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`
`Hepatotoxic Effects of Oncotherapeutic
`and Immunosuppressive Agents
`
`and chemical
`Chemotherapy for neoplastic disease
`imimmosuppression involve the use of agents that inter—
`fere selectively with metabolic pathways or have other
`cytotoxic effects; several of these agents are hepatotoxic
`(1—8). Other agents in the group appear to spare the liver
`or to produce hepatic injury rarely and as the result of
`host idiosyncrasy (5). Although abnormal values for bio-
`chemical tests are common, clinically significant hepatic
`injury is relatively uncommon. It seems almost paradoxi-
`cal that some agents that are potent cell poisons, and that
`are metabolized by the hepatocyte, produce little or no
`hepatic damage.
`Several factors appear to account for the sparing of the
`hepatocyte by agents so lethal
`to the neoplastic cell.
`These agents exert their toxic effects preferentially on
`rapidly proliferating tissues, such as those of the bone
`marrow, gastrointestinal
`tract,
`and neoplasms
`(3).
`Accordingly, the slowly multiplying hepatic tissue should
`be relatively unsusceptible (3). Furthermore, the broad
`range of metabolic activity of hepatocytes may provide
`opportunity for balance between production and disposi—
`tion of toxic metabolites; whereas transformation of the
`drug in the neoplastic cell (e.g., by action ofphosphami-
`dase or cyclophosphamide) may convert it to a cytolytic
`alkylating agent (5). Additionally, administration of anti~
`cancer drugs may lead to amplification of the multidrug-
`resistance gene, which encodes an organic ion transporter
`(p-glycoprotein). Conceivably, this may add protection by
`enhanced excretion of potentially hepatotoxic drugs (8).
`Nevertheless, considering the role of alkylation and ary-
`lation of cell macromolecules of the hepatocyte in the
`production of hepatic injury by known hepatotoxins
`(Chapter 5), the oligotoxicity for the liver of alkylating
`antineoplastic agents is somewhat surprising.
`Also relevant to the hepatotoxic effects of anticancer
`drugs is the difficulty of identifying any hepatic injury
`they may cause. Toxic liver damage resulting from onco—
`
`therapy must be distinguished from the effects on the
`liver of the neoplasm, coincidental viral hepatitis, other
`infections, other drugs, and total parenteral nutrition.
`The number of candidate oncotherapeutic agents stud-
`ied in experimental animals and tested in patients is far
`too great, and the data regarding the possible adverse
`effects of many of them on the liver are too scant, to per-
`mit systematic analysis of the hepatotoxicity of cancer
`chemotherapy. Nevertheless, sufficient
`information is
`available to define the effects of some agents on the liver
`(Table 23.1) and to discern some general principles
`regarding the relation between the type of agent and the
`potential for producing hepatic injury.
`
`FORMS OF HEPATIC INJURY
`
`For the most part, the forms of acute (Table 23.2) and
`chronic (Table 23.3) hepatic injury produced by oncother-
`apeutic agents are similar to those produced by other
`agents, Several forms of the injury, however, are particuo
`larly prominent. Steatosis is more frequently noted in the
`hepatic injury of several anticancer agents than in that pro-
`duced by most other drugs. Steatocirrhosis seen with metl -
`otrexate (MTX) therapy but is not seen with most other
`medicinal hepatic injury. Venn-occlusive disease (VOD),
`the dramatic lesion characteristically resulting from pyrro—
`lizidine alkaloids, is produced by several oncotherapeutic
`and immunosuppressive agents, singly and in various com—
`binations (4—6,8—l l), and not by other medicinals (Table
`23.4). Another unique drug-induced lesion is the scleros-
`ing cholangitis that is seen as a complication of “pump”
`infiision of floxuridine into the hepatic artery for treatment
`of metastatic hepatic carcinoma (12—21) (Table 23.5).
`
`Acute Injury
`
`The acute hepatic lesions of cancer chemotherapy are
`mainly hepatocellular. A few anticancer drugs are intrin-
`
`673
`
`IMMUNOGEN 2041, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`s‘l._
`,_
`
`y.
`
`_
`
`IMMUNOGEN 2041, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

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`674 / HEPATOTOXICITY
`
`
`
`TABLE 23.1. Some hepatic lesions produced by agents used in cancer therapy
`VOD
`Peliosis
`Cholestasis
`Fat
`Necrosis
`Biochemica pattern of injury
`Drug
`______________________________________._.___——————————-——-—-—
`AT
`Aclarubicin
`Cholestatic
`Aminoglutethamide
`Amsacrine
`Hepatoce u ar/cholestatic
`Cholestat'c
`Anabolic steroida
`Hepatoce u ar
`Asparaginase
`Hepatocellular
`Azacytidine
`Hepatoce u ar
`Azatepa
`Hepatocel ular/cholestatic
`Azathioprine
`Hepatoce u ar
`Bacille Calmette-Guérinc
`Hepatoce ular”
`Bleomycin
`Cholestatic
`Busulfand
`Hepatoce u ar/cholestatic
`Carboplatin
`Carmustine
`Hepatocel ular
`Hepatoce u ar
`Chlorambucil
`Hepatocel ular
`Chloropurine
`Chlorozocin
`Hepatocellu ar/cholestatic
`Hepatoce u at
`Cisplatin
`None
`Cladribine
`Cholestatic
`Cyclosporine
`Hepatoce u ar
`Cyclophosphamide
`Hepatocel ular
`Cyproterone
`Hepatocellu ar
`Cytarabine
`Dacarbazine
`Hepatoce u ar
`Hepatocellular
`Dactinomycin (actinomycin D)9
`Daunorubicin
`Hepatoce ulare
`Dichloromethotrexate
`Hepatocellu ar
`Hepatoce lular
`Diethylstilbestrol
`Cholestatic
`Dimethylbusulfan
`Doxorubicin
`Hepatoce ular
`Estramustine
`Hepatocel|u|ar
`Cholestat'c
`Estrogens (Steroids)
`Hepatocellular
`Etoposide
`Floxuridine’
`Hepatoce ular/chotestatic
`AT
`Fluorouracil
`Flutamide
`Hepatoce Iular/cholestatic
`Frentizole
`Hepatoce ular
`AT
`Homoharringtonine
`Hepatoce ular
`Hydrazines
`Cholestatic
`Hydroxyprogesterone
`Hepatocellular
`Hydroxyurea
`AT
`Idarubicin
`AT
`lfosfamide
`Indicine-N-oxide
`Hepatocellular
`AT
`Interferons
`Cholestatic
`Interleukin—29
`Cholestatic
`Interleukin—6
`None
`Lomustine
`AT
`Maytansine
`None
`Mechlorethamine
`Cholestatic
`Medroxyprogesterone
`AT
`Melphalan
`Hepatocellular/cholestatic
`Mercaptopurine
`Methotrexate
`Hepatocel|u|ar
`Hepatocellular
`Mithramycin
`Hepatocellular
`Mitomycin
`AT
`Mitotane
`AT
`Mitoxantrone
`HepatoceHular
`Monomethylformamide
`Ni|utamide
`Hepatocellular
`Pentostatin
`Hepatocellular
`Procarbazine
`Hepatocellulari
`Hepatocellular
`Puromycin
`Hepatocellular
`Pseudisocytidine
`AT
`Semustine
`Hepatoceltular
`treptozocin
`_s_______________________________..____———————————-———
`
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`Phigenix v. Immunogen
`IPR2014-00676
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`IMMUNOGEN 2041, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`—
`—
`—
`+
`—
`~
`
`—
`+
`+
`+
`,
`—
`
`TABLE 23.1. Continued.W
`Drug
`Biochemical pattern of injury
`Fat
`Necrosis
`Cholestasis
`VOD
`Peliosis
`Tacrolimus
`Hepatocellular
`Tamoxifen
`Cholestatic/hepatocelluIar
`Teniposide
`Hepatocellular
`Thioguanine
`Hepatocellular/cholestatic
`Thiotepa
`Hepatocellular
`Trimetrexate
`None
`Triethylenemelamlne
`None
`Uracil mustard
`AT
`-
`+
`—
`+
`-
`Urethane
`Hepatccellular
`
`Vinca alkaloids _WHepatocellular — +517 _ +5
`
`
`
`
`
`AT, increased aminotransferase levels but no jaundice; +, present ;~, absent; i, uncertain.
`alncriminated in hepatic adenoma and carcinoma.
`”Hepatic injury is minor component of adverse effects of drug.
`CGranuloma.
`dAlso incriminated, with other agents, in production of nodular regenerative hyperplasia,
`EOnly when given with other agents or radiotherapy.
`’Characteristic injury is sclerosing cholangitis when drug is administered by pump into hepatic artery,
`9Pattern of injury is consistently cholestatic. Histological changes show more variation.
`hin large parenteral doses.
`’ Rare
`
`+
`_
`+
`_
`_
`-
`
`_
`_
`+
`_
`L
`-
`
`+
`_
`_
`_
`_
`-
`
`TABLE 23.2. Acute hepatic injury associated with agents used in cancer therapy.W
`
`Cytotoxic
`
`Necrosis
`Dose—related, relatively frequent
`
`Dose-unrelated, relatively rare
`
`Steatosis
`Steatosis plus necrosis
`Cholestatic
`
`Mixed cholestatic—cytotoxic
`aIn high dose.
`
`Agents
`
`Mithramycin, N—methyltormamide, mercaptopurine, nitrosoureas, streptozocin,
`methotrexatea
`
`Chlorambucii, cyclophosphamide, cytarabine, cytoproterone, etoposide, flutamide,
`frentlzole, thioguanine
`Dactinomycin, asparaginase, bieomycin, methotrexate, mitomycin,a puromycin
`Asparaginase, cisplatin, methotrexate,a thiotepa
`Anabolic steroids, estrogenic steroids, aminogutethamide, azathioprine, amsacrine,
`busultan, 4,4’—diaminodiphenylamine, medroxyprogesterone, tamoxifen
`Chlorozocin, mercaptopurine, thioguanine, azathlopurine
`
`TABLE 23.3. Chronic hepatic lesions associated with agents used in cancer therapyW
`Type of injury AgentsW
`
`Cytotoxic injury
`Chronic hepatitis
`Steatosis
`Phospholipidosis
`Mallory bodies (alcoholic hyaline)
`Cirrhosis
`Steatocirrhosis
`Biliary cirrhosis
`Congestive cirrhosis
`Cholestatic lesions
`Chronic intrahepatic cholestasis
`Sclerosing cholangitis
`Vascular lesions
`Peliosis hepatis
`
`Azathioprine, doxorubicin
`Daotinomycin, asparaginase, glucocortisteroids, methotrexate, mitomycin C, puromycin
`amphophilic compounds
`Diethylstilbestrol, tamoxifen
`
`Methotrexate
`Azathioprine, floxuridine
`Drugs that lead to VOD or hepatic thrombosis
`
`Azathioprine
`Floxuridine
`
`Anabolic steroids, azathioprine, medroxyprogesterone, hydroxyurea, tamoxifen, OCs,
`DES, thioguanine
`Combination therapy (Table 23.18)
`(Table 23.4)
`Many drugs
`
`Hepatic vein thrombosis
`Veno—occlusive disease
`Granulomas
`Neoplasms
`Adenomas
`Carcinoma, hepatocellular
`Angiosarcoma
`Non-cirrhotic portal hypertension
`Nodular regenerative hyperplasia,
`Combination therapy (Table 28.18)
`hepatoportal sclerosis
`DES, diethylstilbestroi; OCs, oral contraceptives; VOD, veno-occlusive disease.
`
`Anabolic steroids, OCs
`Azathioprine, anabolic steroids, chlorambucil, OCs, DES, methotrexate
`Anabolic, OCs, DES
`
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`676 / HEPATOTOXICITY
`
`TABLE 23.4. Oncotherapeutic and immunisuppressive
`______________________.__._————-—-—————-—-——-
`agents that can lead to veno-occlusive diseasea
`
`wA
`
`zathioprine
`Busultan
`Carmustine
`Cisplatin
`Cyclophosphamimide
`Cytarabine
`
`Dacarbazine
`Dactinomycin
`Daunorubicin
`Dimethylbusufan
`Doxorubicin
`Floxuridine
`Indicine-N-oxide
`Mechlorethamine
`B-Mercaptopurine
`Mitomycin
`Thioguanine
`Urethane
`Vincristine
`X-lrradiation
`Combinations
`__________._____—_.———————————————-———-
`
`aAlone or in combination with other agents or x—irradiation.
`
`sic hepatotoxins that produce necrosis as a dose—depen-
`dent effect. Most produce necrosis relatively rarely as a
`dose-independent idiosyncratic reaction (6). Acute chole-
`stasis is an uncommon form of anticancer drug injury,
`although busulfan (23,24), azathioprine (25,26), amino-
`glutethamide (27,28), amsacrine (6), tamoxifen (29,30),
`medroxyprogesterone (8), and the obsolete agent, 4,4’-
`diaminodiphenylamine (6) can cause cholestatic injury.
`
`Chronic Injury
`
`Cytotoxic Lesions
`
`Steatosis is a frequent chronic cytotoxic lesion resulting
`from several anticancer drugs, especially MTX (6) (Table
`23.3). Chronic hepatitis resembling the autoimmune type,
`a lesion and syndrome that can be produced by several
`
`Imuran
`Myleran
`BCNN. BlCNU
`Platinol
`Cytoxan
`Cyosine arabinoside, ARA-C,
`Cytosar-U
`DTIC
`Actinomycin, Cosmegen
`Cerubidine
`——
`Adriamycin
`FUDR
`——
`Mustargen
`Purinethanol
`Mitocin. Mutamycin
`TG
`Ethyl carbamate
`Oncovin
`
`TABLE 23.5. Published reports of sclerosing cholangitis occurring as a complication of pump infusion of
`floxuridine into the hepatic artery
`
`Authors
`
`No. cases
`
`incidence of lesion (°/o)
`
`Year
`
`Ref no.
`
`16
`1986
`40
`20
`Anderson et al.
`13
`1985
`33a
`2
`Bolton et al.
`14
`1985
`7
`6
`Botet et al.
`18
`1986
`100”
`8
`Doria et al.
`19
`1987
`100
`20
`Hermann et al.
`12
`1986
`56
`31
`Hohn et al.C
`15
`1985
`17
`8
`Kemeny et al.
`20
`1989
`—
`1
`Ludwig et al.
`
`
`
`
`17 100 1986Shea et alf 17W—
`aReflects authors‘ estimate that “one-third" of treated patients develop the lesion.
`thetlects all of patients studied.
`CThe two reports are from the same institution and figures may overlap.
`
`is not readily ascribable to any of the cancer
`drugs,
`chemotherapy agents. However, I have seen the lesion as
`an apparent reaction to azathioprine and in published (31)
`photomicrographs of doxorubicin-induced injury.
`Phospholipidosis, a lesion characterized by phospho-
`lipid—engorged lysosomes and produced by a number of
`amphiphilic drugs (32), has not been recorded as a lesion
`of oncotherapeutic agents other than the investigational
`antileukemic drug, AC3579 (33). The Mallory body, a
`lesion seen in alcoholics and in several other clinical con-
`ditions (Chapter 6), is not seen with any of the usual anti-
`cancer agents. It has been produced in experimental ani—
`mals (34) by administration of diethylstilbestrol and in a
`patient with prostatic carcinoma (35) treated with that
`drug. Tamoxifen also has been implicated in the develop—
`ment of Mallory bodies (35a,35b). Several types of cir-
`rhosis may occur after anticancer therapy (Table 23.3).
`
`Cholestatic Injury
`
`Chronic intrahepatic cholestasis may follow the acute
`cholestasis induced by azathioprine (Fig. 23.1). Refer-
`ence has been made to the striking sclerosing cholangitis
`(Fig. 23.2) produced by hepatic artery infusion of flex-
`uridine (12—21) in the treatment of metastatic hepatic car—
`cinoma (Table 23.5).
`
`Vhscular Lesions
`
`Peliosis Hepatitis. This lesion has been associated in
`the past with terminal
`tuberculosis or carcinomatosis
`(36), more recently with Cl7—alkylated steroids, and,
`rarely, with oral contraceptives (Chapter 4). Peliosis hep-
`atis also has been seen in patients (8) taking tamoxifen
`(37), hydroxyurea (4) thioguanine, medroxyprogesterone
`acid (8), or azathioprine (4) (Table 23.3).
`Hepatic Vein Thrombosis. The drugs most associated
`with hepatic vein thrombosis are the oral contraceptives
`(38). Cancer chemotherapy is .rarely the cause of the
`injury, but the lesion has been reported as a complication
`of chemotherapy for Hodgkin’s disease (39) and adminis-
`
`tration of dacarbazine (DTIC) (40).
`
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`23: ONCOTHERAPEUTIC AND IMMUNOSUPPRESSIVE AGENTS / 677
`
`
`
`FIG 23.1. Liver biopsy from a patient who developed chronic cholestasis (vanishing bile duct syndrome)
`after taking azathioprine for many months. Jaundice had been present for 11 months at that time of the
`biopsy. A: Note cholestasis with huge bile casts in canaliculus. B: Cholate stasis (arrow) reflected by
`foamy striated cells. C: Portal areas (P) showing fibrosis and lack of bile ducts.
`
`Veno-Occlusive Disease. This lesion leads to morpho-
`logic changes and a syndrome resembling that of hepatic
`vein thrombosis, namely the Budd-Chiari syndrome (41).
`In VOD, however, the lesion is fibrotic and involves par-
`tial or complete obliteration of the lumina of the efferent
`venules rather than thrombotic occlusion of the hepatic
`veins (41). The lesion is typical of pyrrolizidine alkaloid
`toxicity, which is the most common cause of the entity
`worldwide (9,41,42). In this country the most common
`causes are anticancer and immunosuppressive drugs
`(22,43—49) and radiation injury (50) of the liver. It is rel-
`atively common in patients receiving chemotherapy or
`
`immunosuppressive therapy, particularly in recipients of
`bone marrow transplants (ll). VOD develops in 10% to
`60% of patients during the first few weeks after bone
`marrow transplantation (4,6,9—1 1,43—49). Superb exposi-
`tion of the VOD that is associated with bone marrow
`transplantation is continued in the writing of Jones et al.
`(9), McDonald et al. (10), and Bearmen (1 1). It is char-
`acterized by partial or complete fibrotic occlusion of ter—
`minal hepatic venules (central veins) with congestion and
`necrosis of the perivenous area (zone 3). The diagnosis
`should be suspected when abdominal
`swelling and
`increased aminotransferase levels develop during or after
`
`
`
`FIG. 23.2. A: Retrograde cholangiogram showing sclerosing cholangitis in a patient after 6 months of
`pump infusion therapy with floxuridine. (Courtesy of Dr. Paul Shorb, George Washington University Med
`ical Center; from ref. 5, with permission.) B: Section from explant liver of patient who underwent trans-
`plantation for sclerosing cholangitis. Note damaged bile ducts and striking periductal sclerosis.
`
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`678 / HEPATOTOXlCITY
`
`chemotherapy. As a therapeutic misadventure, VOD is a
`lesion virtually specifically related to anticancer and
`immunosuppressive drugs and irradiation (Table 23.4).
`No other therapeutic agents lead to it, although several
`herbal preparation taken as alternative medications can
`(Chapter 24).
`Portal ijerz‘enslon. Nodular regenerative hyperpla-
`sia and hepatoportal sclerosis, which are lesions that can
`lead to portal hypertension, have been described in recip—
`ients of chemotherapy involving several anticancer drugs
`in combination (51~57). Hepatoportal sclerosis has been
`produced by organic arsenicals and by azathioprine, and
`nodular regenerative hyperplasia has been attributed to
`azathiopiine, dactinomycin, busulfan plus thioguanine,
`and other protocols employed in preparation for bone
`marrow transplantation (9—1 1,54—57).
`
`Granulomas
`
`Many drugs produce granulomatous lesions (58,59), but
`the anticancer drugs show no special tendency to do so.
`
`Neoplasms
`
`(60), azathioprine (61), MTX (62),
`Chlorambucil
`androgens (63), and diethylstilbestrol
`(64) have been
`implicated in the development of hepatic carcinoma.
`Androgens, estrogens, and procarbazine also have been
`linked to angiosarcoma (65—67).
`
`MECHANISMS OF INJURY
`
`Like other drugs, anticancer agents produce injury as
`intrinsic hepatotoxins or as idiosyncratic reactions. The
`antimetabolites, some selective enzyme poisons, and
`some antibiotics tend to be intrinsic hepatotoxins that
`produce dose—dependent liver damage. Urethane and the
`nitrosourea analogues, which become alkylating agents
`only after biotransformation, also appear to act as hepa-
`totoxins. However, the directly alkylating oncotherapeu-
`tic agents such as nitrogen mustards generally do not
`produce hepatic injury, or do so only as very rare idio—
`syncratic reactions. Hypersensitivity appears to be a less
`common form of idiosyncratic reaction to anticancer
`agents than metabolic idiosyncrasy, as judged from co]-
`lateral clinical features (6).
`The remainder of this chapter describes hepatic injury
`produced by individual drugs.
`
`ALKYLATING AGENTS
`
`Five groups of alkylating agents (Table 23.6) have been
`used for oncotherapy. The nitrogen mustards (Fig. 23.3)
`show little hepatotoxic potential. Mechlorethamine and
`melphalan seem free of responsibility for hepatic injury,
`and the ethylenimine derivatives seem hardly ever to have
`
`caused liver damage. Cholestatic jaundice has been
`attributed to an alkylsulfonate (23,24), but rarely. More
`convincing evidence for some hepatotoxic potential
`applies to the nitrosoureas (68), streptozocin (4), and a
`triazine (4).
`
`Nitrogen Mustards
`
`I?”
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mechlorellzamine (HNg). This alkylating agent (Mus-
`targen, Merck & Co, West Point, PA), the first to be used,
`has been found to produce little or no hepatic injury. One
`report described focal hepatic necrosis in three patients
`and worsening of jaundice in two others among 50
`patients receiving the drug (69). in a prospective study,
`my group found no hepatic injury (70).
`Melphalari (MLD). This drug (Alkeran, Glaxo Well-
`come, NC) has not been incriminated in significant
`hepatic injury to my knowledge. Large doses have been
`accompanied by mildly abnormal aminotransferase levels
`(7).
`(CLB). This agent (Leukeran, Glaxo
`Clllormnbucil
`Wellcome, NC) has been implicated in several reports of
`hepatic injury (71,72). The cases are few, but the form of
`injury appears to have been uniformly hepatocellular.
`Massive necrosis can occur (4). The possible hepatocar-
`cinogenic role of the agent has been reported (60).
`Cyclop/zosplzamicle (CTX). This drug (Cytoxan, Bris-
`tol-Myers Squibb Oncology/1mmLmology, Princeton, NJ)
`seems to have led to a few instances of hepatic injury.
`Several reports have drawn attention to mild hepatic
`injury in humans and in experimental animals. Instances
`of marked elevation of aspartate aminotransferase (AST),
`of massive necrosis, and of VOD have been reported
`(73—75). This drug also has been incriminated, both in
`concert with busulfan and other drugs (76—80) and alone
`(81,82), in the production ofVOD.
`[fro/amide.
`I fosfamide (lfex, Bristol—Mvers Squibb
`Oncology/1771mmology, Princeton, NJ), a derivative, has
`seemed largely clear of hepatotoxic potential. Two cases
`of severe Cholestatic injury have been described in
`patients receiving both ifosfamide and etoposide (83).
`Uracil Mustard. This agent was incriminated in sev-
`eral instances of mild hepatic injury, but apparently none
`lately (6).
`
`
`
`
`
`
`
`
`
`
`
`Ethylenimine Derivatives
`
`Triethylenemelamine (TEM) seems not to have caused
`hepatic injury. Triethylenethiophosphoramide, or thiotepa,
`has been incriminated in a case of liver failure (84), and a
`derivative, azatepa, has been implicated in severe hepatic
`injury resembling phosphorus poisoning (85) (Fig. 23.4).
`
`Alkylsulfonatcs
`
`Busulfan (Myleran, Glaxo Wellcome, NC) (Fig. 23.5),
`an agent long in use in the treatment of granulocytic-
`
`
`
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`23: ONCOTHERAPEUTIC AND IMMUNOSUPPRESSIVE AGENTS / 679
`
`TABLE 23.6. Adverse effects on liver of alky/ating anticancer drugsW
`_._______..__—-————-———————-———————————————-—————————
`Drug
`Hepatic injury
`Type
`Mechanism
`Nitrogen mustards
`Mechlorethamine (HNz Mustargen)
`Melphaian (MLP Alkeran)
`Cyclophosphamide (CTX Cytoxan)
`Chlorambucil (Leukeran)
`Uracil Mustard (Ura-M)
`Itasfamide (lfex)
`Ethylenimine
`Triethylenemelamine (TEM)
`Thiotepa (Thioplex)
`Azatepa
`Alkylsulfonates
`Busulfan (Myleran)="
`Dimethylbusulian
`Nitrosoureas
`Carmustine (BCNU)
`Lomustine (CCNU)
`Semustine (Methyl—CCNU)
`Estramustine (Emcyt)
`Streptozocin (Zanosar)
`Chlorozocin
`Triazines
`TOX, Idio
`VOD
`Yes
`Dacarbazine (DTlC)
`
`Procarbazine (Matulane) IdioWVR ' H-Cell
`
`
`
`VR, very rare; H—Ceil, Hepatocellular; Chol, Cholestasis; Necr, necrosis, AT, levels of aminotrans-
`ferases increased, but overt liver disease very rare; Idio, idiosyncrasy;TOX, intrinsic toxicity;VOD, veno—
`occlusive disease.
`ain concert with other treatment has led to VOD, portal hypertension due to hepatoportal sclerosis or
`nodular regenerative hyperplasia (see Table 23.18).
`
`——
`—
`H-Cell/Necr
`H—Cell/Necr
`H<Cell/Mild
`
`-
`—
`Idio
`Idio
`Idio
`
`——
`ldio
`ldio
`
`ldio
`ldio
`
`TOX
`TOX
`TOX
`——
`TQX
`TOX
`
`None
`None
`VR
`VFt
`VFi
`
`None
`VR
`VR
`
`VR
`VR
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`—
`H-Cell
`H-Cell
`
`Chol
`Chol
`
`H-Ceii
`AT
`AT
`H-Celi
`H—Cell
`H-Cell/Chol
`
`chN:
`
`CH -CH ~Cl
`2
`2
`CHz-CHZ-Ci
`
`.CHz-CHz-Cl
`0 M
`GEOCW‘CHz-Cl
`
`0
`
`'t‘H
`
`it:
`
`o
`
`,CHz—CHz-CI
`N‘
`
`CHz-CHz-Cl
`
`Mechlorelhamine
`
`Cyclophosphamide
`
`Uracil Mustard
`
`,CHz-CH2~CI
`HOOC-GH-CH2‘©‘N‘
`CHz'CHz'CI
`NH;
`
`0. (,0
`F’s
`<
`_
`_
`LAO“. CH2 CH2 (3'
`CHZ-CHa-Ci
`
`,CHfCH >Cl
`COOH—CHg—CHg—CH2~@~N\
`2
`CH -CH -Ci
`2
`2
`
`Melphalan
`
`iiosfamide
`
`Chlorambucil
`
`FIG. 23.3. Derivatives of nitrogen mustard.
`
`N
`N
`,CTz
`(I3H2\
`CH! YNY ‘CHQ
`NON
`Y
`N
`CH{—‘CH2
`
`CH2WCH2
`CHA
`9‘
`,CH2
`N—P—N\
`i
`l
`CH{
`'3'
`CH2
`
`,CH2
`9
`(3 WP N]
`l
`\il/CZHS
`CH2
`N——N
`
`2
`
`Triethylenemelamine (TEM)
`
`Thiolepa
`
`Azalepa
`
`FIG. 23.4. Derivatives of ethyleneimine.
`
`CHS‘SOZ’O-‘CHZ-CHg-CHz-CHa—O-SOQ-CH3
`FIG. 23.5. Busultan
`
`IMMUNOGEN 2041, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
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`IMMUNOGEN 2041, pg. 7
`Phigenix v. Immunogen
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`
`

`

`680 / HEPATOTOXICITY
`
`H
`
`eHon
`0H
`
`OH
`
`O
`0
`CI-CHQ-CHz-tf-(E‘NH‘CHZ'CHZ'CI C‘_CH2.CH2.N_E_NH_<:>
`NO
`NO
`
`OH
`
`no
`OH
`H NH~§-N~CH3
`o
`
`Carmustine (BCNU)
`
`9
`4. _ -
`_
`.
`CH
`9' CHECK)“ c “HO 3
`NO
`
`Semustlne
`
`Lornusline (CCNU)
`
`Streptozolncin
`
`H
`
`CHEOH
`O H
`
`OH?
`H
`OH NO.
`on 0H
`OH
`H NH-(E—N-CHg-CHz-Cl
`(CICHZCH2)2N-COO @.
`O
`Ch’orozotocin
`Estramustine
`
`logues of folic acid, pyrimidines, and purines (Table 23.7).
`
`FIG. 23.6. Nitrosourea derivatives.
`
`(methyl-CCNU) have led to elevated aminotransferase
`concentrations (9).
`Streptozocin. This antibiotic (Zanosar, Pharmacia &
`Upjohn, Bridgewater, NJ), a nitrosourea—related com-
`pound, can produce hepatocellular
`injury including
`necrosis (4). Abnormal aminotransferase levels have been
`reported in 15% (3) and 67% (9) of recipients of the drug;
`but the abnormalities are of little clinical moment (3).
`Chlorozocin has been reported to cause cholestatic injury
`accompanied by hepatocellular damage (7,8,9). The
`injury appears to be dose related (9).
`Triazenes. Despite the antimetabolite structure of
`dacarbizine (DTIC, Bayer Pharmaceutical Products Inc,
`Liberty Corner, NJ) (Fig. 23.7), its antitumor effect is
`mediated apparently by metabolic activation in the liver
`to an alkylating agent (7). The hepatic injury attributed to
`this drug may also result from production of the alkylat-
`ing metabolite in the liver. The most important lesion is
`VOD, of which a number of fatal cases have been
`reported (4,89,11,41). Some of these cases developed
`during the administration of DTIC concurrently with
`other agents; others followed the use of DTIC alone.
`Hepatic vein thrombosis also has been recorded in recip-
`ients of DTIC (39,40).
`Procarbazine. This drug (Matulane, Roche Pharma-
`ceuticals, Basel, Switzerland) appears to produce little
`hepatic injury in most recipients, although jaundice,
`apparently hepatocellular, has been noted in about 1%
`(1,9). The extrahepatic threat, however, outweighs in
`importance the hepatotoxicity of this agent (9).
`
`_
`
`ANTIMETABOLITES
`
`Antimetabolites employed in oncotherapy include ana-
`
`leukemia, polycythemia vera, and primary thrombocyto-
`sis and in the preparation for bone marrow transplanta—
`tion, has been implicated in several cases of cholestatic
`jaundice (23,24) and in a case of porphyria cutanea tarda
`(86).
`In concert with thioguanine,
`it also has been
`incriminated in the production of nodular regenerative
`hyperplasia and portal hypertension (54—57). Also, in
`combination with cyclophosphamide, busulfan has been
`incriminated in the production of VOD (11,87).
`Dimethylbusulfan, a related agent, also has been asso-
`ciated with VOD (9,49).
`
`Nitrosoureas
`
`These compounds apparently act as alkylating agents
`through the liberation of active products (7) (Fig. 23.6).
`The parent compound, carmustine (BCNU), has pro—
`duced hepatic injury in experimental animals and hepatic
`dysfunction in up to 25% of patients taking therapeutic
`doses (68,88—90). The hepatic injury, manifested by
`increased AST activity and jaundice as well as necrosis,
`appears to be reversible. Kupffer cell injury is presumed
`to account for abnormal hepatic scans when radioactive
`colloid is used for scintigraphy (68). In animals, BCNU
`has been found to lead to pericholangitis and necrosis of
`bile ducts
`(6). Lomusrine
`(CCNU)
`and semustine
`
`CHZ—u—u—CHQ
`H H
`
`HCI
`
`o
`
`CH
`
`tort—NH—b'
`CH2
`
`o.
`
`.
`C‘NH
`
`2
`,CH3
`N=N—N‘
`CH3
`
`N
`
`f
`HN—-
`
`Dacarbazine
`
`Procarbazine
`
`FlG. 23.7. Triazines
`
`IMMUNOGEN 2041, pg. 8
`Phigenix v. Immunogen
`|PR2014—00676
`
`IMMUNOGEN 2041, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`23: ONCOTHERAPEUTIC AND IMMUNOSUPPRESSIVE AGENTS / 681
`
`Fat, cirrhosisa
`Fat, necrosis
`Hepatoceliular
`
`Hepatocellular/cholestatic
`Hepatocellular/cholestatic
`Hepatoceiluiar/VOD
`H-Ceil, Chol, VOD, peiiosis
`Fat, necrosis, cirrhosis
`Hepatoceilular
`None reported
`None reported
`
`TABLE 23.7. Hepatotoxic effects of anticancer and immunosuppress/ve drugs: ant/metabolites
`Mechanism
`Hepatic injury
`Drugs
`______________________________.__.——————————————-——-—-—-
`Antitolates
`Intrinsic toxicity
`Methotrexate (Mexate)
`intrinsic toxicity
`Dichloromethotexate
`Intrinsic toxicity
`083717”
`Antipurines
`Mercaptopurine (Purinethol)
`Chloropurine
`Thioguanine (TG, Lanvis)
`Azathioprine (lmuran)
`Frentizoie
`Pentostatin (Nipent)
`Cladribine (Leustatin)
`Fludarabine (Fludara)
`Antipyrimidines
`Hepatocellularc
`5-Fiuorouracilc (Adrucii)
`Cholestatic,d VOD
`Floxuridine (FUDFI)
`Fat, Necrosis
`5-Azacytidine
`Hepatocellular
`6-Azacytidine
`Hepatocellular, VOD
`Cytarabine (ara-C)
`Hepatoceliular
`Pseudoisocytidine
`H-cell, hepatocellular, presumably necrosis; Chol, cholestasis; VOD, veno-occlusive disease.
`aCan cause necrosis in large parenteral doses.
`”08371 7 is a quinazoline thymidylate synthase inhibitor; it is Ni0-propargyl-5,8-dideazoiolic acid.
`COnly with parenteral administration.
`dCholestasis due to scierosing cholangitis when drug administered by pump—perfusion into hepatic
`artery.
`
`intrinsic toxicity
`intrinsic toxicity
`intrinsic toxicity idiosyncrasy
`intrinsic toxicity idiosyncrasy
`intrinsic toxicity
`—
`—
`——
`
`intrinsic toxicity
`Intrinsic toxicity
`intrinsic toxicity
`intrinsic toxicity
`Intrinsic toxicity idiosyncrasy
`intrinsic toxicity
`
`Each category contains agents that can cause hepatic
`injury (6). L-Asparaginase is an enzyme discussed with
`the natural products. Although not an antimetabolite in the
`usual sense, it behaves like one, because it leads to selec-
`tive deprivation of an amino acid (6).
`
`plastic disease, where usually very large doses are given
`intermittently,
`the hepatic injury has been acute bio-
`chemical abnormality or clinical disease of no lasting
`importance. In rheumatoid arthritis, hepatic injury has
`been relatively minor, consisting of biochemical abnor—
`malities and fibrosis.
`
`Methotrexate
`
`This folate antagonist (Fig. 23.8) has been used in th'e
`treatment of leukemia and other neoplastic disease for
`many years. Its mode of action appears to be inhibition of
`dihydrofolate reductase and a consequent inhibition of
`synthesis of purines and pyrimidines (7). A voluminous
`literature details its hepatotoxic effects (l~9,88’187).
`Within a few years after the introduction of MTX into
`clinical use, hints that it might be hepatotoxic appeared.
`At first in children with leukemia (9le94), and later in
`patients with psoriasis (95’135), evidence of the hepato-
`toxic potential of MTX accumulated. Treatment of neo-
`plastic disease including leukemia (9i—94,l42—i45),
`choriocarcinoma (146), localized tumors, and other male
`ignant states (147—153) and of uveitis (145) also led to
`hepatic injury. In more recent years, decade, widespread
`use of MTX for the treatment of rheumatoid arthritis has
`led to limited evidence of hepatic injury (154—167).
`Adverse effects of the drug relate to the clinical set—
`ting. In psoriasis, the significant hepatic injury attrib—
`uted to MTX has been steatosis and cirrhosis. In neo~
`
`Hepatic Injury in the Treatment of Psoriasis
`Most of the information on the hepatotoxic effects of
`this anticancer agent has been acquired in the course of
`its use in psoriasis. During three decades of that use,
`many recipients of MTX were found to have fatty liver,
`and some had fibrosis or cirrhosis (6,96—136). Figures
`for cirrhosis ranged from 4% to more than 25%; for
`fibrosis, from 8% to 30%; and for cirrhosis plus fibrosis,
`about 50% in some reports (Table 23.8). Most of the
`reports, however, did not distinguish between preexisting
`liver abnormalities and the effects of MTX, because in
`most instances information on pretreatment status of the
`liver was not available (134). Only with reports of hepatic
`
`H2N
`
`N
`N
`Y
`CH3
`0
`COOH
`,
`. /
`.
`.
`NO 0 H r'r-@~'c c'H
`N
`e
`N
`CHa-CHZ-COOH
`NH2
`H
`H
`
`FIG. 23.8. Structure of methotrexate.
`
`IMMUNOGEN 2041, pg. 9
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`

`

`Year
`1970
`1971
`1971
`1972
`
`1972
`
`1973
`1973
`1973
`1974
`1974
`1977
`1980
`
`injury from MTX treatment, confirmed by comparison of
`pretreatment and posttreatment biopsies, was the phe-
`nomenon clearly established and the issue put in perspec—
`tive (134,136). The suspicion that some of the abnormal—
`ities attributed to MTX were preexisting and apparently
`associated with the psoriasis was confirmed (134). Stea-
`tosis, inflammation, and necrosis are common in the liv-
`ers of untreated patients with psoriasis. Fibrosis and cir-
`rhosis, however, are not common (129), and the reported
`incidence of these lesions in patients treated with MTX,
`although wide—ranging (Table 23.8), demonstrates an
`adverse effect of the drug. Perhaps the most important
`figures are those of Zacchariae et al. (129), who found
`that psoriatic patients who had not received MTX had a
`0.6% prevalence of cirrhosis, whereas those treated with
`the drug for 5 years had a 25% incidence.
`There is now a consensus that MTX can be hepato—
`toxic, that attention to factors modifying the hepatotoxic
`potential can decrease the likelihood of significant hep—
`atic injury, and that appropriate monitoring can keep it
`contained (134,136). However, there is also the view that
`the hepatotoxic threat of MTX, although real, has been
`
`682 / HEPATOTOXlClTY
`TABLE 23.8. Incidence of hepatic fibrosis cirrhosis or both after methotrexate treatment for psoriasis
`(no "baseline" biopsies obtained)
`°/o
` incidence ( )
`
`Fibrosis
`