Med. Oncol. & Tumor Pharmacother, Vol. 8, No. 2, pp. 79--86, 1991
0736-0118/91 $3.00 + .00 Pergamon Press plc
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INTERACTION
BETWEEN
CYTOSTATICS
AND NUTRIENTS
R O G E R H E N R I K S S O N , K H A M A O. R O G O and K J E L L G R A N K V I S T Departments of Oncology and Clinical Chemistry, University Hospital, S-901 85 Ume~, Sweden (First received 19 December 1990; accepted in revised form 23 January 1991) Cancer patients have the highest prevalence of malnutrition of any group of hospitalized patients. The presence of the tumor alone may lead to reduced intake of different nutrients and treatment modalities such as surgery, chemotherapy and radiation therapy may further exacerbate nutritional disturbances. Dietary manipulation in experimental systems has shown improvement of tumor response to cancer therapy. Drug pharmacokinetics has been shown to be altered by changes in nutritional delivery. This article reviews the present knowledge, from experimental and clinical standpoints, of the potential role of different nutritional factors on the specific cancer treatment. It is obvious that alteration of at least some dietary factors affect the outcome of different forms of cancer treatment. Indeed, although interest in the clinical significance of optimal dietary intake and supplementation during cancer therapy so far remain marginal, accumulating data indicate that this area deserves further research attention.
Key words: Nutrition, Diet, Cancer treatment, Resistance.
tumor growth, considerably less interest has been devoted to the effects of exogenous factors on the outcome of cancer treatment. The interactions between cytotoxic anticancer drugs and other pharmaceuticals have recently been reviewed. 3 In general the effects of food on drug bioavailability have received scant attention. The therapeutic efficacy of drugs due to food, the frequency of food related changes, and the magnitude of some of the effects, suggest that observed alterations in drug activity would have clinical consequences particularly with drugs that have narrow therapeutic indices, a steep dose-response curve, or established therapeutic or toxic levels in the body. 4 Although, the alteration in nutritional status seems to be an
INTRODUCTION The last few years have seen an increasing awareness of the association between nutrition and cancer. Malnutrition of different kinds is thought to comprise 20-50% of hospitalized patients, and a significant portion of these are cancer patients. The importance of adequate dietary intake, and the need for additional dietary nutrients is now accepted in the total m a n a g e m e n t of these patients. A great deal of interest has also come from the field of cancer prevention. Epidemiologic studies have suggested that neoplastic occurrence is associated with nutrition, e.g. diets high in total fat and low in certain fibers are associated with an increase in large bowel cancer. The presence of disease may interfere with absorption, increase the utilization, or accelerate the loss of essential nutrients. These nutritional defects sooner or later reduce the physiologic reserve, and eventually may make patients more susceptible to complications of anticancer therapy (Table 1). Interactions between different cancer chemotherapeutics, ~ and between radiation and chemotherapeutics are rather well studied. 2 Although the problems of drug resistance have drawn attention to the effects of other drugs on
Table 1. Causes of nutritional disturbances in cancer patients Psychogenic Cancer as chronic disease I a t r o g e n i c - Chemotherapy Surgery Radiation Immunotherapy Altered taste Food aversion Other drugs used Pain
Address for correspondence: Dr Roger Henriksson, Department of Oncology, University Hospital, S-901 85 UMEA,, Sweden. 79
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important independent prognostic factor in cancer patients, the possibility of nutritional intervention (e.g. total parenteral nutrition) to favorably influence outcome in cancer treatment is less evaluated, s A shallow interest has been shown in the possible influence of different nutritional factors per se on the direct outcome of cancer treatment. Therefore, we have summarized the present state of knowledge and views, both from experimental and clinical standpoints, on the influence of diet and its components on cytostatic treatment and the effects of this influence on tumor growth and drug toxicity.
BASIC CONCEPTS A better understanding of the complexity of interactions can be achieved by first defining factors that are of importance for the efficacy and toxicity of different substances. Interactions may arise either from alteration of absorption, distribution, biotransformation, or excretion of one drug by the other, or from combinations of their actions or effects. Physicochemical interactions or incompatibilities may occur in the solution prior to administration, and can be divided into three groups; solubility phenomena, cationic-anionic incompatibilities, and acid-base or pH-effects. This type of interaction, not being biological, will not be discussed further. Pharmacokinetic interaction includes changes in absorption, distribution, or elimination of a drug. Several mechanisms are involved, e.g. gastric pH, gastrointestinal motility, competition for plasma protein or tissue binding, inhibition of biotransformation, induction of liver enzyme systems, and competition for renal secretion. Decreased absorption of drugs may also result from prior interaction in the gastrointestinal tract. Food has been shown to have varying effects, especially on drug absorption, and changes seen are not solely predictable from a mechanistic viewpoint. While drug-food interactions give rise to a variety of effects the most common interactions seen are either reduced or delayed drug levels in blood, a It also has to be emphasized that food can interact with processes other than absorption. Its effects on drug metabolism, the various effects on enzyme systems, and changes in regional blood flow, point out that the final drug action may also be influenced by alterations in distribution and eliminations.4 Pharmacodynamic interaction relates to the end effects of drugs. It includes drug interactions at receptor sites and cell membranes, and also druginduced changes in electrolyte metabolism or other physiological variables that modify the action of another drug.
BIOAVAILABILITY Variable plasma concentrations following oral intake of many drugs have been reported in man. Standard diet is known to decrease the gastric emptying rate and, consequently, has led to-lower drug absorption. 6 The major factor involved in this variability is absorption from the gastrointestinal tract. These aspects have been especially studied in patients with hematological malignancies treated orally or intravenously with melphalan and chlorambucil, v-w In fact it was shown that the plasma peak level of the chemotherapeutics was achieved after 102 rain in non-fasting patients compared to 44 min under fasting conditions, s It was also demonstrated that the bioavailability of both melphalan and chlorambucil can be significantly reduced under non-fasting conditions. A recent study on an in situ rat intestinal model showed that competitive inhibition of drug absorption by amino acids may be one of the mechanisms involved in the observed reduction in melphalan bioavailability (but not for chlorambucil) under non-fasting conditions. 8 Thus, it seems that the mechanisms by which food affects the bioavailability of chlorambucil and melphalan differ. Furthermore, blood levels of 6mercaptopurine given orally after a standard breakfast were lower than required for therapeutic effects. ~ Dietary manipulation with elemental diet (containing crystalline amino acids and dextrose) seemed to alter methotrexate pharmacokinetics in rats. Increased levels of methotrexate in serum and small intestine were reported to increase gastrointestinal toxicity and mortality.12 An increased intestinal drug exposure, due to a prolonged enterohepatic drug circulation, seems also to be of importance for the toxicity. Cholestyramine, however, improved this survival and decreased the gastrointestinal toxicity. ~3 The mechanisms underlying this protection seem to include binding methotrexate in bile and reducing the delay in systemic clearance of the drug, and a local protective effect due to binding intraluminal bile acids to cholestyramine. In addition, it is now also accepted that estramustinephosphate should not be given in close connection to ingestion of calcium containing foods, e.g. milk, or antacids, due to interaction and reduced uptake of the drug. ~4 In comparison with water it was shown that the AUC-value for estramustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding values for the peak values were 32 and 57%, respectively. Other possible effects than drug binding to dietary constituents can also be of importance for the bioavailability of drugs. Indeed, a decreased gastric emptying rate and subsequent
Diet and cancer treatment
increased time for hydrolytic activity is plausible as a cause of a rapid breakdown of chlorambucil. ~5 In view of these and other observations, it is suggested that at least some orally administered chemotherapeutics should be given before food if maximum blood levels are to be achieved. However, as some chemotherapeutics can be local irritants to the mucosal tissue, the possibility of protective influence of food also has to be considered.
ENERGY INTAKE Higher body weight seems to be associated with an increased relative risk of cancer incidence.16 The pharmacokinetics of chemotherapeutics as cyclophosphamide has been shown to be related to the body weight. ~7 A significant positive correlation was observed between body weight and plasma elimination half-life, and a significant negative correlation between body weight and cyclophosphamide clearance. Cachexia, i.e. weight-loss and impaired nutritional intake, has been proposed to be an important prognostic factor of decreased survival in patients with established cancer. However, the impact of nutritional intervention on the improvement of clinical outcome in cancer treatment is not clearly evaluated. The role of nutritional support, in particular total parenteral nutrition (TPN), in cancer therapy has been critically discussed. 5 In most trials no significant improvement in either response or survival was seen with addition of TPN to chemotherapeutic treatment of different forms of adult cancer. However, two randomized studies suggested that energy support using TPN, where effective cancer therapy is lacking, might stimulate tumor growth. This has also found support in some animal studies in which stimulation of tumor growth by nutritional repletion of protein-depleted animals was seen. 5 It must be observed that, as discussed above, not only manipulation of the total nutritional energy ingestion is of importance, but also the composition of the diet. Although, cancer patients often display an abnormal glucose metabolism, 5 manipulation of the glucose utilization in man by using hydrazin or insulin has not yet been found to influence tumor growth or prognosis. The clinical significance of all these observations dedicated to optimize cancer treatment by manipulating energy intake certainly require further studies.
METALS The importance of iron on the effects of doxorubicin are well documented; for details see Myers, ~s
81
and Grankvist and Henriksson. I'j ICRF-187 (now A D R 529), converted in vivo to an effective ironand copper-chelating agent, blocked the cardiac toxicity of doxorubicin in beagles 2~ and daunorubicin in rabbits. 2~ The toxicity on murine fibroblasts in a clonogenic survival assay of both epirubicin and doxorubicin was significantly inhibited by the clinically used iron chelator, desferrioxamine. 22 In contrast, desferrioxamine was without effect on hydroxyurea cytotoxicity on murine leukemia cells, sarcoma cells, and Ehrlich ascites tumors. 23 It is plausible to suggest that the mechanisms, by which iron interferes with the effects of drugs, involve different stages in the generation of free oxygen radicals, The importance of iron for the effects of different drugs such as Neomycin, anthracyclines, estramustine and mitoxantrone has also been documented, ts'1~'24 The fact that iron is of importance for cell growth, 25 differentiation, and functional development :6"27 must also be emphasized when discussing the mechanisms underlying the effects of iron. Cells deprived of iron will stop dividing, depending partly on an impaired function of the ribonucleotide reductase and a concomitant suppression of synthesis of 2'-deoxy-nucleoside-5triphosphatase necessary for D N A synthesis. 2s Together, these results imply that further experimental and clinical studies are needed to evaluate the role of iron, and elucidate if iron chelators can prevent toxicity to normal tissue of, especially, anthracyclines without altering antitumor activity. Recently published observations clearly indicate that the chelator ICRF-187 ( A D R 529) can be of clinical value in protection of doxorubicin-induced cardiotoxicity, without affecting its antitumor activity, 29 and lately randomized trials have begun on breast cancer and lymphoma. Metals other than iron (Cu 2+, Au 3+) also seem to be of direct importance for cell proliferation. 3~ Zinc is an essential component of numerous enzymes involved in lipid, glucose, protein, and nucleic acid metabolism. Both zinc deficiency and high levels of dietary zinc were reported to reduce tumor growth. 3~ In a model, using Ehrlich ascites tumor cells in mice, zinc gave protection against doxorubicin toxicity, and also increased the antitumor activity of anthracyclines. 32
VITAMINS AND SELENIUM The importance of selenium and vitamin E in the process of carcinogenesis has recently drawn considerable interest. Few studies have, however, investigated their possible role in the toxicity and antitumor effects during cancer therapy. Pretreat-
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ment of rabbits with selenium displayed abrogation of doxorubicin-induced cardiotoxicity. 33 These authors also reported that selenium had no effect on leukemia cells in vitro. Vitamin E and manganese also prevented cardiac toxicity caused by doxorubicin. Mice deficient in manganese and/or vitamin E displayed higher lipid peroxidation and decreased superoxide dismutase activity in cardiac tissue, which could explain the increased anthracycline toxicity in this model. 34 Amelioration of doxorubicin-induced cardiotoxicity in rabbits has been observed following combinations of vitamin A (a singlet oxygen quencher), vitamin E (a free radical scavenger) and the calcium modifier prenylamine. 35 Enhancement of the antitumor effects of BCNU and cyclophosphamide by vitamin A has been shown in murine leukemia. 36 In a preliminary study it has also been shown that vitamin A (150IU g-L diet) and arginine had an additive antitumor effect as the combination decreased tumor burden, and lowered the frequency of metastases in mouse Lewis lung tumors. 37 A combination of a synthetic retinoid (N-(4-hydroxyphenyl)retinamide) given orally in dosages of 400 mg kg-1 diet and tamoxifen administered subcutaneously, was suggested to be of value in reducing tumorrelated mortality in female Spraque-Dawley rats with mammary carcinoma. 38 Some clinical observations also support a beneficial role for vitamin A in cancer treatment. Daily doses of 350,000-500,000 IU of vitamin A seemed to enhance treatment effects of different chemotherapeutics in a randomized study (with regard to vitamin A) on metastatic breast cancer in post-menopausal women, y) Vitamin K (K-3 menadione) on its own had antineoplastic effect and potentiated the antineoplastic effects of traditional antineoplastic drugs in different experimental situations and in humans. 4~-42 It has to be emphasized that the dosages used (20300 mg day - l ) were without significant toxicity in man. A synergy was demonstrated with vitamin K3 (intraperitoneally) and methotrexate in rats bearing carcinosarcoma in the thigh without increase in toxicity. 4t It is not known what levels of vitamin K3 are necessary for synergistic effect in man. Preliminary data point out that plasma levels causing in vitro cytotoxicity and synergy are achieved after a single dose of menadiol sodium diphosphate (converted to menadione) of 20 gg M-2. 41 In another somewhat controversial study, methylcobolamine ('vitamin B12') increased the influx of methotrexate into mammary adenocarcinoma cells and the small intestine in mice. 43 Further analysis revealed that the optimal dose to methylcobolamine for improved antitumor drug action was 0.01
mg kg-1 body weight. Recently, it has been demonstrated that proliferation of human malignant tumors in nude mice is retarded in situations of reduced availability of vitamin B6. 44 It was suggested that not only the amount of vitamin B6 in diet, but also the contribution of the intestinal flora has to be considered. Water-soluble vitamins have on the whole received less attention. With regard to vitamin C, conflicting reports have appeared, some showing enhanced activity of some chemotherapeutic agents and others indicating antagonistic activity of vitamin C. 35"45'46 Ascorbic acid has been shown to enhance the effects of misonidazole on hypoxic cells in vitro. It has been suggested that L-ascorbic acid has an antiproliferative effect on its own as it inhibits growth of neuroblastoma and human endometrial carcinoma cells in culture at concentrations of 100 ~tM 1-1. This effect was greatly potentiated by copper chelates. 47 Combined pretreatment of ascitic tumor-bearing mice with ascorbic acid and vitamin K considerably increased the antitumoral efficacy of six different cytotoxic drugs, whereas general and organ toxicity that accompanied the different drugs were unaffected. 4s It was suggested that induction of peroxide production might be involved in this selective potentiation. There are results, however, indicating that the potentiating effect of vitamin C with some antitumoral drugs is not prevented by the addition of catalase, suggesting that HzO2 released is not the exclusive mediator of the effects. 17 In contrast to these results, ascorbic acid did not affect doxorubicin toxicity in human ovarian cancer cells, a9 It has to be emphasized that in most studies, vitamins have been administered as supplements. Whether similar effects can be obtained in "normal' (non-pharmacological) dietary intake remains to be seen. LIPIDS Polyunsaturated fatty acids ( P U F A ) have attracted a great deal of interest with regard to prevention of cardiovascular diseases. Recently it was shown that a variety of malignant cells were killed following exposure to different P U F A , whereas normal cells were not. 5~ Gamma-lineolenate and arachidonate were especially toxic to human breast cancer cells. It was demonstrated that the antitumor effects were dependent on the ability of the fatty acids to stimulate the production of superoxide radicals. Iron and copper augmented this cytotoxicity, whereas vitamin E inhibited the effect. These studies suggest that the fat content of the diet may possibly be of importance in the management of cancer. Interestingly. another study demonstrated
Diet and cancer treatment
that a variety of organic anions such as bile salts and folic acid inhibited intestinal absorption of methotrexate. 5~ Thus, manipulation of bile salts by different types of fat containing foods, as well as drug intake, e.g. cholestyramine and sucralfate, 52 may modify methotrexate absorption and subsequent toxicity.
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warranted. Sodium chloride showed protection against nephrotoxicity caused by cisplatin in rats. 65 Ethanol enhanced the antitumor effects of bleomycin and hyperthermia in an animal model, 66 and enhanced hepatoxicity was demonstrated when methotrexate was concomitantly administered with ethylalcohol in patients with psoriasis. 67
CAFFEINE
CONCLUDING REMARKS
Caffeine (coffeine), a methylxanthine, might have an antineoplastic effect as it inhibits mitoses, influences cell differentiation in man, and slows tumor growth in experimental systems. 53"54 Caffeine alone, or in combination with chlorpromazine has been shown to enhance the cytotoxicity of alkylating agents in various rodent transplantation tumor systems, 55 and in a human melanoma xenograft. 56 The antitumor activity of phleomycins and bleomycins on carcinosarcoma and Ehrlich ascites tumor cells in rats and mice was enhanced by caffeine given at dosages of 847 mg kg -~ body weight. Caffeine alone had no effect. 57 Caffeine also increased cytotoxicity of chlorambucil in vitro, probably through increased metabolic activation.SS Furthermore, caffeine has also been shown to increase cytotoxicity of cisplatinum, 59 mitomycin, 6~ bifunctional alkylating agents 61 and cyclophosphamide. 62 Finally, a randomized clinical trial compared the effect of semustine alone or in combination with chlorpromazine and caffeine on patients with disseminated malignant melanoma. No difference was detected between the two treatments with respect to tumor response or toxicity. 63 Similar disappointing results were obtained in a clinical trial comparing the combination of caffeine, chloroquine (also suggested to inhibit DNA repair), cyclophosphamide and prednisone in melphalan-resistant multiple myeloma patients. ~4 The negative clinical efforts do not necessarily mean that this approach should be abandoned; responses to caffeine are variable depending on the experimental system used, and the metabolism of caffeine differs between animals and man; caffeine is rapidly eliminated in some animal species, including man and has minimal tendency to penetrate tissue; these factors must be considered as possible reasons for failure in v i v o . 5~ Further studies are warranted to evaluate the possible significance of caffeine in cancer therapy.
Antineoplastic drugs are generally delivered at dosages close to toxic levels. Whether the alteration in drug bioavailability can be of clinical significance depends on the type of drug and the extent of the change. It would be less important for a drug which is effective over a wide concentration range, but may be hazardous for a drug with a low therapeutic ratio or with a steep dose-response curve, for drugs which have well-defined blood or tissue levels for optimal therapeutic efficacy, agents with deleterious doserelated side effects or which are absorbed by saturable site-specific processes. The effects of drugs with short biological half lives may also be affected significantly by food. 4 Thus, a slight increase of the biological activity caused by alteration in nutritional balance, and subsequent impairment of patient status, could be deleterious to the patient. Although conclusive information is lacking, it is, from the above, evident that a possibility exists that food and its constituents could be of considerable importance, not only for the well-being of the cancer patient, but also directly in the treatment of the actual malignancy. Increased life expectancy of the population raises the number of individuals likely to develop malignancy and receive cancer treatment. Physiologic and metabolic changes of aging have important implications for tolerance of antineoplastic treatment, and have recently been reviewed. 68 Age and the neoplastic process itself affect bioavailability of drugs (impaired patient status - - e.g. reduced hepatic and renal function). Several reports have shown that a large proportion of the elderly exhibit sub-clinical signs of malnutrition, including low levels of nutritional proteins, vitamins and trace elements. Factors that influence absorption, distribution, elimination or end effect of the drugs (e.g. hypoalbuminemia and urine pH), are largely dependent on nutritional balance, and, thus, on intake of an optimal diet. Consequently, in some instances, supplemental delivery of specific nutrients may be needed, e.g. patients with ileal resection require vitamin B12, whereas other vitamins, minerals or micronutrient supplements may be necessary in patients with or without intestinal resections.
MISCELLANEOUS Mention of the effects of several miscellaneous components of diet on cancer therapy is also
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Although, there is still limited evidence that nutritional factors per se have any effect on overall mortality, the clinician should at least be aware that optimal pharmacological treatment of cancer patients is not solely based on individualization of treatment depending on a particular tumor, but also on multidrug interaction, host pharmacokinetics, and the role of nutritional factors. Indeed, although interest in the clinical significance of optimal dietary intake or supplementation during cancer therapy has so far remained marginal, acctimtllating data indicate that this is one area deserving further research attention with a view to optimizing cancer treatment. Acknowledgements - - The present work was supported by
grants from the Swedish Association Against Cancer, the Children Cancer Foundation, and the Lions Cancer Research Foundation, Umefi, Sweden.
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cells treated with bifunctional alkylating agents. Nature 285, 326 (1980). 62. Walker ! G, Reid B D: Caffeine potentiation of the lethal action of alkylating agents on L-cells. Mutat Res 12, 101 (1971). 63. Cohen M H, Schoenfeld D, Wolter J: Randomized trial of chlorpromazine, caffeine, and methyl-CCNU in disseminated melanoma. Cancer Treat Rep 64, 151 (1980). 64. Kyle R A, Seligman B R, Wallace H J Jr, et al.: Multiple myeloma resistant to melphalan (NSC-8806) treated with cyclophosphamide (NSC-26271), prednisone (NSC-10023), and chloroquine (NSC-187208). Cancer Chemother Rep 59, 557 (1975).
65. Daley-Yates P T, McBrien D C H: A study of the protective effect of chloride salts on cisplatin nephrotoxicity. Biochem Pharmac 34, 2363 (1985). 66. Takiyama W, Hirai T, Miyoshi Y, Yoshihara T, Hattori T: Enhanced antitumor effects~of bleomycin and moderate hyperthermia by additional use of ethanol. Jap J Surgery 14, 262. 67. Tobias H, Auerbach R: Hepatotoxicity of a long-term methotrexate therapy for psoriasis. Arch Intern Med 132, 391 (1973). 68. Balducci L, Philips M, Wallace C, Hardy C: Cancer chemotherapy in the elderly. Am Family Phys 35, 133 (1987).
0736-0118/91 $3.00 + .00 Pergamon Press plc
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INTERACTION
BETWEEN
CYTOSTATICS
AND NUTRIENTS
R O G E R H E N R I K S S O N , K H A M A O. R O G O and K J E L L G R A N K V I S T Departments of Oncology and Clinical Chemistry, University Hospital, S-901 85 Ume~, Sweden (First received 19 December 1990; accepted in revised form 23 January 1991) Cancer patients have the highest prevalence of malnutrition of any group of hospitalized patients. The presence of the tumor alone may lead to reduced intake of different nutrients and treatment modalities such as surgery, chemotherapy and radiation therapy may further exacerbate nutritional disturbances. Dietary manipulation in experimental systems has shown improvement of tumor response to cancer therapy. Drug pharmacokinetics has been shown to be altered by changes in nutritional delivery. This article reviews the present knowledge, from experimental and clinical standpoints, of the potential role of different nutritional factors on the specific cancer treatment. It is obvious that alteration of at least some dietary factors affect the outcome of different forms of cancer treatment. Indeed, although interest in the clinical significance of optimal dietary intake and supplementation during cancer therapy so far remain marginal, accumulating data indicate that this area deserves further research attention.
Key words: Nutrition, Diet, Cancer treatment, Resistance.
tumor growth, considerably less interest has been devoted to the effects of exogenous factors on the outcome of cancer treatment. The interactions between cytotoxic anticancer drugs and other pharmaceuticals have recently been reviewed. 3 In general the effects of food on drug bioavailability have received scant attention. The therapeutic efficacy of drugs due to food, the frequency of food related changes, and the magnitude of some of the effects, suggest that observed alterations in drug activity would have clinical consequences particularly with drugs that have narrow therapeutic indices, a steep dose-response curve, or established therapeutic or toxic levels in the body. 4 Although, the alteration in nutritional status seems to be an
INTRODUCTION The last few years have seen an increasing awareness of the association between nutrition and cancer. Malnutrition of different kinds is thought to comprise 20-50% of hospitalized patients, and a significant portion of these are cancer patients. The importance of adequate dietary intake, and the need for additional dietary nutrients is now accepted in the total m a n a g e m e n t of these patients. A great deal of interest has also come from the field of cancer prevention. Epidemiologic studies have suggested that neoplastic occurrence is associated with nutrition, e.g. diets high in total fat and low in certain fibers are associated with an increase in large bowel cancer. The presence of disease may interfere with absorption, increase the utilization, or accelerate the loss of essential nutrients. These nutritional defects sooner or later reduce the physiologic reserve, and eventually may make patients more susceptible to complications of anticancer therapy (Table 1). Interactions between different cancer chemotherapeutics, ~ and between radiation and chemotherapeutics are rather well studied. 2 Although the problems of drug resistance have drawn attention to the effects of other drugs on
Table 1. Causes of nutritional disturbances in cancer patients Psychogenic Cancer as chronic disease I a t r o g e n i c - Chemotherapy Surgery Radiation Immunotherapy Altered taste Food aversion Other drugs used Pain
Address for correspondence: Dr Roger Henriksson, Department of Oncology, University Hospital, S-901 85 UMEA,, Sweden. 79
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R. Henriksson et al.
important independent prognostic factor in cancer patients, the possibility of nutritional intervention (e.g. total parenteral nutrition) to favorably influence outcome in cancer treatment is less evaluated, s A shallow interest has been shown in the possible influence of different nutritional factors per se on the direct outcome of cancer treatment. Therefore, we have summarized the present state of knowledge and views, both from experimental and clinical standpoints, on the influence of diet and its components on cytostatic treatment and the effects of this influence on tumor growth and drug toxicity.
BASIC CONCEPTS A better understanding of the complexity of interactions can be achieved by first defining factors that are of importance for the efficacy and toxicity of different substances. Interactions may arise either from alteration of absorption, distribution, biotransformation, or excretion of one drug by the other, or from combinations of their actions or effects. Physicochemical interactions or incompatibilities may occur in the solution prior to administration, and can be divided into three groups; solubility phenomena, cationic-anionic incompatibilities, and acid-base or pH-effects. This type of interaction, not being biological, will not be discussed further. Pharmacokinetic interaction includes changes in absorption, distribution, or elimination of a drug. Several mechanisms are involved, e.g. gastric pH, gastrointestinal motility, competition for plasma protein or tissue binding, inhibition of biotransformation, induction of liver enzyme systems, and competition for renal secretion. Decreased absorption of drugs may also result from prior interaction in the gastrointestinal tract. Food has been shown to have varying effects, especially on drug absorption, and changes seen are not solely predictable from a mechanistic viewpoint. While drug-food interactions give rise to a variety of effects the most common interactions seen are either reduced or delayed drug levels in blood, a It also has to be emphasized that food can interact with processes other than absorption. Its effects on drug metabolism, the various effects on enzyme systems, and changes in regional blood flow, point out that the final drug action may also be influenced by alterations in distribution and eliminations.4 Pharmacodynamic interaction relates to the end effects of drugs. It includes drug interactions at receptor sites and cell membranes, and also druginduced changes in electrolyte metabolism or other physiological variables that modify the action of another drug.
BIOAVAILABILITY Variable plasma concentrations following oral intake of many drugs have been reported in man. Standard diet is known to decrease the gastric emptying rate and, consequently, has led to-lower drug absorption. 6 The major factor involved in this variability is absorption from the gastrointestinal tract. These aspects have been especially studied in patients with hematological malignancies treated orally or intravenously with melphalan and chlorambucil, v-w In fact it was shown that the plasma peak level of the chemotherapeutics was achieved after 102 rain in non-fasting patients compared to 44 min under fasting conditions, s It was also demonstrated that the bioavailability of both melphalan and chlorambucil can be significantly reduced under non-fasting conditions. A recent study on an in situ rat intestinal model showed that competitive inhibition of drug absorption by amino acids may be one of the mechanisms involved in the observed reduction in melphalan bioavailability (but not for chlorambucil) under non-fasting conditions. 8 Thus, it seems that the mechanisms by which food affects the bioavailability of chlorambucil and melphalan differ. Furthermore, blood levels of 6mercaptopurine given orally after a standard breakfast were lower than required for therapeutic effects. ~ Dietary manipulation with elemental diet (containing crystalline amino acids and dextrose) seemed to alter methotrexate pharmacokinetics in rats. Increased levels of methotrexate in serum and small intestine were reported to increase gastrointestinal toxicity and mortality.12 An increased intestinal drug exposure, due to a prolonged enterohepatic drug circulation, seems also to be of importance for the toxicity. Cholestyramine, however, improved this survival and decreased the gastrointestinal toxicity. ~3 The mechanisms underlying this protection seem to include binding methotrexate in bile and reducing the delay in systemic clearance of the drug, and a local protective effect due to binding intraluminal bile acids to cholestyramine. In addition, it is now also accepted that estramustinephosphate should not be given in close connection to ingestion of calcium containing foods, e.g. milk, or antacids, due to interaction and reduced uptake of the drug. ~4 In comparison with water it was shown that the AUC-value for estramustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding values for the peak values were 32 and 57%, respectively. Other possible effects than drug binding to dietary constituents can also be of importance for the bioavailability of drugs. Indeed, a decreased gastric emptying rate and subsequent
Diet and cancer treatment
increased time for hydrolytic activity is plausible as a cause of a rapid breakdown of chlorambucil. ~5 In view of these and other observations, it is suggested that at least some orally administered chemotherapeutics should be given before food if maximum blood levels are to be achieved. However, as some chemotherapeutics can be local irritants to the mucosal tissue, the possibility of protective influence of food also has to be considered.
ENERGY INTAKE Higher body weight seems to be associated with an increased relative risk of cancer incidence.16 The pharmacokinetics of chemotherapeutics as cyclophosphamide has been shown to be related to the body weight. ~7 A significant positive correlation was observed between body weight and plasma elimination half-life, and a significant negative correlation between body weight and cyclophosphamide clearance. Cachexia, i.e. weight-loss and impaired nutritional intake, has been proposed to be an important prognostic factor of decreased survival in patients with established cancer. However, the impact of nutritional intervention on the improvement of clinical outcome in cancer treatment is not clearly evaluated. The role of nutritional support, in particular total parenteral nutrition (TPN), in cancer therapy has been critically discussed. 5 In most trials no significant improvement in either response or survival was seen with addition of TPN to chemotherapeutic treatment of different forms of adult cancer. However, two randomized studies suggested that energy support using TPN, where effective cancer therapy is lacking, might stimulate tumor growth. This has also found support in some animal studies in which stimulation of tumor growth by nutritional repletion of protein-depleted animals was seen. 5 It must be observed that, as discussed above, not only manipulation of the total nutritional energy ingestion is of importance, but also the composition of the diet. Although, cancer patients often display an abnormal glucose metabolism, 5 manipulation of the glucose utilization in man by using hydrazin or insulin has not yet been found to influence tumor growth or prognosis. The clinical significance of all these observations dedicated to optimize cancer treatment by manipulating energy intake certainly require further studies.
METALS The importance of iron on the effects of doxorubicin are well documented; for details see Myers, ~s
81
and Grankvist and Henriksson. I'j ICRF-187 (now A D R 529), converted in vivo to an effective ironand copper-chelating agent, blocked the cardiac toxicity of doxorubicin in beagles 2~ and daunorubicin in rabbits. 2~ The toxicity on murine fibroblasts in a clonogenic survival assay of both epirubicin and doxorubicin was significantly inhibited by the clinically used iron chelator, desferrioxamine. 22 In contrast, desferrioxamine was without effect on hydroxyurea cytotoxicity on murine leukemia cells, sarcoma cells, and Ehrlich ascites tumors. 23 It is plausible to suggest that the mechanisms, by which iron interferes with the effects of drugs, involve different stages in the generation of free oxygen radicals, The importance of iron for the effects of different drugs such as Neomycin, anthracyclines, estramustine and mitoxantrone has also been documented, ts'1~'24 The fact that iron is of importance for cell growth, 25 differentiation, and functional development :6"27 must also be emphasized when discussing the mechanisms underlying the effects of iron. Cells deprived of iron will stop dividing, depending partly on an impaired function of the ribonucleotide reductase and a concomitant suppression of synthesis of 2'-deoxy-nucleoside-5triphosphatase necessary for D N A synthesis. 2s Together, these results imply that further experimental and clinical studies are needed to evaluate the role of iron, and elucidate if iron chelators can prevent toxicity to normal tissue of, especially, anthracyclines without altering antitumor activity. Recently published observations clearly indicate that the chelator ICRF-187 ( A D R 529) can be of clinical value in protection of doxorubicin-induced cardiotoxicity, without affecting its antitumor activity, 29 and lately randomized trials have begun on breast cancer and lymphoma. Metals other than iron (Cu 2+, Au 3+) also seem to be of direct importance for cell proliferation. 3~ Zinc is an essential component of numerous enzymes involved in lipid, glucose, protein, and nucleic acid metabolism. Both zinc deficiency and high levels of dietary zinc were reported to reduce tumor growth. 3~ In a model, using Ehrlich ascites tumor cells in mice, zinc gave protection against doxorubicin toxicity, and also increased the antitumor activity of anthracyclines. 32
VITAMINS AND SELENIUM The importance of selenium and vitamin E in the process of carcinogenesis has recently drawn considerable interest. Few studies have, however, investigated their possible role in the toxicity and antitumor effects during cancer therapy. Pretreat-
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ment of rabbits with selenium displayed abrogation of doxorubicin-induced cardiotoxicity. 33 These authors also reported that selenium had no effect on leukemia cells in vitro. Vitamin E and manganese also prevented cardiac toxicity caused by doxorubicin. Mice deficient in manganese and/or vitamin E displayed higher lipid peroxidation and decreased superoxide dismutase activity in cardiac tissue, which could explain the increased anthracycline toxicity in this model. 34 Amelioration of doxorubicin-induced cardiotoxicity in rabbits has been observed following combinations of vitamin A (a singlet oxygen quencher), vitamin E (a free radical scavenger) and the calcium modifier prenylamine. 35 Enhancement of the antitumor effects of BCNU and cyclophosphamide by vitamin A has been shown in murine leukemia. 36 In a preliminary study it has also been shown that vitamin A (150IU g-L diet) and arginine had an additive antitumor effect as the combination decreased tumor burden, and lowered the frequency of metastases in mouse Lewis lung tumors. 37 A combination of a synthetic retinoid (N-(4-hydroxyphenyl)retinamide) given orally in dosages of 400 mg kg-1 diet and tamoxifen administered subcutaneously, was suggested to be of value in reducing tumorrelated mortality in female Spraque-Dawley rats with mammary carcinoma. 38 Some clinical observations also support a beneficial role for vitamin A in cancer treatment. Daily doses of 350,000-500,000 IU of vitamin A seemed to enhance treatment effects of different chemotherapeutics in a randomized study (with regard to vitamin A) on metastatic breast cancer in post-menopausal women, y) Vitamin K (K-3 menadione) on its own had antineoplastic effect and potentiated the antineoplastic effects of traditional antineoplastic drugs in different experimental situations and in humans. 4~-42 It has to be emphasized that the dosages used (20300 mg day - l ) were without significant toxicity in man. A synergy was demonstrated with vitamin K3 (intraperitoneally) and methotrexate in rats bearing carcinosarcoma in the thigh without increase in toxicity. 4t It is not known what levels of vitamin K3 are necessary for synergistic effect in man. Preliminary data point out that plasma levels causing in vitro cytotoxicity and synergy are achieved after a single dose of menadiol sodium diphosphate (converted to menadione) of 20 gg M-2. 41 In another somewhat controversial study, methylcobolamine ('vitamin B12') increased the influx of methotrexate into mammary adenocarcinoma cells and the small intestine in mice. 43 Further analysis revealed that the optimal dose to methylcobolamine for improved antitumor drug action was 0.01
mg kg-1 body weight. Recently, it has been demonstrated that proliferation of human malignant tumors in nude mice is retarded in situations of reduced availability of vitamin B6. 44 It was suggested that not only the amount of vitamin B6 in diet, but also the contribution of the intestinal flora has to be considered. Water-soluble vitamins have on the whole received less attention. With regard to vitamin C, conflicting reports have appeared, some showing enhanced activity of some chemotherapeutic agents and others indicating antagonistic activity of vitamin C. 35"45'46 Ascorbic acid has been shown to enhance the effects of misonidazole on hypoxic cells in vitro. It has been suggested that L-ascorbic acid has an antiproliferative effect on its own as it inhibits growth of neuroblastoma and human endometrial carcinoma cells in culture at concentrations of 100 ~tM 1-1. This effect was greatly potentiated by copper chelates. 47 Combined pretreatment of ascitic tumor-bearing mice with ascorbic acid and vitamin K considerably increased the antitumoral efficacy of six different cytotoxic drugs, whereas general and organ toxicity that accompanied the different drugs were unaffected. 4s It was suggested that induction of peroxide production might be involved in this selective potentiation. There are results, however, indicating that the potentiating effect of vitamin C with some antitumoral drugs is not prevented by the addition of catalase, suggesting that HzO2 released is not the exclusive mediator of the effects. 17 In contrast to these results, ascorbic acid did not affect doxorubicin toxicity in human ovarian cancer cells, a9 It has to be emphasized that in most studies, vitamins have been administered as supplements. Whether similar effects can be obtained in "normal' (non-pharmacological) dietary intake remains to be seen. LIPIDS Polyunsaturated fatty acids ( P U F A ) have attracted a great deal of interest with regard to prevention of cardiovascular diseases. Recently it was shown that a variety of malignant cells were killed following exposure to different P U F A , whereas normal cells were not. 5~ Gamma-lineolenate and arachidonate were especially toxic to human breast cancer cells. It was demonstrated that the antitumor effects were dependent on the ability of the fatty acids to stimulate the production of superoxide radicals. Iron and copper augmented this cytotoxicity, whereas vitamin E inhibited the effect. These studies suggest that the fat content of the diet may possibly be of importance in the management of cancer. Interestingly. another study demonstrated
Diet and cancer treatment
that a variety of organic anions such as bile salts and folic acid inhibited intestinal absorption of methotrexate. 5~ Thus, manipulation of bile salts by different types of fat containing foods, as well as drug intake, e.g. cholestyramine and sucralfate, 52 may modify methotrexate absorption and subsequent toxicity.
83
warranted. Sodium chloride showed protection against nephrotoxicity caused by cisplatin in rats. 65 Ethanol enhanced the antitumor effects of bleomycin and hyperthermia in an animal model, 66 and enhanced hepatoxicity was demonstrated when methotrexate was concomitantly administered with ethylalcohol in patients with psoriasis. 67
CAFFEINE
CONCLUDING REMARKS
Caffeine (coffeine), a methylxanthine, might have an antineoplastic effect as it inhibits mitoses, influences cell differentiation in man, and slows tumor growth in experimental systems. 53"54 Caffeine alone, or in combination with chlorpromazine has been shown to enhance the cytotoxicity of alkylating agents in various rodent transplantation tumor systems, 55 and in a human melanoma xenograft. 56 The antitumor activity of phleomycins and bleomycins on carcinosarcoma and Ehrlich ascites tumor cells in rats and mice was enhanced by caffeine given at dosages of 847 mg kg -~ body weight. Caffeine alone had no effect. 57 Caffeine also increased cytotoxicity of chlorambucil in vitro, probably through increased metabolic activation.SS Furthermore, caffeine has also been shown to increase cytotoxicity of cisplatinum, 59 mitomycin, 6~ bifunctional alkylating agents 61 and cyclophosphamide. 62 Finally, a randomized clinical trial compared the effect of semustine alone or in combination with chlorpromazine and caffeine on patients with disseminated malignant melanoma. No difference was detected between the two treatments with respect to tumor response or toxicity. 63 Similar disappointing results were obtained in a clinical trial comparing the combination of caffeine, chloroquine (also suggested to inhibit DNA repair), cyclophosphamide and prednisone in melphalan-resistant multiple myeloma patients. ~4 The negative clinical efforts do not necessarily mean that this approach should be abandoned; responses to caffeine are variable depending on the experimental system used, and the metabolism of caffeine differs between animals and man; caffeine is rapidly eliminated in some animal species, including man and has minimal tendency to penetrate tissue; these factors must be considered as possible reasons for failure in v i v o . 5~ Further studies are warranted to evaluate the possible significance of caffeine in cancer therapy.
Antineoplastic drugs are generally delivered at dosages close to toxic levels. Whether the alteration in drug bioavailability can be of clinical significance depends on the type of drug and the extent of the change. It would be less important for a drug which is effective over a wide concentration range, but may be hazardous for a drug with a low therapeutic ratio or with a steep dose-response curve, for drugs which have well-defined blood or tissue levels for optimal therapeutic efficacy, agents with deleterious doserelated side effects or which are absorbed by saturable site-specific processes. The effects of drugs with short biological half lives may also be affected significantly by food. 4 Thus, a slight increase of the biological activity caused by alteration in nutritional balance, and subsequent impairment of patient status, could be deleterious to the patient. Although conclusive information is lacking, it is, from the above, evident that a possibility exists that food and its constituents could be of considerable importance, not only for the well-being of the cancer patient, but also directly in the treatment of the actual malignancy. Increased life expectancy of the population raises the number of individuals likely to develop malignancy and receive cancer treatment. Physiologic and metabolic changes of aging have important implications for tolerance of antineoplastic treatment, and have recently been reviewed. 68 Age and the neoplastic process itself affect bioavailability of drugs (impaired patient status - - e.g. reduced hepatic and renal function). Several reports have shown that a large proportion of the elderly exhibit sub-clinical signs of malnutrition, including low levels of nutritional proteins, vitamins and trace elements. Factors that influence absorption, distribution, elimination or end effect of the drugs (e.g. hypoalbuminemia and urine pH), are largely dependent on nutritional balance, and, thus, on intake of an optimal diet. Consequently, in some instances, supplemental delivery of specific nutrients may be needed, e.g. patients with ileal resection require vitamin B12, whereas other vitamins, minerals or micronutrient supplements may be necessary in patients with or without intestinal resections.
MISCELLANEOUS Mention of the effects of several miscellaneous components of diet on cancer therapy is also
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Although, there is still limited evidence that nutritional factors per se have any effect on overall mortality, the clinician should at least be aware that optimal pharmacological treatment of cancer patients is not solely based on individualization of treatment depending on a particular tumor, but also on multidrug interaction, host pharmacokinetics, and the role of nutritional factors. Indeed, although interest in the clinical significance of optimal dietary intake or supplementation during cancer therapy has so far remained marginal, acctimtllating data indicate that this is one area deserving further research attention with a view to optimizing cancer treatment. Acknowledgements - - The present work was supported by
grants from the Swedish Association Against Cancer, the Children Cancer Foundation, and the Lions Cancer Research Foundation, Umefi, Sweden.
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