Nutritional Consequences of Cancer Chemotherapy and Immunotherapy1

(CANCER RESEARCH 37, 2395-2406, July 1977] Nutritional Consequences of Cancer Chemotherapy and Immunotherapy1

Takao Ohnuma2 and James F. Holland

Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, New York 10029

Summary its consequences. Otherwise the vicious cycle of cachexia produced by tumor and toxic agents will not end, even if the The nutritional consequences of major cancer chemo tumor is apparently regressing. It is important to weigh the therapeutic and immunotherapeutic agents are reviewed. In risks of treatment versus the possible benefits. Adverse addition, nutritional approaches to cancer treatment are nutritional consequences produced by treatment are 1 com discussed. Effects on host nutrition are related to two pni ponent of the equation. Many of the nutritional conse many drug functions, i.e., biochemical interaction with the quences of chemotherapy are explained as the result of target tissues and pharmacological action on the host. interference in necessary metabolic reactions (â€œbiochemi Treatments with these agents result in profound effects on cal nutritionâ€•) and pharmacological effects on the host the gastrointestinal, central nervous, cardiopulmonary, target tissue(s) (â€œpharmacologicalnutritionâ€•).For example, renal, musculoskeletal, hematopoietic, and constitutional the megaloblastic anemia produced by cytosine arabino systems of cancer patients who have already been nutrition side can be readily explained by its biochemical effects ally compromised. selectively on DNA synthesis of erythrocyte precursors. On Prevention and treatment of the nutritional consequences the other hand, the profound host effects of methotrexate in of chemotherapy and immunotherapy include specific patients with even mild renal impairment result from the treatment against particular agents and nonspecific symp drug's excretion from the host nearly exclusively by the tomatic or supportive therapy. A modern concept of panen renal route. teral nutrition combined with chemotherapy and immuno In this paper the nutritional impact of commonly used therapy is one example of a nonspecific approach with a chemotherapeutic and immunothenapeutic agents is re high promise for general use. viewed. In addition, the effects of several less commonly More importantly, increasing success in the long-term used compounds of particular interest are discussed (Ta control of leukemia, Hodgkin's disease, and certain other bles 1 and 2). Finally, the consequences of nutritional ap neoplasms has interrupted the vicious cycle promulgated proaches to the treatment of human cancer are summa on the host nutrition by neoplasia and toxic agents. New nized. No attempts have been made to detail the nutritional concepts of chemotherapy, e.g. , short intensive treatment consequences of combination chemotherapy on combined instead of prolonged treatment, and surgical adjuvant treat modalities of therapy, dietary manipulation, or hormonal ment instead of therapy of patients with advanced cancer, treatment. have minimized the nutritional consequences of chemo therapeutic and immunotherapeutic agents. ImpairedNutritiondue to DecreasedIntake p.o. and Tox icity in the Alimentary Canal Introduction Nausea and vomitingfollowingchemotherapyonimmu Cachexia and malnutrition are among the major causes notherapy with antineoplastic agents are mediated by the of morbidity in patients with advanced cancer. Anorexia, chemoreceptor trigger zone located in the area postrema of inanition, and progressive weight loss are commonplace. the 4th ventricle (10, 22). Nausea and vomiting are the Therapeutic approaches with chemotherapy, immuno most common immediate manifestations Of administration therapy, radiotherapy, surgery, and anesthesia unavoidably of many chemotherapeutic or immunotherapeutic agents. In affect host cells, often producing a variety of side effects, deed, this complication occurs with almost every major e.g. , nausea, vomiting, oral pain, diarrhea, fever and chills, class of compounds including a majority of alkylating and further decrease in appetite, physical activity, and body agents (e.g. , mechlorethamine and cyclophosphamide), the weight. These effects, together with biochemical and histo nitrosouneas, folate analogs, punine analogs, pynimidine an logical injuries to major organ systems, may leave the pa alogs, derivatives of tniazene and hydrazene, anthracycline tient with a profound nutritional insufficiency. Treatment is antibiotics (daunorubicin and adniamycin), and other anti therefore justified only when the patient can recover from biotics (e.g. , mitomycin C, bleomycin, actinomycin D, and mithramycin), enzymes (e.g., aspanaginase), the simple

I Presented at the Conference on Nutrition and Cancer Therapy, No molecule hydroxyurea and certain immunotherapeutic vember 29 to December 1, 1976, Key Biscayne, Fla. Supported in part by compounds [e. g., poly(IC),3 Corynebacterium parvum, and USPHS Grant 5 P01 CA15936-03 from the National Cancer Institute, Depart ment of Health, Education and Welfare. 3 The abbreviations used are: poly(lC), polyriboinosinic, polyribocytidylic 2 Presenter. acid; CNS, central nervous system; BCG, Bacillus Calmette-Gudrin.

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Table 1 Chemotherapeuticagents Recommended as 1st-line drugs for a variety of human neoplasms (137). Some other drugs have also been used as 1st-line drugs alone or in combination. Others are listed for their nutritional implications. Alkylating agents Mechlorethamine (nitrogen mustard, HN2) Cyclophosphamide L-Phenylalaninemustard (melphalan, Alkeran) Chlorambucil (Leukeran) Triethylene melamine Dibromomannitol

Alkyl sulfonate Busulfan (Myleran)

Nitrosoureas BCNUa CCNU MethyI@CCNUb Streptozotocin

Antimetabolites Folate analogs Methotrexate Dichloromethotrexate

Punine analogs Azaserinec 6-Mercaptopunine 6-Thioguanine

Pyrimidine analogs 5-Fluorouracil Cytosinearabinoside 5-azacytidine@

Derivatives of tn- Dimethyltriazenoimidazole carboxam azene and hydra- ide (DTIC, DIC) zine Procarbazine

Natural products Antibiotics Mitomycinb Bleomycin b Daunorubicin Adriamycin Actinomycin D Mithramycin'@ Vincaalkaloids Vincnistine Vinblastineb

Enzyme Asparaginaseb

Heavy metal Organic platinum cis-Diamminedichloroplatinum 1'

Hormone Corticosteroid

Miscellaneous Hydroxyureac Methylglyoxalbisguanylhydrazone 1,1-Dichloro-2-(o-chlorophenyl)-2-(p- chlorophenyl)ethane a The abbreviations used are: BCNU, 1 ,3-bis(2-chloroethyl)-1-nitrosourea; CCNU, 1-(2- chloroethyl)-3-cyclohexyl-1-nitrosourea;methyl-CCNU, 1-(2-chloroethyl)-3-methylcyclo hexyl-1 -nitrosourea.

â€˜IThe drug has been used as 1st-line drug alone or in combination.

C Listed for its nutritional implications. levamisole]. Violent and prolonged nausea and vomiting cation 1 on more days before the emetogenic drug is help may occur after administration of procarbazine (16, 46, 109, ful. 118, 120), streptozotocin (13, 112), cis-diamminedichloro Nausea, vomiting, and accompanying anorexia not only platinum (for review see Ref. 49), and 5-azacytidine (60, for result in decreased oral intake, but also produce fluid and review see Ref. 127), and may be dose limiting. Presently electrolyte imbalance, general weakness, and weight loss. available antiemetics are not wholly effective in the control cis-Diamminedichloroplatinum-induced anorexia may be of drug-induced vomiting. Initiation of phenothiazine med i cumulative, and some patients develop less and less appe

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Table 2 not, however, been systematically studied during chemo Immunotherapeutic agents used in therapy. Positive Shilling tests with and without intrinsic man factor compatible with malabsorption syndrome were noted BCG during the nadir of serum albumin and body weight in a Methanol extraction residueof BCG patient with acute myelocytic leukemia who was treated C, parvum with asparaginase (95). Levamisole tRNA Diarrhea. This is part of the general mucosaltoxicity Immune RNA produced by a number of chemotherapeutic agents. Diar Thymosin ne rhea is particularly severe after actinomycin D, 5-fluoroura Antiviral agent used in man with neo cii, and methylglyoxal bisguanylhydnazone. Abdominal pain plastic disease may accompany it. Diarrhea is also commonly seen after Poly(lC) methotrexate, hydroxyunea, nitrosouneas, and 5-azacytidine and less frequently after 6-mencaptopunine, cyclophospha mide, procanbazine, and levamisole. In severe cases, procti tite while they are responding to the treatment (52, 53). tis, mucosal ulceration, bleeding, and perforation accom There are only a few cancer chemotherapeutic agents pany diarrhea. Diarrhea alternates with constipation after which are not associated with nausea and vomiting. These vincnistine treatment. Prolonged uncontrolled diarrhea re are certain alkylating agents (e.g. , L-phenylalanine mustard, suits in dehydration, electrolyte imbalance, inanition, and chlorambucil, busulfan, dibromomannitol), vincnistine, and accelerated malnutrition. Hospitalization may be indicated, steroids. and adequate supportive cane is essential. Stomatitis, in the form of oral ulceration, cheilosis, glos Additional effects of chemothenapeutic compounds on sitis and pharyngitis, and other mucosal toxicities of the the alimentary canal include jaw pain seen after vincnistine alimentary canal are common with many of the chemothera (57) and peptic ulcer in patients receiving corticosteroid peutic agents. The alimentary canal is one of the most hormones (Table 3). vulnerable targets of chemotherapeutic agents. This is probably due to a rapid turnover of the epithelial cells of the mucosa. Rapid cell division at the depths of mucosal crypts Nutritional Consequences due to Dysfunction of Specific produces cells that are pushed in migration up the crypt Major Organ Systems Produced by Chemotherapeutic wall. The squamous mucosa of the oral, pharyngeal, and and ImmunotherapeuticAgents esophageal surfaces also displays more rapid turnover than skin. Tumors of the alimentary canal usually do not grow as The HematopoieticSystem.This is anotherof the most rapidly as do the adjacent normal mucosa (see Ref. 78). vulnerable targets of cancer chemothenapeutic agents. He Certain phases of the cell cycle are more sensitive to matological toxicities, especially leukopenia and thrombo cytotoxic effects of cancer chemotherapeutic compounds, cytopenia, are dose limiting in a majority of cancer chemo and even â€œcyclenonspecificâ€•drugs have greater effects on therapeutic compounds. This is true for all agents except cells which periodically expose to injury their most vulnera adrenocortical steroids and most imm unothenapeutic ble cell phase. Dose-limiting oral mucosal toxicities occur agents. Certain drugs active against hematological neo after actinomycin D (61, 116, 123), methotrexate (see be plasms exploit this principle. Although vincnistine, bleomy low), and methylglyoxal bisguanylhydrazone (105). Oral cm, and asparaginase are relatively free from hematological mucosal toxicity is unpredictable in patients receiving high toxicity, they induce hematopoietic depression in a few dose methotrexate and leucovonin rescue (33). Severe esophagitis may occur after methylglyoxal bisguanylhydra Table 3 zone. Severe oral toxicity has also been observed after Nutritional consequences of long-term administration of adrenal azasenine, daunorubicin, adniamycin, and 5-fluorouracil. steroid During infusion treatment with 5-fluorouracil, hematologi Modified from Ref. 67. cal toxicity is less and oral toxicity may become the dose limiting complication (114). Mucosal ulcerations are rare Cushingoid appearance Gastrointestinal with alkylating agents but may be seen with phenylalanine Peptic ulceration Endocrine abnormalities Acute pancreatitis mustard and cyclophosphamide (91). Polyphagia These toxicities are accompanied by inability to continue Hyperglycemiaand glycosunia Immunological adequate intake p.o. and result in dehydration and further Obesity Infectious complications deterioration of the nutritional status of the patient. Bacterial,fungal, and tu Fluid and electrolyte disturbances berculous infection Constipationand AdynamicIleus. Theseare the major Edema toxicities of vincnistine. In 1 broad study troublesome con Hypokalemic alkalosis Psychological stipation was reported in one-third of the patients with a Euphoria greaten frequency, severity, and earlier onset at a higher Musculoskeletal Insomnia dose (57). Muscleatrophy and myopathy Psychosis Osteoporosis and vertebral MalabsorptionSyndrome. It is likelythat the profound compression fractures Dermal effects of the chemotherapeutic agents on the intestinal Atrophy(striae) mucosa and/on major secreting organs result in the devel Circulatory Acne opment of malabsorption syndrome. These effects have Hypertension Hirsutism

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1977 American Association for Cancer Research. T. Ohnuma and J. F. Holland patients (57, 93, 97). Profound leukopenia is often accom complications include lassitude, apathy, and confusion fol panied by infection. Fever, chills, anorexia, and increased lowing azasenine (37), cenebellan dysfunction from 5-fluo energy consumption accelerate the deterioration of the nu nouracil (58, 86, 104), and headache after iv. levamisole and tnitional status of the patient. C. parvum (see Ref. 92). Levamisole also produces insom Anemia, a nutritionally important consequence, is fre nia, nervousness, irritability, euphonic sensory stimulation, quently seen after administration of chemothenapeutic and mone severe psychiatric reactions (92). These compli agents. Megaloblastic anemia is a predictable toxic effect of cations may also have important nutritional consequences. chemothenapeutic agents that interfere with DNA synthesis. Narcotics given to patients with cancer most frequently This complication has been reported with folate analogs affect the CNS and compromise nutrition. Somnolence (128), 6-mercaptopunine, 5-fluonounacil (12), cytosine anabi from drug effects leads to missed nourishment. Constipa noside (122), cyclophosphamide (6), and hydnoxyunea (18). tion from intestinal side effects of narcotics may also dim in Anemia induced by other agents has been less clearly ish appetite. defined. Anthracycline antibiotics produce anemia (7) and The AlimentarySystem.The liver,whichplaysa critical probably normochromic and normocytic anemia (126). Acti role in overall nutrition, is often influenced by chemothena nomycin D, another agent that binds with DNA, also pro peutic on immunotherapeutic agents, leading to serious duces anemia as part of general marrow depression (see nutritional problems. Anorexia is particularly common after Ref. 79). The same appears to be true for high dose cis hepatic injury. Diffuse hepatocellulan damage leads to hy diamminedichloroplatinum administration (60 mg/sq m poalbuminemia, a classic form of malnutrition. Liven dam twice weekly) (D. J. Higby, personal communication). Some age is commonly seen after administration of aspanaginase insignificant anemia was also seen after nitnosouneas (87) (see below). Glutamine antagonists such as azasenine and and dimethyltniazenoimidazole carboxamide (82). The gen duazomycin also cause hepatic impairment (see below). enal mechanism of drug-induced megaloblastic anemia is Jaundice occurred in about one-third of the patients who pnesumed to be the same as the one that results in megalo took 6-mencaptopunine in reported series (34, 37). Histologi blÃ¡stosis in vitamin B,2 and folate deficiencies, i.e. , DNA cally, bile stasis and hepatic necrosis have been reported. synthesis is retarded in growing cells, whereas the synthe Hepatic dysfunction is also common after methotrexate (see sis of cytoplasmic constituents is affected to a lessendegree below), nitnosouneacompounds(13, 112), mithnamycin (14), or not at all (136). However, the â€œbiochemicalanemiaâ€• and 5-azacytidine (4, 127). Several cases of hepatic fibrosis produced by drugs may be different from the anemia that and cirrhosis have been reported in leukemic children and results from pure nutritional deficiency. The clinical charac in patients with psoniasis after long-term administration of tenistics of anemia produced by biochemical interference at methotrexate (107). In contrast, intensive courses given to different stages of maturity from stem cell to enythrocyte women with trophoblastic neoplasia and in whom remission have not been well defined. This is in part related to the lasted more than 10 years were not followed by late compli clinical material; i.e. , most patients with advanced cancer cations (67). Thus, the exact role of the compounds in the and leukemia already have preexisiting anemias of various development of this condition has not been completely kinds (see Ref. 72), and many have received frequent tnans defined. Dose, schedule, and chronicity may all be critical. fusions of blood components. Abnormalities in hepatic function tests occur in a small The dose-limiting toxicity of mithnamycin is a hemon number of patients treated with cytosine arabinoside; how rhagic diathesis produced by alterations of the vascular even, evidence of definite hepatic toxicity related to this bed, platelets, coagulation factors, and fibninolytic activity compound is not well established (Ref. 35; for review see (88). Ref. 71). Cyclophosphamide, chlonambucil, and dimethyl CNS. Thisis influencedbya varietyof chemothenapeutic tniazenoimidazole canboxamide rarely cause hepatic dys agents (133). Especially noteworthy are intnathecal metho function. tnexate, which can cause meningeal irritation, panapanesis, BCG-induced hepatic dysfunction ranges from mild ele and encephalopathy (68, 85, 115); procanbazine, which can vation of alkaline phosphatase and aspartate aminotrans induce somnolence, confusion, cerebral ataxia, psychosis, ferase to clinical jaundice and hepatomegaly (3). Granu and coma (16, 109, 118, 120); vincnistine, which at higher lomatous hepatitis was documented by liver biopsy in all 3 doses can produce weakness, insomnia, confusion, psy jaundiced patients treated by intratumoral injection of BCG chosis, disorientation, and hallucination (57, 110); aspara in Sparks' series (117). BCG administered via the aerosol ginase, which can produce unpredictable lethargy, depres route appears to avoid hepatic toxicity (45). sion, disorientation, confusion, and hallucination (20, 50, Pancreatic dysfunction is produced by aspanaginase (see 93-95, 135); 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloro below). Streptozotocin affects islet cells, resulting in hyper phenyl)ethane, which can produce somnolence and leth glycemia and abnormal glucose tolerance tests. Insulin was argy (62, 81); cycloleucine, which can produce dizziness, required in none (108). Severe hypoglycemia and coma lethargy, hallucination, ataxia, and convulsion (see below); were produced by methylglyoxal bisguanylhydnazone (105). and corticosteroids, which can produce psychosis (Table Exocnine pancreatic function has not been systematically 3). Administration of high doses of cis-diamminedichlono studied during cancer chemotherapy. platinum (60 mg/sq m twice weekly) can result in confusion, TheCardiovascularSystem.Cardiacdamageisa serious coma, increase in cenebrospinal fluid pressure, and death complication of anthracycline antibiotics which include (D. J. Higby, personal communication). CNS dysfunctions both daunonubicin and Adniamycin (see Refs. 7 and 32). often result in impaired oral intake. Other neurological Clinically, cardiac toxicity manifests as a fnank picture of

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congestive heart failure with water retention and electrolyte and persists for as long as 24 hr. Prunitus or a rash at the site imbalance. No specific antidote on preventive measures are of injection develops in most patients (3, 117). The metha available at present except limitation of the cumulative nol extraction residue of BCG (131, 132) produces fever, dose. malaise, and severe local pain at the site of intradermal Certain chemothenapeutic agents are local tissue irritants immunizations that ulcerate (see Ref. 132). poly(IC) (38, 74) and produce tissue necrosis when extravasated (e.g. , ymca is a double-stranded, helical synthetic RNA with a molecular alkaloids, most alkylating agents, actinomycin D, and an weight of the order of 1,000,000. There is evidence that the thracycline compounds). Other compounds are thnombo size distribution may be biologically important in terms of genic at the local venipunctune site (e.g., bleomycmn) (see both toxicity and activity (74). poly(lC) produces fever which Ref. 8). Repeated venipunctune results in inability to find appears by 6 to 8 hr and peaks at 24 to 36 hr. Indeed, fever suitable peripheral veins for panenteral fluid, electrolyte, appears to be a prerequisite for the production of interferon and nutritional support, thus exacerbating problems of nu (29, 38). C. parvum has been reported to exercise its immu tnition in the advanced stages of disease in patients who nostimulatony effects through the neticuloendothelial sys have had extensive chemotherapy., tem and B-cells, thus differing from BCG (48, 59, 99, 113). It The UrinarySystem.Renalcomplicationsleadto varying is of note that these chemotherapeutic and immunothera degrees of the unemic syndrome, with its attendant nutni peutic agents are all macromolecular, and, in certain in tional disorder. They are particularly apparent after admin stances, with the exception of poly(IC), contamination with istration of cis-diamminedichlonoplatinum , methotnexate extraneous pyrogens is possible. Fever has also been as (see below), and stneptozotocin . cis-Diamminedichlonopla sociated with the administration of cyclophosphamide, 6- tinum (see Ref. 49) produced dose-limiting renal complica mercaptopunine, and cytosine anabinoside. A â€œflu-likeâ€•syn tions. cis-Diamminedichlonoplatinum-induced nephnotoxic drome has been reported after dimethyltriazenoimidazole ity manifests clinically as a rise in blood urea nitrogen and carboxamide (66, 79) and BCG (117) with nausea, myalgia, creatinine and as decreased cneatinine clearance. Histolog and, occasionally, arthralgia lasting 8 to 9 weeks. ically, cis-diamminedichlonoplatinum appears to cause Electrolyte Imbalance. This condition, induced by cyclo renal tubular necrosis. Renal toxicity is similar to that seen phosphamide, includes hyponatremia, which has been re with other heavy metal poisoning and appears to be dose ganded as due to inappropriate antidiuretic hormone pro related, cumulative, and only partly reversible. Renal toxic duction . Mithramycin , diazo-oxo-nonleucine (89), metho ity of stneptozotocin manifests as pnoteinunia occurring 2 to trexate (90), and actinomycin D (21) are known to produce 3 weeks into the course of therapy. Decrease in creatinine hypocalcemia. Mithramycin is used to treat hypercalcemia clearance and increase in cneatinine on blood urea nitrogen (102). Renal impairment produced by other chemothena were observed (13, 112). Renal tubular acidosis and Fan peutic agents can also be associated with varying degrees coni's syndrome (aminoacidunia, renal glycosunia, and of electrolyteimbalance. renal hyperphosphatunia) have also developd in 15 to 20% Weight Loss. This is a compositephenomenonin pa of patients (13). Fatal renal toxicity was recorded in 5 of 46 tients who have decreased oral intake, poor intestinal absonp patients with islet cell carcinoma. Aminoacidunia also oc tion, diarrhea, fever, CNS dysfunction, myopathy, and other curs after cycloleucine (see below) (5). causes of negative nitrogen balance. Fluid overload in pa A slight rise in blood urea nitrogen commonly observed tients with hypoalbuminemia and hyponatnemia often after aspanaginase treatment represents pnenenalazotemia, masks important weight loss related to the treatment. Dis but in a few cases frank renal failure with marked oligunia tinct weight loss after treatment with asparaginase may has been described. This usually accompanies other severe reflect decreased protein biosynthesis (see below). toxic manifestations (50). Renal complications also occur The malnutrition effect of the antivitamins is implicit in after other nitnosoureas (30), mithnamycin (14), high-dose their mechanism of action and is very different from the cyclophosphamide (more than 50 mg/kg body weight) (28), malnutrition caused by corticosteroids onymca alkaloids. and after immunotherapy with C. parvum (92). A syndromeassociatedwithlate toxicityof busulfanhas The MusculoskeletalSystem. Musculoskeletalconse been described. It consists of hypenpigmentation, asthenia, quences of chemothenapeutic agents are exemplified by hypotension, nausea and vomiting, amenorrhea, and muscle atrophy, osteoporosis, and pathological fractures weight loss, sometimes associated with pulmonary fibrosis produced by corticostenoids (Table 3). Vincnistine can also (72, 91, 98). Although the clinical picture suggests adrenal cause muscle atrophy as a consequence of its neurotoxic insufficiency, this has not been documented. The patho ity. Methotrexate given over long periods of time can lead to genesis of the syndrome is not well understood, but it may osteoporosis and pathological fractures. be due to the prosthetic group of the bus@uIfanmolecule rather than to its aikylating properties (67). Pulmonary fibro sis produced by busulfan may be nodular on diffuse histo Nutritional Consequences due to Systemic Effects of logically (69) and can lead to fatal outcome (98). Chemotherapyand Immunotherapy One of the most serious systemic nutritional complica tions of chemotherapy and immunotherapy is graft-versus Fever and Chills. These are common and immediate side host disease in patientswith acute leukemiatreatedwith effects of treatment with bleomycin (see Ref. 8), asparagi bone marrow transplantation. In a recent review by Thomas nase (19, 50, 93, 94), BCG (117), i.v. poly(IC)(29), and i.v. C. et a!. (124), cyclophosphamide treatment plus total-body parvum (92). radiation plus syngeneic transplantation using monozygotic BCG induces fever which begins 4 to 8 hr after injection twin marrow, and subsequent immunotherapy with normal

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1977 American Association for Cancer Research. T. Ohnuma and J. F. Holland twin buffy-coat lymphocytes and s.c. injections of irradiated Lipid Antagonists.Tniparanolis a hypocholestenolemic autologous leukemic cells produced remissions of from 3 to agent that inhibits the conversion of desmostenol to choles more than 49 months in 10 of 13 leukemic patients. Inten tenol. The drug likewise exerts modifying effects on the sive combination chemotherapy is being added to the regi formation of adrenocortical steroid hormones in man. In 3 men to reduce the total-body burden of leukemic cells be patients with metastatic prostate carcinoma, treatment with fore the bone marrow tranplantation. In the overall marrow tnipananol produced disappearance of pain, X-ray evidence graft experience, despite use of sibling donors matched at of healing of bony metastases, and a decrease in acid the major histocompatibility leukocyte antigen and despite phosphatase in each case for a year on more (27). There was postgraft immunosuppression , graft-versus-host disease no clinical evidence that tnipananol exerted an estrogenic has occurred in approximately 70% of successfully grafted effect. Eight patients with metastatic breast carcinoma were patients. Evidently, incompatibility for histocompatibility re also treated with tnipananol (70). All had prior surgical cas gions other than the major complex is an important deter tration on were at least 10 years postmenopausal. Tempo minant of graft-versus-host disease . Clinically, the principal nary subjective and objective antitumon response was ob target organs of graft-versus-host disease are the skin, gas served in only 1 patient. Two of 4 patients, including the 1 trointestinal tract, and liven. The initial organ involved in who responded, had a decrease in urinary estrogen excre almost all cases is the skin, and the disease manifests as a tion, and it was postulated that an inhibition of adrenal maculopapulan rash; in severe cases it manifests as gener estrogen production might have caused the antitumon ef alized erythnodermia with bullae and desquamation. He fects. Alternatively, hypocholestenolemia per se or the accu patic and intestinal involvement usually appear several days mulation of intermediary steroids or steroid precursors after the rash. Intestinal involvement is usually manifested might be causally related to the antitumor effect. Complica as diarrhea but may progress to abdominal pain and ileus. tions of this compound include cataract, alopecia, and den Liver disease is characterized by rises in bilirubin (mainly matosis. conjugated), aspartate aminotransferase, and alkaline Boxidine, 1- [2-[[4' -tnifluonomethyl)-4- diphenyloxy]ethyl phosphatase. Fever, wasting, and debility status are also pyrrolidine, is a nonsteroidal hypocholesterolemic agent. regularly seen. Chronic graft-versus-host disease is chanac The compound blocks the conversion of 7-dehydroxycho tenized by a more indolent clinical course involving the lestenol to cholesterol, thus producing hypocholestenolemia same tissues. A fatal outcome may ensue with profound with an accumulation of 7-dehydroxycholestenol in blood nutritional impairment. and tissues. Of 13 patients with advanced cancer of various AdrenalCorticosteroid-inducedMalnutrition.The wide sites, objective regression of pulmonary metastatic lesions spread metabolic consequences of corticostenoids are of was observed in 1 patient with nonfunctional adrenal canci ten seen in cancer patients given large doses for prolonged noma (43). Side effects include anorexia, nausea, and vom periods. These consequences are summarized in Table 3. iting. Decrease in serum cholesterol and appearance of 7- The nutritional impact of newer immunothenapeutic dehydnoxycholestenol were also shown. agents such as thymosine, a calf thymus fraction (25, 111), Amino Acid Antagonists.Cycloleucine,1-amino-cyclo transfer factor (80), and immune RNA (103) has yet to be pentane carboxylic acid, is a synthetic amino acid with determined. antitumon effects in experimental neoplasms. Cycloleucine antagonizes the incorporation of valine into protein, proba Nutritional Consequences of a Specific Nutritional Ap bly by preventing the attachment of valine to tRNA (17). In proach to Chemotherapy cancer patients treatment with cycloleucine results in a reversible, marked amino acidunia primarily involving cys Although few qualitative differences have been observed tine, ornithine, lysine, and arginine (15). Cycloleucine has in the essential nutrient requirements of tumor and normal been reported to be effective against Ieiomyosancoma (1, 2). cells, there are some quantitative differences that are prob It also produced a partial response in a small number of ably dependent on growth rate, and this observation has led patientswith head and neck cancer, colorectalcancer, to the design of new therapies using inhibitors of glucose, ovarian carcinoma (125), melanoma (1, 125), and chondro lipids, amino acids, and vitamins. sarcoma (65). Beneficial effects have also been seen in a CarbohydrateAntagonist.2-Deoxy-D-glucose,aglucose small number of patients with multiple myeloma (84). Toxic antagonist, competes with glucose for phosphorylation by effects of cycloleucine in man include nausea, vomiting, hexokinase and thus diminishes the utilization of glucose anorexia, diarrhea, weight loss, thnombocytopenia, a fall in by tissues. Inhibition of glycolysis by treatment with 2-deox concentration of all the serum proteins, and neurological yglucose produced inhibition of the growth of mouse and toxicities (1, 5). rat tumors. This is in keeping with the high glucose con Selenocystmnehas been reported to be an effective agent sumption of rapidly growing tumor tissue, independently of in the treatment of animal tumors. Inorganic selenium per whether the glucose is subsequently metabolized by nespi se could not reproduce the antitumon effect. The compound ration or glycolysis to lactate. 2-Deoxyglucose was given by was thought to act by competing with L-cysteine for incor infusion to 8 patients with various neoplastic diseases (75). poration into protein. Two patients with acute leukemia and The patients developed diaphonesis, drowsiness, headache, 2 with chronic myelocytic leukemia were treated with selen generalized flush, and tachycandia, but tumor growth was ocystine daily for 10 to 57 days (130). In each of these not affected. The major limitation of this approach is the patients there was a marked reduction in the circulating exquisite sensitivity of the CNS to glucose deprivation. leukocytes, and splenomegaly became less pronounced.

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However, treatment with this drug produced severe nausea and vomiting, and it was not possible to continue its admin istration to determine whether remission could be induced. E

Ethionine, a structural analog of methionine, has been 0 known to impair the growth of experimental tumors. In 6 U) patients with advanced cancer of various sites, treatment -j -j for short periods of time with ethionine and a diet relatively w C., low in methionine led to various toxic manifestations in w cluding skin rash, diarrhea, liver damage, renal injury, and -j psychotic disturbances (134). No significant antitumor ef > L@. fects were observed. 0 Azasenine, O-diazoacetyl-L-senine, is a glutamine antago w fist isolated from cultures of a strain of Streptomyces. It exerts antitumon activity by inhibition of punine and pynimi z, dine synthesis through the inhibition of amidation reactions utilizing glutamine. Azasenine was tested in 56 patients with various types of cancer (36). Toxicities appeared in 5 to 20 DAYS days. The alimentary tract was most prominently involved, Chart 1. Cell growth of 2 T-Iymphocyte lines (MOLT 3 and RPMI 8402) and with redness of the tongue and buccal mucosa, progressing 4 B-lymphocyte lines in culture in the presence (â€¢)andin the absence ( 0) of i. asparagine in Roswell Park Memorial Institute Medium 1640 with 10% di to ulceration. Nausea and vomiting were commonly ob alyzed fetal calf serum. Call growth was shown by the number of viable cells served. One-fourth of these patients developed anorexia, as measured by the dye exclusion test (from T. Ohnuma at al (96). apathy, electrolyte imbalance, and jaundice. These tended to occur in old and debilitated patients. Marrow depression and leukopenia were also observed. Brief partial remission VIII, and IX, prothrombin, and fibninogen). Microscopic ob was seen in 3 of 14 children with acute lymphocytic leuke servation has shown severe fatty metamorphosis of the mia. Azasenine was tested p.o. in the treatment of multiple liven. The endocrine and exocnine functions of the pancreas myeloma without therapeutic effect (56). are also commonly affected by aspanaginase, and approxi Escherichia coli aspanaginase exerts its antineoplastic mately 5% of adults have overt pancreatitis. Hyperglycemia activity by depleting host L-aspanagine which is critical for and hypoinsulinemia without clinical evidence of pancreati the survival of certain neoplastic cells. Aspanaginase is ac tis have frequently been recognized (44). Toxic effects on tive in inducing remission in about 35 to 60% of patients the CNS appear to be due to depression of necessary amino with acute lymphocytic leukemia (see Ref. 19). This thera acids. CNS dysfunction ranging from mild depression and peutic effect appears to be related to specific nutritional drowsiness to impaired sensonium, psychosis, and frank requirements for L-asparagine by malignant and presum coma has been noted in adults. Electroencephalograms ably by normal T-lymphocytes. â€œNormal'â€˜andâ€œmalignantâ€•obtained from patients exhibiting CNS dysfunction have B-lymphocytes do not require L-aspanagine in culture (Chart been diffusely abnormal. The CNS dysfunction from aspara 1) and, in comparison to T-lymphocyte lines, are affected ginase might be due to a decreased amount of available L only at 800 to 2000 times higher concentrations of the en asparagine on L-glutamine onto the increased concentration zyme (96). The majority of patients with acute lympho of L-aspartate and L-glutamate. L-Asparagine administration cytic leukemia have â€œnullâ€•cells,some of which appear to in such patients coincided with clinical improvement of have been on the path to T-cell differentiation where prolif mental status (54, 94, 95). Loss of up to 20% of pretreatment enation of the malignant clone led to the clinical neoplasm. body weight was seen after aspanaginase treatment (Chart Because there would be a deficiency of T-ceII leukemias to 2) (95). Aspanaginase has minimal effects on the bone man account for the asparaginase responses, some of these row and is not cytotoxic to oral and intestinal mucosa on to cells must share the nutritional requirement for L-aspana hair follicles. gine. In general, differential nutritional requirements of in Vitamin Antagonists. Galactoflavin,6,7-dimethyl-9-(2'- dividual host and neoplastic cells have not yet been clearly acetoxyethyl)isoalloxazine, is a potent riboflavin antagonist elucidated. L-Aspanagine depletion by the enzyme treatment in rats. Six patients with advanced neoplasms were treated results in profound effects on host organ systems leading to with galactoflavin in combination with a synthetic diet (76). a variety of nutritionally important toxicities (19, 20, 50, 93, All developed riboflavin deficiency, i.e., weight loss, chei 94). The toxic effects on liven and pancreas are largely the losis, glossitis, seborrheic dermatitis, and normochnomic result of inhibition of protein synthesis in these organs. nonmocytic anemia. Two suggestive instances of transient Patients may complain of nausea and vomiting, chills, and clinical improvement were seen. fever within hours of the 1st dose of aspanaginase. Bio 4-Deoxypynidoxine is a vitamin B6 antagonist. Three pa chemical hepatic dysfunction is observed in a majority of tients with histiocytic lymphoma and 3 with acute lympho patients. Elevation of blood ammonia, a product of the cytic leukemia on a vitamin B6-poor diet were fed the antag enzyme reaction, has not produced majorconcomitant neu onist (47). Two of the patients were treated with 4-deoxypyn rological problems. Hepatic functional impairment is ac idoxine, and both developed grand mal seizures. The re companied by profound hypoalbuminemia, hypocholesten maining patients were treated with a smaller dose of 4- olemia, and diminished clotting proteins (Factors V, VII, X, deoxypynidoxmne.A slight reduction in lymph node size for a

JULY 1977 2401

T. Ohnuma and J. F. Holland

Asporag nose may be related to the subclinical folate deficiency com l000!U/kQ monly observed in patients with neoplastic diseases, partic ularly with cancer of the head and neck. Low pretreatment levels of serum folate appear to predispose patients to the @ @3:O@ toxic effects of methotnexate, but correlation with the de gree of tumor response has not been good. Oral mucosal toxicity occurs as redness, pain, and ulceration. Diarrhea is seen occasionally. Skin rash occurs in approximately 10 to I 20% of patients treated with therapeutic doses. Nausea, anorexia, and, less commonly, vomiting are noted during on >- after methotnexate administration, especially with large 0 doses. Subclinical injury is particularly noteworthy, and @ 0 @:1@t@ Tâ€œiâ€•tâ€•[â€•Tâ€•fâ€•Iâ€•i'[â€•iâ€•iâ€•iII I repeated doses could prove catastrophic since methotnex 0 2 4 6 8 10 2 14 6 8 20 ate is excreted almost exclusively by the kidney. Liven dam WEEKS age is rarely noted after moderate doses because of rather Chart 2. Changes in serum albumin and body weight after treatment rapid clearance, but hepatic fibrosis and cirrhosis have with 1000 IU of E. coil asparaginase per kg in a patient (D. W.) with acute myalocytic leukemia. been reported after long-term administration of methotnex ate (see above). Clinical toxicity of methotrexate is almost a direct func brief duration was noted in 2 patients with histiocytic lym tion of the duration of administration of the drug and, to a phoma. lessen extent, a function of the dose of the drug (121). This Four patients with acute lymphocytic leukemia who were is shown distinctly in high-dose treatment with methotnex on a normal diet were treated with 4-deoxypynidoxine for 33 ate followed by leucovonin rescue which extends the useful to 80 days (129). Two of the patients developed sebonrheic ness of this compound in other types of solid tumors with, dermatitis, which is taken as evidence of vitamin B. defi in general, remarkably little hematological toxicity (33). This ciency. However, there was no clinical evidence of bone has been particularly therapeutic in osteogenic sarcoma marrow remission. (41, 64). At high doses methotnexate appears to exert its 6-Aminonicotinamide is an antagonist of nicotinamide. It therapeutic effects by entering into the tumor cells by filtna has been shown to be active against a number of expeni tion, diffusion, on by other passive mechanisms rather than mental tumors. 6-Aminonicotinamide produced 1 negres by carrier transport alone (41). The clinical toxicity has been sion in 25 patients with renal cell carcinoma. Toxicity ap correlated with the drug concentration in the circulating pears to take 2 clinical forms. One is a â€œdeficiency'â€˜state blood. New data indicate that administration of high-dose and occurs as a form of stomatitis which includes buccal methotnexate (more than 50 mg/kg) is accompanied by ulceration, cheilosis, and glossitis, as well as blephanitis excretion of significant amounts ofthe metabolite 7-hydrox with photophobia and dryness. The other manifestation is ymethotrexate (63). The lower aqueous solubility of the 7- neurological, i.e. , 8th nerve damage manifested by a gross hydnoxy metabolite may have significant toxicological im on audiometnically detectable hearing defect and tinnitus. portance. Nausea and vomiting are also commonly seen (26, 51). Trace Metalsand Electrolytes.Manyof the metalsfound Methotnexate (amethoptenin) is the folate antagonist. De in trace quantity in normal and neoplastic tissues are known nivatives of tetrahydrofolate function as cofactors for many to be essential for certain biological reactions. The biologi of the enzymes that are required for the de novo synthesis of cal role of some metals that are often present in tissues is nucleotides, punines, and thymidylate. Modifying the struc not known. In some cases their presence may simply nepre tune of folic acid by substituting an amino group for the 4- sent contamination from the environment. Funst (42) has hydnoxy group in the ptenidine nucleus produced amino indicated that most antitumor drugs can act as chelating ptenin, a very potent and specific inhibitor of dihydnofolate agents and has speculated that this property may be impor neductase. Both aminoptenin and its N'Â°-methyl derivative, tantly involved in chemothenapeutic action. 3-Ethoxy-2- methotnexate, proved to be effective chemothenapeutic oxo-butylaldehyde bis-thiosemicanbazone (kethoxal thio agents in the treatment of acute lymphocytic leukemia in semicanbazone) is a copper chelating agent. Thirty-four children. Antifols are also of curative value in choniocanci patients treated with this compound developed dose-limit noma and related tnophoblastic tumors of women. Metho ing neunotoxicity, e.g. , panesthesias, myalgia, motor weak tnexate has broad spectrum activity in a modest percentage ness, and hallucinations. Nausea, vomiting, and bone mar of cases against squamous cell carcinomas of the head and row depression were also observed (106). neck and in adenocancinoma of the breast (see Ref. 79). Regression of malignant tumors was observed in magne The bone marrow and alimentary tract epithelium are the sium and potassium depletion induced by diet and hemodi 2 tissues most affected by folic acid analogs. Bone marrow alysis (101). This observation will undoubtedly stimulate toxicity manifests as neticulocytopenia, anemia, leuko continuing investigation into the effects of minerals and penia, and thrombocytopenia. After a single iv. dose of electrolytes on tumor growth. methotnexate the bone marrow begins to recover in 10 to 14 days. The toxicity may be more severe and pronounced if Perspectives patients are in poor condition or have infection on com pro mised liven or bone marrow function. This increased toxicity Years ago when chemotherapy was considered the last

2402 CANCER RESEARCH VOL. 37

resort for the hopelessly ill patient with advanced cancer, More importantly, the concept of chemotherapy has antitumon drugs were frequently given too late to be effec changed from last resort in the treatment of advanced dis tive. Even active drugs were often indicted for shortening ease to surgical adjuvant in the treatment of breast cancer the lives of cancer patients. This is understandable when (9, 39) and other neoplasms. Chemotherapy is now given to one recognizes that the list of complications of chemothen patients who show no evidence of disease, who are ambula apeutic and immunothenapeutic agents is long and the nu tory and maintain normal activity, and who thus have nor tnitional impact is formidable. The risks, however, must be mal appetite and nutrition. Chemotherapy is given to these viewed in proper perspective. Most of the complications patients with minimal nutritional consequences. listed are reversible and resolve in a matter of weeks. The As cancers become more definitely characterized and risks of cancer chemotherapy and immunotherapy are small understood, the nutritional treatment of tumor and normal compared to the natural consequences of untreated cancer tissues may be more effectively approached. on the host. The most drastic reactions described rarely occur in day-to-day management. Many nutritionally impon tant untoward effects can be prevented on treated nonspe References cifically with antiemetics, analgesics, antidiannheal agents, 1. Aust,J.B.,Andrews, N. C.,Schroeder,J. M., and Lawton, R. C. Clinical antibiotics, and transfusions of blood components during Note: Phase II Study of 1-Aminocyclopentane Carboxylic Acid (NSC the initial critical phase of chemotherapy and immunothen 1026) in Patients with Cancer. Cancer Chemotherapy Rept., 54: 237- apy to maintain an appropriate nutritional status. 241, 1970. 2. Aust, J. B., and Roux, K. Phase I Study of 1-Aminocyclopentane Car Cancer patients who were placed on an elemental diet boxylic Acid (NSC-1026) in Cancer Patients. Cancer Chemotherapy rich in calories, amino acids, and vitamins before and dun Rept., 49: 63-64, 1965. ing treatment with 5-fluonounacil and, in some cases, radio 3. Bast, A. C., zbar, B., Borsos, T. and Rapp, H. J. BCG and Cancer. New EngI. J. Med., 290: 1413-1429, 1458-1469, 1974. therapy showed no drug-related rectal lesions and main 4. Bellet, R. E., Mastrangelo, M. J., Engstrom, P. F., Strawitz, J. G., tamed their pretreatment body weight (11). Chemotherapy Weiss, A. J., and Tarbro, J. W. Clinical Trial with Subcutaneously Administered 5-Azacytidine (NSC-102816). Cancer Chemotherapy in combination with panentenal nutrition is well tolerated Rept., 58: 217-222, 1974. (23, 24) in cancer patients who are nutritionally depleted 5. Bergsagal, D. E., Ross, S. W., and Baken, D. T. Evaluation of New and who would otherwise have been deprived of adequate Chemotherapeutic Agents in the Treatment of Multiple Myeloma. V. 1- Aminocyclopentane Carboxylic Acid (NSC-1026). Cancer Chemother antitumon chemotherapy for fear of complications from apy Rept., 21: 101-106, 1962 malnutrition and inanition. Suggestive evidence has been 6. Berndt, J., and Hiller, I. Formininoglutaminsaure Auscheidung unter presented that nutritionally less deprived patients are more der Therapie mit Cyclophosphamid, KIm. Wochschr., 43: 333-334, 1965. likely to respond to chemotherapy (77). Specific antidotes 7. BIum, A. H., and Carter, S. K. Adriamycin, a New Anticancer Drug with have been used to counteract toxic effects of the chemo Significant Clinical Activity. Ann. Internal Med., 80: 249â€”259,1974. 8. Blum, R. H., Carter, S. K., and Agre, K. Clinical Review of Bleomycin â€”a therapeutic agents. Leucovonin against methotnexate, de New Antineoplastic Agent. Cancer, 31: 903-914, 1973. oxycytidine against cytosine arabinoside (100), thymidine 9. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A. , Brugnatelli, against 5-iodo-2'-deoxyunidine (83), and L-asparagine L. , Brambilla, C., DeLena, M. , Tancini, G., Bajetta, E., Musumeci, R., and Veronessi, U. Combination Chemotherapy as an Adjuvant Treat against aspanaginase (54, 94, 95) are some examples. ment in Operable Breast Cancer. New EngI. J. Med., 24: 405â€”410,1976. Additionally, increasing success in the long-term control 10. Borison, J. L. Arena Postrema: Chemoreceptor Trigger Zone for Vomit of acute leukemia (55), Hodgkin's disease (31) and other ing. Life Sci., 14: 1807â€”1817,1974. 11. Bounous, G., Gentile, J. M., and Hugon, J. Elemental Diet in the lymphomas, and certain carcinomas and sarcomas has 5ev Management of the Intestinal Lesion Produced by 5-Fluorouracil in ened the vicious cycle promulgated on the host by neoplasia Man. Can.J.Surg.,14:312-324,1971. 12. Brennan, M. J., Vaitkevicius, V. K., and Rebuck, J. W. Megaloblastic and toxic agents. Indeed, with the use of appropriate induc Anemia Associated with Inhibition of Thymidine Synthesis. Blood, 16: tion regimens, certain diseases can be brought under sat 1535-1545, 1960. isfactony clinical control within a few weeks. With mainte 13. Broder, L. E., and Carter, S. K. Pancreatic Islet Cell Carcinoma. II. Results of Therapy with Streptozotocin in 52 Patients. Ann. Internal nance therapy, such patients may enjoy good health and Med.,79:108-118,1973. normal daily activity for a period of years. The time is at 14. Brown, J. H., and Kennedy, B. J. Mithramycin in the Treatment of hand when physicians must consider chemotherapy as pni Disseminated Testicular Neoplasms. New Engl. J. Med., 272: 111-118, 1965. many therapy with the objective of cure or with the intent of 15. Brown, R. R. Amino Aciduria Resulting from Cycloleucine administra effecting increase in life-span for patients with certain tion in Man. Science, 157: 432â€”434,1967. highly sensitive tumors. In such cases it makes no sense to 16. Brunner, K. W., and Young, C. W. A Methylhydrazine Derivative in Hodgkin's Disease and Other Malignant Neoplasms: Therapeutic and wait until the patient is far along in his disease and suffers Toxic Effects Studied in 51 Patients. Ann. Internal Med., 63: 69â€”86, from advanced nutritional consequences of metastatic can 1965 17. Burdinguet, L., Begin, N., and Sarkar, N. K. Mechanism of Antitumor cer. Action of 1-Aminocyclopentane Carboxylic Acid. Nature, 194: 1082- It has been shown that tumor growth is slowed by starva 1083, 1962. tion and that i.v. nutrition makes tumors grow fasten (119). 18. Calabresi, P., and Parks, R. E., Jr. Alkylating Agents, Antimetabolites, Hormones, and other Antiproliferative Agents. In: L. 5. Goodman and In experimental animal systems and in man, accumulating A. Gilman (eds.), The Pharmacological Basis of Therapeutics, Ed. 4, evidence indicates that intermittent intensive treatment is pp. 1348-1395. New York: The MacMillan Co., 1970. superior to continuous treatment (see Ref. 40). These find 19. Capizzi, R. L., Bertino, J. R., and Handschumacher, A. E. L-Asparagi nase. Ann. Rev. Med., 21: 433-444, 1970. ings should lead to short-term intensive combined modali 20.Capizzi,A.L.,Bertino,J.R.,Skeel,R.T.,Creasey,W.A.,Zanes,A., ties to attempt tumor debulking, remission induction, on Olayon, C., Peterson, A. G., and Handschumacher, A. E. L-Asparagi nase: Clinical, Biochemical, Pharmacological and Immunological Stud cure, rather than long continuous treatment with nutritional ies. Ann. Internal Med., 74: 893â€”901,1971. maintenance. 21. Chauvergne, J., LaPorte, G., Hoerni, B., and Legendre, P. Hypocal

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cdmie par Actinomycine D. Presse Med., 78: 847, 1970. Chemotherapy Rept., 59: 621-628, 1975. 22. Cockel, P. Antiemetics. Practitioner, 206: 56â€”63,1971. 50. Haskell, C. M., Canellos, G. P., Leventhal, B. G., Carbone, P. P., Block, 23. Copeland, E. M., MacFadyen, B. V., Lanzotti, V. J., and Dudrick, 5. J. J. B. , Serpick, A. A. , and Selawry, 0. S. L-Asparaginase, Therapeutic Intravenous Hyperalimentation as an Adjuvant to Cancer Chemother and Toxic Effects in Patients with Neoplastic Disease. New Engl. J. apy. Am. J. Surg., 129: 167-173, 1975. Med.,281:1028-1034,1969. 24. Copeland, E. M., MacFadyen, B. V., MacComb, W. S., Guillamondegni, 51. Hailer, F. P., Weismann, S. G., Thompson, H. G., Jr., Hyman, G., and 0. , Jesse, A. H., and Dudrick, S. J. Intravenous Hyperalimentation in Martin, D. S. Clinical Experience with 6-Aminonicotinamide. Cancer Patients with Head and Neck Cancer. Cancer, 35: 606-61 1, 1975. Rca., 21: 31-37, 1961. 25. Costanzi, J., Gagliano, A., Loukas, D., Sakai, J., Thurman, G., Harris, 52. Higby, D. J., Wallace, J. J., Jr., Albert, D., and Holland J. F. D@mmino N., and Goldstein, A. The Use of Thymosin (thy.) in Patients with dichloroplatinum in the Chemotherapy of Testicular Tumors. J. Urol., Disseminated Neoplasia: Toxicity and immunological Correlation. 112: 100-104, 1974. Proc. Am. Assoc. Cancer Res., 16: 135, 1975. 53. Higby, D. J. , Wallace, J. J., Jr., and Holland, J. F. Diamminodichloro 26. Cowan, D. H., and Alison, A. E. Evaluation of 6-Aminonicotinamide in platinum (NSC-119875): a Phase I Study. Cancer Chemotherapy Rept., the Treatment of Metastatic Hypernephroma. Cancer Chemotherapy 57: 459-463, 1973. Aept., 54: 175-179, 1970. 54. Holland, J. C. B., Fasanelio, S., and Ohnuma, T. Psychiatric Symptoms 27. Davis, P. L. Decrease in X-ray Evidence of Bone Metastasis in Prostatic Associated with L-Asparaginase Administration. J. Psychiat. Ras., 10: Cancer during Use of Triparanol. Clin. Med., 8: 2360-2362, 1961. 105-113, 1974. 28. DeFronze, A. A. , Colvin, 0. M., Braine, H., Robertson, G. L., and Davis, 55. Holland, J. F. The Acute Leukemias. In: P. B. Beeson and W. Mc P. J. Cyclophosphamide and the Kidney. Cancer, 33: 483-491 , 1974. Dermott (eds.), Textbook of Medicine, Ed. 14, pp. 1485-1492. Philadel 29. DeVita, V. T., Canellos, G., Carbone, P. P., Baron, S., Levy, H., and phia:W. B. Saunders Co., 1975. Gralnick, H. Clinical Trials with the Interferon (lnF) Inducer Polyino 56. Holland, J. F., Gehan, E. A., Brindley, C. 0. , Dederick, M. M., Owens, A. sinic-cytidylic Acid. Proc. Am. Assoc. Cancer Res., 11: 21, 1970. H., Jr., Shnider, B. I., Taylor, A., Frei, E., Ill, Selawry, 0. S., Aegelson, 30. DeVita, V. T., Carbone, P. P., Owens, A. H., Jr., Gold, G. L., Krant, M. W., and Hall, T. C. A Comparative Study of Optimal Medical Care with J., and Edmonson, J. Clinical Trials with 1,3-Bis(2-chloroethyl)-1-nitro and without Azaserine in Multiple Myeloma. Clin. Pharmacol. Therap., sourea, NSC-409962. Cancer Res., 25: 1876-1881, 1965. 2: 22-28, 1961. 31. DeVita, V. T., Serpick, A. A., and Carbone, P. P. Combination Chamo 57. Holland, J. F., Scharlau, C., Gailani, S., Krant, M. J., Olson, K. B., therapy in the Treatment of Advanced Hodgkin's Disease. Ann. Internal Horton, J., Shnider, B. â€˜.,Lynch,J. J., Owens, A., Carbone, P. P., Med.,73:881-895,1970. Colsky, J. , Grob, D., Miller, S. P., and Hall, T. C. Vincristine Treatment 32. DiMarco, A. , and Lenaz, L. Daunomycin and Adriamycin. In: J. F. of Advanced Cancer: A Cooperative Study of 392 Cases. Cancer Res., Holland and E. Frei, Ill (eds.), Cancer Medicine, pp. 826-835. Philadel 33: 1258-1264, 1973. phia: Lea & Febiger, 1973. 58. Horton, J. , Olson, K. B. , Sullivan, J., Reilly, C., Shnider, B., and the 33. Djerassi,I., Rominger,J., Kim, J. S., Turchi, J., Suransri, U., and Eastern Cooperative Oncology Group. 5-Fluorouracil in Cancer: an Huges, D. Phase I Study of High Doses of Methotrexate with Citrovorum Improved Regimen. Ann. Internal Med., 73: 897-900, 1970. Factor in Patients with Lung Cancer. Cancer, 30: 22-30, 1972. 59. Howard, J. G., Scott, M. T., and Christie, G. H. Cellular Mechanisms 34. Einhorn, M., and Davidsohn, I. Hepatotoxicity of Mercaptopurine. J. Underlying the Adjuvant Activity of Corynebacterium parvum ; lnterac Am. Med. Assoc., 188: 802-806, 1964. tions of Activated Macrophages with T and B Lymphocytes. In: Immu 35. Ellison, A., Holland, J. F., Weil, M., Jacquillat, C., Boiron, M., Bernard, nopotentiation, pp. 101-120. New York: American Elsevier Publishing J., Sawitsky, A., Rosner, F., Gussoff, B., Silver, A. T., Karanas, A., Co., 1973. Cuttner, J., Spurr, C. L., Hays, D. M., Blom, J., Leone, L. A., Haurani, 60.Hrodak,0.,and Vesely,J.5-AzacytidineinChildhoodLeukemia. F., Kyle, A., Hutchison, J. L. , Forcier, R. J. , and Moon, J. M. Arabinosyl Neoplasma, 18: 493-503, 1971. Cytosine: A Useful Agent in the Treatment of Acute Leukemia in Adults. 61. Humphrey, E., Hymes, A., Ausman, A., and Ferguson, D. J. An Evalua Blood, 32: 507-523, 1968. tion of Actinomycin D and Mitomycin C in Patients with Advanced 36. Ellison, A. A., Karnofsky, 0. A., Sternberg, S. S., Murphy, M. L., and Cancer. Surgery,50: 881-885,1961. Burchenal, J. H. Clinical Trials of O-Diazoacetyl-L-serina (Azaserine) in 62. Hutter, A. M., and Kayhoe, D. E. Adrenal Cortical Carcinoma: Results of Neoplastic Diseases. Cancer, 7: 801-814, 1954. Treatment with op-ODD in 138 Patients. Am. J. Med., 41: 581-592, 37. Ellison, A. A., Silver, R. T., and Engle, R. L. ,Jr. Comparative Study of 6- 1966. Chloropurine and 6-Mercaptopurine in Acute Leukemia in Adults. Ann. 63. Jacobs, 5. A. , Stoller, R. G. , Chabner, B. A. and Johns, D. G. 7- InternalMed.,51: 322-338, 1959. Hydroxymethotrexate as a Urinary Metabolite in Human Subjects and 38. Field,A. K.,Young,C. W., Krakoff, I. H.,Tytell,A.A., Lampson,G. P., Rhesus Monkeys Receiving High Dose Methotrexata. J. CIin. Invest., Nemas, M. M., and Hilleman, M. A. Induction of Interferon in Human 57: 534-538, 1976. Subjects by Poly I:C. Proc. Soc. Exptl. Biol. Med., 136: 1180-1186, 64. Jaffe,N., Frei,E.,Ill, Traggio,D., andBishop,T. AdjuvantMethotrexate 1971. and Citrovorum Factor Treatment of Osteogenic Sarcoma. New EngI. J. 39. Fisher, B., Carbone, P., and Economou, S. G. L-Phenylalanine Mustard Med., 291: 994-997, 1974. (L-PAM) in the Management of Primary Breast Cancer: a Report of Early 65. Johnson, A. 0. Preliminary Phase II Trials with 1-Aminopentane Car Findings.New EngI.J. Med., 292: 117-122, 1975. boxylic Acid (NSC-1026), Cancer Chemotherapy Rept., 32: 67-71 , 1963. 40. Frei,E., III.Effectof DoseandScheduleon Response.In:J. F. Holland 66. Johnson, A. 0., Matter, G., Wilson, W., Hice, G., and Kramentz,E. and E. Frei, Ill (eds.), Cancer Medicine, pp. 717-730. 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2406 CANCERRESEARCHVOL. 37

Takao Ohnuma and James F. Holland

Cancer Res 1977;37:2395-2406.

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