxorubicin (adriamycin) in mouse pretreated with alpha-tocopherol or coenzyme Q10. Acta Med Okayama. 1991 Jun;45(3):195-199.
Abstract: The tissue concentration of doxorubicin (adriamycin; ADM) and its major metabolite (aglycone I) was examined in mice pretreated with alpha-tocopherol (VE) or coenzyme Q10 (CoQ). In VE-pretreated group, the concentrations of aglycone I of the liver (1, 3 and 5 h after the administration), kidney (1 and 3h) and heart (3h) were significantly higher than those in the saline group. The clinical application of VE or CoQ concomitant with anti-tumor drugs especially ADM, requires caution.

Shinozawa S, Gomita Y, Araki Y. Protection against adriamycin (doxorubicin)-induced toxicity in mice by several clinically used drugs. Acta Med Okayama. 1987 Feb;41(1):11-17.
Abstract: Protective effects of clinically used drugs against adriamycin (ADM)-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.). The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg), 402.2% for dextran sulfate (MDS, 300 mg/kg), 121.6% for flavin adenine dinucleotide (20 mg/kg), 236.3% for adenosine triphosphate disodium (50 mg/kg), 213.7% for reduced glutathione (100 mg/kg), 121.6% for phytonadione (50 mg/kg), 155.2% for inositol nicotinate (Ino-N, 500 mg/kg), 335.5% for nicomol (1000 mg/kg), 157.5% for nicardipine (10 mg/kg) and 123.3% for dipyridamol (50 mg/kg). Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.

Shinozawa S, Etowo K, Araki Y, Oda T. Effect of coenzyme Q10 on the survival time and lipid peroxidation of adriamycin (doxorubicin) treated mice. Acta Med Okayama. 1984 Feb;38(1):57-63.
Abstract: The effect of coenzyme Q10 (Co Q10) was examined on the survival time and lipid peroxidation of adriamycin (ADM)-treated ICR mice. Co Q10 showed a protective effect against a subacute toxicity in mice induced by two intraperitoneal administrations of ADM (15 mg/kg). The group treated orally with 10 mg/kg of Co Q10 showed the longest survival time of all the groups studied (16.81 +/- 10.29 days, mean +/- S.D.) and a significantly longer survival time (p less than 0.001) than the ADM-alone group (7.48 +/- 1.99 days). The inhibitory effect of Co Q10 on the plasma and tissue lipid peroxidation levels did not correlate with the effect of prolonging the survival time of mice. Co Q10 tended to inhibit rises in plasma and liver lipid peroxidation levels induced by ADM administration, but there was no statistically significant difference between treatments. There was a statistically significant different inhibitory effect in the kidney lipid peroxidation levels, but was not in those of the heart.

Schmitt-Graff A, Scheulen ME. Prevention of adriamycin cardiotoxicity by niacin, isocitrate or N-acetyl-cysteine in mice. A morphological study. Pathol Res Pract. 1986 May;181(2):168-74.
Abstract: Adriamycin is known to produce treatment limiting cardiotoxicity. We studied the effect of niacin, isocitrate, and N-acetyl-cysteine on cumulative adriamycin-induced cardiotoxicity in NMRI mice. Pathologic grading of the hearts indicated a significant reduction in myocardial injury. In addition, according to median survival and weight changes there was a significant decrease in toxicity. As demonstrated in Ehrlich ascites tumor, coadministration of N-acetyl-cysteine may interfere with the antitumor activity of adriamycin. In contrast, niacin and isocitrate did not show significant inhibition of antineoplastic activity. Our experiments suggest a promising role of niacin and isocitrate as potential cardioprotectors in the course of chemotherapy with adriamycin.

Shimpo K, Nagatsu T, Yamada K, Sato T, Niimi H, Shamoto M, Takeuchi T, Umezawa H, Fujita K. Ascorbic acid and adriamycin toxicity. Am J Clin Nutr 1991 Dec;54(6 Suppl):1298S-1301S.
Abstract: Adriamycin (ADR) is effective against a wide range of human neoplasms. However, its clinical use is compromised by serious cardiac toxicity, possibly through induction of peroxidation in cardiac lipids. Ascorbic acid, a potent antioxidant, was examined for effect in reducing ADR toxicity in mice and guinea pigs. Ascorbic acid had no effect on the antitumor activity of ADR in mice inoculated with leukemia L1210 or Ehrlich ascites carcinoma, but it significantly prolonged the life of animals treated with ADR. ADR elevated lipid peroxide levels in mouse heart, and ascorbic acid prevented the elevation. The significant prevention of ADR-induced cardiomyopathy in guinea pigs by ascorbic acid was proved by electron microscopy. Ascorbic acid and the derivatives may delay general toxicity of ADR and also prevent the cardiac toxicity. The results also suggest the clinical efficacy of the combined treatment of ADR and ascorbic acid or the derivatives.

Sonneveld, P. Effect of alpha-tocopherol on the cardiotoxicity of Adriamycin in the rat. Cancer 1978 Jul;62(7):1033-1036.
Abstract: Adriamycin (ADR)-induced cardiomyopathy was studied in a rat model by means of electrocardiograms (ECGs), light microscopy, and determination of heart weight. Pretreatment with D-alpha-tocopherol (alpha-T) 24 hours prior to a high dose of ADR diminishes cardiotoxic effects, as judged by ECG changes, decreases in heart weight, and histologic changes. The response of an acute myeloid leukemia in a rat model to ADR was not affected by this pretreatment. The results provide evidence that alpha-T might be used to improve the therapeutic index of ADR.

Weiji NI, Cleton, F.T, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treatment Rev 1997 Jul;23(4):209-240. (Review)

Wood, LA. Possible prevention of Adriamycin-induced alopecia by tocopherol. N Engl J Med 1985;312:1060. (Letter)