GOODMAN and GILMAN’s
`
`The
`
`Pharmacological
`
`Basis of
`
`Therapeutics
`
`SEVENTH EDITION
`
`MACMILLAN PUBLISHING COMPANY
`NewYor'k
`
`COLLIER MACMILLAN CANADA,
`
`INC.
`Toronto
`
`COLLIER MACMILLAN PUBLISHERS
`London
`
`MEDAC Exhibit 2006
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`ANTARES v. MEDAC
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`MEDAC Exhibit 2006
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`
`COPYRIGHT © 1985, MACMILLAN PUBLISHING COMPANY.
`A DIVISION OF MACMILLAN. INC.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`All rights reserved. No part of this book may be reproduced or
`transmitted in any form or by any means. electronic or mechanical,
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`
`Earlier editions entitled The Pharmacological Basis afThera.c-eatlcs
`copyright 1941 and 1955, © copyright 1965, copyright © 1970, and
`copyright © 1975 by Macmillan Publishing Company. Earlier edition
`entitled Goodman and Gf.lm(m’.s' The Pharmacological Basis Q!"
`The:-apcailcs copyright ® 1980 by Macmillan Publishing Company.
`
`MAcMILLAN PUBLISI-IING COMPANY
`866 Third Avenue - New York, NY. 10022
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`COLLIER MACMILLAN CANADA, INC.
`
`COLLIER MACMILLAN PUISLISHERS - London
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`In this textbook. reference to proprietary names of drugs is ordinar-
`ily made only in chapter sections dealing with preparations. Such
`names are given in sMALL—cAP TYPE, usually immediately following
`the official or nonproprietaly titles. Proprietary names of drugs also
`appear in the Index.
`
`
`age 0002
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`(cid:3) (cid:55)(cid:75)(cid:76)(cid:86)(cid:3)(cid:80)(cid:68)(cid:87)(cid:72)(cid:85)(cid:76)(cid:68)(cid:79)(cid:3)(cid:80)(cid:68)(cid:92)(cid:3)(cid:69)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:87)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:79)(cid:68)(cid:90)(cid:3)(cid:11)(cid:55)(cid:76)(cid:87)(cid:79)(cid:72)(cid:3)(cid:20)(cid:26)(cid:3)(cid:56)(cid:17)(cid:54)(cid:17)(cid:3)(cid:38)(cid:82)(cid:71)(cid:72)(cid:12)(cid:3)
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`
`‘r-
`
`FoL1c ACID ANALoGs
`
`'
`
`1263
`
`Therapeutic Uses and Clinical Toxicity. At pres-
`ent, dacarbazine is employed principally for the
`treatment of malignant melanoma; .the overall re-
`sponse rate is about 20%. Beneficial responses
`have also been reported in patients with Hodgkin's
`disease, particularly when the drug is used concur-
`rently with doxorubicin, bleomycin, and vinb1as-
`tine (Santora and Bonadonna, 1979), as well as in
`various sarcomas when used with doxorubicin
`(Costanzi, 1976: Gottlieb er al., 1976). Toxicity in-
`cludes nausea and vomiting in mo1'e than 90% of
`patients; this usually develops 1 to 3 hours after
`treatment. Myelosuppression. with both leukope-
`nia and thrombocytopenia, is usually mild to mod-
`erate. A flulike syndrome, consisting in chills.
`fever, malaise, and myalgias, may occur during
`treatment. Hepatotoxicity, alopecia, facial flush-
`ing, neurotoxicity, and dermatological reactions
`have also been reported.
`
`II. Antimetabolites
`
`FOLIC ACID ANALOGS
`
`Mrrruornsxme
`
`This class of antimetabolites not only
`produced the first striking, although tempo-
`rary, remissions in leukemia (Farber at al.,
`1948) but also includes the first drug to
`achieve
`cures of
`choriocarcinoma
`in
`women (Hertz, 1963). The attainment of a
`high percentage of permanent remissions in
`this otherwise-lethal disease provided great
`impetus to chemotherapeutic investigation.
`Interest in folate antagonists has increased
`greatly with the introduction of “rescue“
`technics that employ leucovorin (folinic
`acid, citrovorurn factor) andfor thymidine
`to protect normal
`tissues against
`lethal
`damage. These methods permit the use of
`very high doses of folate analogs such as
`methotrexate and extend their utility to
`tumors such as osteogenic sarcoma that do
`not respond to lower doses.
`Methotrexate has also been used with
`benefit
`in the therapy of psoria.vi'.r, a
`nonneoplastic disease of the skin character-
`ized by abnormally rapid proliferation of
`epidermal cells (McDonald, 1981). Addi-
`
`tionally, folate antagonists are potent inhib-
`itors of some types of immune reactions
`and have been employed as immunosup-
`press-Eve agems,
`for example,
`in organ
`transplantation. (For recent reviews, see
`Symposium, 1981b; Chabner, 1982c; Johns
`and Bertino, 1982; Jackson, 1984.)
`
`Structure—Activity Relationship. Folic acid is an
`essential dietary factor from which is derived a
`coenzyme, tetrahydrofolic acid, and a group of
`structurally related derivativcs;...these are con-
`cerned with the metabolic transfer of one-carbon
`units. A detailed description of the biological func-
`tions and therapeutic applications of folic acid ap-
`pears in Chapter 5'.-'.
`Although there are many metabolic loci where
`folate analogs (antifols) might act, the enzyme di-
`hydrofolate reductase (D1-IFR) is the primary site
`of action of most analogs studied to date (see Fig-
`u1‘e 5'}'—1). This enzyme has been purified from a
`number of species. Important structural differences
`among the various enzymes have enabled the
`design of important
`therapeutic agents for the
`treatment of bacterial and malaria]
`infections
`(see discussion of trimethoprim, Chapter 49; Pyri-
`methamine, Chapter 45). These inhibitors have
`much greater activity against the bacterial and pro-
`tozoal DHFRs than they do against the mammalian
`enzyme. Such developments have introduced a
`new level of sophistication into the science of
`chemotherapy and suggest the possibility of devel-
`oping new analogs of folate that have unique ad-
`vantages for the chemotherapy of neoplastic dis-
`eases.
`_
`Because folic acid and many of its analogs are
`very polar,
`they cross the blood-brain barrier
`poorly and require specific transport mechanisms
`to enter mammalian cells. Once in the cell, addi-
`tional glutamyl residues are added to the molecule
`by the enzyme folylpolyglutamate synthetase. In-
`tracellular methotrexate polyglutamates have been
`identified with as many as five glutamyl residues.
`Since these polyglutarnates cross cellular mem-
`branes poorly. if at all, this serves as a mechanism
`of entrapment and may account for the prolonged
`retention of methotrcxate in tissues such as liver.
`Evidence indicates that polyglutamylated folates
`have
`substantially
`greater
`affinity
`than
`the
`monoglutamate form for enzymes such as thymidy-
`late synthetase. Other findings indicate that distinct
`differences exist in the -folate influx system in cer-
`tain tumors in comparison with normal
`tissues
`(e.g., bone marrow). Novel folate antagonists have
`been devised to attempt to exploit these difier-
`ences. The analog 1(l—deaza,l0-ethyl aminopterin
`is transported into many tumor cells much more
`
`0
`CH3
`N
`HZNYN
`NO Ck N O -C
`iii“ /
`-_
`II
`I
`
`- NH2
`
`H
`
`Metholrexate
`
`coon
`C
`\N/ \CH2—CH2—COOH
`]_/I
`
`H
`
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`
`Page 00004
`
`

`
`12.64
`
`ANTIMETABOLI’1‘ES
`
`[Chap. 55]
`
`is poly-
`tissues,
`efficiently than into normal
`glutamylated, and is an excellent
`inhibitor of
`DHFR. This promising new compound will be eval-
`uated clinically in the near future (Sironialc, I983).
`In efforts to bypass the obligatory me1_nbrane trans-
`port system and facilitate penetration of the blood-
`brain barrier. a number of lipid~soluble'-folate an-
`tagonists have been synthesized; several of these
`are in the early stages of clinical trial (Johns and
`Bertino, 1982; Jackson I984). (For recent reviews,
`see Chabner, 1982c; -Goldman ct (IL, 1983; Hitch-
`ings. 1983; Jolivet and Chabner, 1983; McGuire
`er (IL, 1983; Sirotnak, 1983; Cadman, 1984: Jack-
`son, 1984.)
`
`Mechanism of Action. To understand the mecha-
`nism of action of folate analogs such as methotrex—
`ate, it_ is necessary to appreciate the complexities of
`the metabolism of folate cofactors and their multi-
`plicity of functions; this is discussed in Chapter 5?.
`To function as a cofactor in one-carbon transfer
`reactions_, folate must first be reduced by DHFR to
`tetrahydrofolate (Fl-L4). Single—carbon fragments
`are added enzymatically to FH4 in various configu-
`rations and may then be transferred in specific syn-
`thetic reactions. A key metabolic event is catalyzed
`by thymidylate synthetase and involves the conver-
`sion oi' 2—deoxyuridy]ate (dUMP) to thymidylate,
`an essential component of DNA. The methyl group
`transferred to the uracil moiety of dUMP is do-
`nated by l‘~l5"°-mcthylene FH4. Significantly, this
`ca1'bon atom is transferred to the pyrimidine ring at
`the oxidation level of formaldehyde and is reduced
`to methyl by the pteridine ring of the folate coen-
`zyme; the result is the formation of dihydrofolatc
`(F1111). Thus, to function again as a cofactor, FH2
`must first be reduced to FH4 by DHFR. Inhibitors
`with a high affinity for DHFR prevent the forma-
`tion of PH, and cause major disruptions in cellular
`metabolism by producing an acute intracellular de-
`ficiency of folate coenzymes. The folate coen-
`zymes become trapped as FH2 polyglutamates,
`which cannot function metabolically. One-carbon
`transfer reactions crucial for the dc-nova synthesis
`of purine nucleotides and of thymidylate cease,
`with the subsequent interruption of the synthesis of
`DNA and RNA (as well as other vital metabolic
`reactions).
`. Understanding of these events enables apprecia-
`tion of the rationale for the use of thymidine andior
`leucovo1'in (N5—formyl Fl-I4; folinic. acid) in the
`‘frescue" of normal cells from toxicity caused by
`drugs such as methotrexate. Leucovorin is a fully
`reduced, metabolically functional folate coenzyme;
`it enters cells"via the specific ca1'1'icr-mediated
`transport system and is -convertible to other folate
`cofactors. Thus. it may function directly. without
`the need for reduction by DHFR in reactions such
`as those required for purine biosynthesis. On the
`other hand, thymidine may be converted to thy1ni—
`dylate by thymidine kinase. thus bypassing the re-
`action catalyzed by thymidylate synthetasc and
`providing the necessary precursor for DNA synthe-
`813.
`
`An important feature of the binding of active fo-
`late antagonists with DHFRs is the very low inhibi-
`tion constants observed (on the order of 1 nM).
`
`Covalent bonds are not involved in the enzyme-
`inhibitor interactions despite the high affinity of the
`antagonists for the protein. Substantial progress
`has been made-in defining the chemical basis for
`the binding of methotrex-ate to DHFR (see Mat-
`thews er al.,
`l9’i'8; Chabner,
`l982C).
`As with most inhibitors of cellular reproduction,
`a selective effect on neoplastic cells is obtainable to
`only a partial extent with methotrexatc. Folate an-
`tagonists kill cells during the S phase of the cell
`cycle, and evidence indicates that methotrexate is
`much more efiective when the cellular population
`is in the logarithmic phase of growth, rather than in
`the plateau phase. Because it is also capable of in-
`hibiting RNA and protein synthesis, however,
`methotrexate slows the entry of cells into S phase
`and its cytotoxic action has been referred to as
`“self-limiting” (Skipper and Schabel. 1982).
`
`Mechanism of Resistance to Antifolates. Al-
`though evidence is incomplete, three biochemical
`mechanisms of acquired resistance to methotrexate
`have been clearly demonstrated: (1) impaired trans-
`port of methotrexate into cells, (2) production of
`altered forms of DHFR that 11ave decreased affinity
`for the inhibitor, and (3) increased concentrations
`'0i"int1‘accllular DHFR. It has been known for years
`that blood elements with marked increases in the
`activity of DHFR appear within days after treat-
`ment of patients with leukemia with single doses of
`methotrexate. This may reflect induction of new
`enzyme synthesis, temporary elimination from the
`marrow of cells that are susceptible to the drug
`because of low enzymatic activity, or protection of
`DH FR against cataboiic degradation by intracellu-
`lar proteases. It is well established that the en-
`zyme, complexed with methotrexate, undergoes
`conformational changes that render it remarkably
`resistant to proteolysis.
`_
`Of special interest is the phenomenon of gene
`amplification and its relationship to acquired resis-
`tance to methotrexate and, perhaps. other cytotoxic
`agents. Methotrexate—resistant cell lines have been
`isolated that have .several hundrcdfold more
`DHFR than do wild type cells because of compara-
`ble increases in the mRNA specific for the enzyme.
`This is due to the occurrence in these resistant cells
`of increased numbers of copies of the gene for
`DHFR.
`(For
`further discussion,
`see Schimke
`et at, 1978; Bertino er al., 1983; Stark and Wahl.
`1984.)
`Various therapeutic tactics have been recom-
`mended to avoid selection of resistant cells. The
`use of high doses of methotrexate with leucovorin
`“rescue” may permit the intracellular accumula-
`tion of methotrexate in concentrations that inacti-
`vate DHFR even when the-enzyme is present at
`markedly elevated levels. Alternation of treatment
`with methotrexate with other active therapeutic
`agents that function by different mechanisms is
`another way to attempt to kill cells that are resis-
`tant.
`
`General Toxicity and Cytotoxic Action.
`The actions of 4-amino analogs of folate in
`animals have been studied extensively.
`
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`
`
`
`
`
`——..__......j..,_.________,__.....T:
`
`FOLIC ACID ANALOGS
`
`1365
`
`Animals given a minimal lethal dose sur-
`vive for at -least 48 hours and usually die
`within 3 to 5 days. Anorexia, progressive
`weight loss, bloody diarrhea, leukopenia,
`depression, and coma are the outstanding
`features of fatal intoxication. The major le-
`sions occur in the inmrtinal tract and bone
`marrow. Swelling and cytoplasmic vacuoli-
`zation of the mucosal cells of the intestinal
`epithelium are evident within 6 hours.
`These changes are followed by desquama-
`tion of epithelial cells, extrusion of plasma
`into the lumen of the bowel, and leukocytic
`infiltration of the submucosa. Terminally,
`the entire intestinal tract exhibits a severe
`hemorrhagic desquamating enteritis. De-
`generation of bone marrow develops rap-
`idly. Within 24 hours there is evident'dis-
`turbance in the maturation of erythrocytes.
`Proliferation of erythroid precursors is in-
`hibited, and significant proportions of prim-
`itive erythroid elements have the appear-
`ance of megaloblasts. Rapid pathological
`alteration in myelopoiesis also occurs, and
`within a few days the bone marrow be-
`comes aplastic. There is diminution in con-
`tent of lymphoid cells in lymphatic tissue,
`but there is no evidence of necrosis. The
`disturbance in hematopoiesis is reflected in
`the circulating blood by a marked granule-
`cytopenia and reticulocytopenia and a mod-
`erate lymphopenia.
`Folic acid antagonists seriously interfere
`with embryogeriesis. The site of action is on
`the embryonic mesenchyrne. Decidual and
`placental tissues. are unaffected by doses of
`the drugs that cause fetal death. Young
`embryos "are much more susceptible than
`are the more developed. The administration
`of methotrexate during pregnancy obvi-
`ously is accompanied by great hazards to
`the fetus.
`
`' Absorption, Fate, and Excretion. Metho-
`trexate is readily absorbed from the gastro-
`intestinal tract at doses routinely employed
`in clinical practice (0.1 mgfkg), but larger
`doses are incompletely absorbed. The drug
`is also absorbed from parenteral sites of in-
`jection. Peak concentrations in the plasma
`of 1 to l0 ;.tM are obtained after doses of 25
`to 100 Ingisq In, and concentrations of 0.1
`to 1 mM are achieved after-high-dose infu-
`sions of 1.5 gfsq -m or more (Chabner,
`1982c). A direct relationship exists between
`
`dose and plasma concentrations_ Foilowing
`intravenous administration, the drug digapt
`pears from plasma in a triphasic fashion
`(Huffman er al., 1973). The first phase, due
`to the distribution into body fluids, has a
`half-time of about 45 minutes. The second
`phase reflects renal clearance (rm of about
`2 hours). The final phase has a half-time of
`approximately 3'' hours and begins when the
`concentration in plasma
`approximates
`0.1 ,uM. This terminal half-life,
`if unduly
`prolonged, may be responsible for major
`toxic effects of the drug on the marrow and
`gastrointestinal tract. Distribution of meth-
`otrexate into body spaces, such as the pleu-
`ral or peritoneal cavities, may ‘occur. If
`such spaces are expanded (e.g., by ascites
`or pleural effusion), they may act as a site
`of storage and release of drug with resultant
`prolonged elevation of plasma concentra-
`tions and more severe toxicity.
`Approximately 50% of the drug is bound
`to plasma proteins. Laboratory studies sug-
`gest that it may be displaced from plasma
`albumin by a number of drugs, including
`sulfonamides,
`salicylates,
`tetracycline,
`chloramphenicol, and phenytoin; caution
`should be used if these are given concomi-
`tantly. Of the drug absorbed, from 40 to
`50% of a small dose (2.5 to 15_ ,u.gfkg) to
`about 90% of a larger dose (150 pglkg) is
`excreted unchanged in the urine within 48
`hours, mostly within the first 8 hours. A
`small amount of methotrexate is also ex-
`creted in the stool, probably through the
`biliary tract. Metabolism of methotrexate in
`man does not seem to occur to a significant
`degree. "After high doses, however, metab-
`olites do accumulate; these include a poten-
`tially nephrotoxic 7-hydroxylated com-
`pound (see Chabner, 1982c). The portion of
`each dose of methotrexate that normally is
`excreted rapidly gains access to the urine
`by a combination of glomerular filtration
`and active tubular secretion. Therefore, the
`concurrent use of drugs that also undergo
`tubular secretion, as well as impaired renal
`functi.on,'.can influence markedlythe re-
`sponse to this drug. Particular caution must
`be exercised in treating patients with renal
`‘insufficiency.
`The portion of methotrexate that is re-
`tained in human tissues remains "for long
`periods, forexample, for weeks in the kid-
`neys and for several months in the liver.
`
`Page 00006
`
`Page 00006
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`

`
`1266
`
`ANTIME‘I‘ABOLl'I'ItS
`
`[Chap. 55]
`
`The drug is converted to polyglutamates in
`hepatocytes, and there is also evidence for
`enterohepatic recirculation (Chabner er al.,
`198.1).
`-
`It is important to emphasize that metho-
`trexate is very poorly transported across
`the blood-brain barrier; hence, neoplastic
`cells that have entered the CNS probably
`are not affected by usual concentrations of
`drug in the plasma. When high doses of
`methotrexate are given, followed by leu-
`eovorin “rescue” (see below). substantial
`concentrations of methotrexate may be at-
`tained in the CNS. The pharrnacokinetie
`properties of methotrexate have been dis-
`cussed by Goldin (19378); see also Appendix
`II.
`
`Preparations, Dosage. and Routes of Adminis-
`tration.- . Methotrexate
`(amet:'t0pte:'£n;
`FOLEX,
`ME}(A'l‘l:‘.} is provided in scored, 2.5-mg tablets and
`also as a dry powder (the sodium salt) in vials con-
`taining 20 to 250 mg for preparation of sterile in-
`jcctable -solutions.
`Although the standard daily oral dosage of meth-
`otrexate .ordina1'ily employed in patients with leu-
`kemia has been 2.5 to 5 mg for children and 2.5 to
`10 mg for adults, newer therapeutic concepts have
`emerged involving revised dosage schedules and
`the use of multiple drugs sequentially and concur-
`rently. Methotrexate induces remission slowly,
`probably because the cells in advanced leukemia
`are not in the logarithmic phase of growth. For in-
`duction of remission it has been superseded by the
`more rapid and efiective therapy with vineristine
`plus prednisone, with or without daunorubicin.
`Methotrexate is of great value in the maintenance
`of remissions. particularly when administered in-
`termittently at doses of 30 mgfsq m, intramuscu-
`larly, twice a week. or by intensive 2-day "pulses"
`of ITS to 525 mglsq m at monthly intervals.
`The_ intrathecal administration of methotrexate
`has been employed. particularly when manifesta-
`tions of cerebral involvement in either leukemia or
`ehoriocarcinoma have appeared. as occurs not in-
`frequently ‘even during Systemic remissions. This
`route of administration achieves high concentra-
`tions of methotrexate in the CSF and is effective
`also in patients whose systemic disease has become
`resistant to methotrexate. since the leukemic cells
`in the CNS beyond the blood-brain barrier have
`survived in a pharmacological sanctuary and retain
`their original degree of sensitivity to the drug. The
`recommended intrathecal dose is 0.2 to 0.5 mgfkg,
`given once or repeated at intervals of 2 to'5 days,
`depending on the severity of involvement and-the
`response .to therapy: another dosage schedule is
`12 mgfsq m once weekly for 2 weeks and then
`monthly. Leucovorin may be administered intra-
`muscularly to counteract the systemic toxicity of
`methotrexate.
`'
`In the treatment of choriocareinoma with metho-
`
`If»
`
`tI'cxate, 15 mgffiq in (15 to 30 mg} is administered
`daily for 5 days orally or parenterally. Courses are
`repeated at 1- to 2-week intervals, toxicity permit-
`ting, and urinary gonadotnopin titers are used as a
`guide for persistence of disease.
`Methotrexate has been used iii the treatment of
`severe. disabling psoriasis in doses of 2.5 mg orally
`for 5 days, followed by a rest period of at least 2
`days. or 10 to 25 mg intravenously weekly. An ini-
`tial parente1'al test dose of 5 to 10 mg is recom-
`mended to detect any possible idiosyncrasy. Com-
`plete awareness of the pharmacology and toxic
`potential of methotrexate is a prerequisite for its
`use in this nonneoplastie disorder
`(Weinstein,
`1977).
`Continuous infusion of relatively large amounts
`of rnethotrexate may be employed (from 250 mg to
`lgfsq m, or more, weekly), _ but only when the
`tcchnic of leueovorin “rescue" is used. The ratio-
`nale for the administration of high doses is to
`achieve an excess of intracellular unbound drug,
`such that DNA synthesis is inhibited almost com-
`pletely. Extremely high (0.1 to 1 mM)' concentra-
`tions of drug must be achieved cxtracellularly in
`order to overcome any deficiency of the carrier-
`mediated transport system. After infusion of meth-
`otrexate for‘ 6 hours,
`leueovorin is injected at a
`dose of 6 to 15 mglsq m every 6 hours for 72 hours;
`the goal is to rescue normal cells and thereby pre-
`vent toxicity. The administration of methotrexate
`in high dosages may be extremely dangerous and
`should be performed only by experienced chemo-
`therapists whoare capable of quantification of the
`concentrations of mcthot1'exate and leueovorin in
`plasma. With appropriate precautions, these inves-
`tigational schedules are surprisingly free of toxic-
`ity. It is imperative to maintain the output of a la1'gc
`volume of alkaline urine, since methotrexate pre-
`cipitates in the renal tubules in acidic urine. In the
`presence of malignant effusions. delayed clearance
`may cause severe toxicity. Although the use of
`methotrexate in high closes with leueovorin “res-
`cue" has been studied clinically for several years
`with very encouraging results, the optimal timing,
`dose of leueovorin required, and proof of enhanced
`therapeutic efficacy remain to be established (see
`Goldin, 1978; Symposium, 1981b; Chabner. 1982c).
`
`Therapeutic Uses and Clinical Toxicity. Metho-
`trexate is a useful drug in the management of acute
`lymph0bla.sfic leukemia in children. However,
`mcthotrexate is of very limited value in the types of
`leukemia seen in adults. It is of established value in
`choriocarcinoma and related trophoblastic tumors
`of women, with complete and lasting remissions
`occurring in approximately 75% of women treated
`sequentially with methotrexate and daetinomycin,
`and in over 90% when early diagnosis is accompa-
`nied by a low concentration of gonadotropin in the
`urine‘. A number of these patients are living without
`evidence of disease -more than 25 years after initia-
`tion of therapy. In addition, many women with
`nonmetastatic trophoblastie disease, hydatidiform
`mole, and chorioadenoma destruens have been
`treated successfully with methotrexate. Beneficial
`results have also been reported in patients with
`
`:_—.n
`
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`
`l
`
`PYRIMIDINE ANALOGS
`
`1267
`
`mycosis fungoides, Burkitt’s and other non-Hodg-
`kin’s lymphomas, and carcinomas of the breast,
`tongue, pharynx. bladder. and testes (in conjunc-
`tion with chlorambucil and dactinomycin), as well
`as in occasional patients with other tumors. 1-ligh-
`dosc rnethotrexate. with subsequent leucovorin
`“reseue,“ can cause substantial tumor regression
`in at least two tumors highly refractory to most
`chemotherapeutic agents: carcinoma of the lung
`and osteogenic sarcoma. (For references, see Sym-
`posium, 1981b: Chabner,
`l982e: Calabresi er ui.,
`1985.) Striking improvement has been observed
`with the use of methotrexate in the treatment of
`severe psoriasis. Furthermore, methotrexate is an
`effective immunosuppressive agent and has been
`used for prevention of graft-versus-host reactions
`_that result from marrow transplantation, as well as
`in the management of dermatomyositis, rheuma-
`toid arthritis, Wegener’s granulomatosis, and pity-
`riasis rubra pilaris {see Wcirrstein, 1977; Goldin,
`I978).
`Treatment with methotrexate requires constant
`surveillance of the patient in order to judge dosage
`properly and to avoid serious toxic reactions.
`in
`persons treated with conventional doses or with
`concomitant leucovorin, it is frequently possible to
`avoid severe leukopenia or aplasia of the bone mar-
`row. Tlrrombocytopcnia with bleeding can be
`treated with platelet transfusions. but it may be dif-
`ficult to control, particularly in the presence of in-
`fection. It is imperative that a skilled medical team
`and sophisticated facilities, particularly abundant
`platelet transfusions and measures for preventing
`and combating infections, be available in order to
`provide the intensive supportive therapy necessary
`to control the severe toxic manifestations that may
`result when intensive dosage schedules are used.
`Other untoward reactions also may complicate
`the use of methotrexate {Wiemann and Calabresi.
`1985). Ulcerative stomatitis and diarrhea are fre-
`quent side effects and require intcr'r‘uption of the
`therapeutic regimen; hemorrhagic enteritis and
`death from intestinal perforation may occur. Addi-
`tional toxic manifestations include alopecia, der-
`matitis.
`interstitial pneumonitis, neurotoxicity,
`nephrotoxicity. defective oogenesis or spermato-
`genesis, abortion, teratogenesis, and hepatic dys-
`function, usually reversible but-sometimes leading
`to cirrhosis. The long—term complications associ-
`ated with the use of mcthotrexate for immunosup-
`pressive therapy are discussed by Schein and
`Winokur (I975).
`-
`
`PYRIMIDINE ANALOGS
`
`This class of agents encompasses a di-
`verse and interesting group of drugs that
`have in common the capacity to impede the
`biosynthesis of pyrimidine nucleotides or to
`mimic these natural metabolites to such an
`extent that they interfere with vital cellular
`activities, such as the synthesis and func-
`tioning of nucleic acids. Certain of the
`
`drugs in this group are employed in the
`treatment of a variety of alllictions. includ-
`ing neoplastic diseases, psoriasis, and in-
`fections caused by fungi and DNA-contain-
`ing viruses. When selected members of the
`group are used together or concurrently
`with other antimctabolites, synergistic ef-
`fects have been demonstrated against vari-
`ous experimental
`tumors, and some of
`these treatment schedules are being investi-
`gated clinically. (Seereviews by Maley,
`1977; Chabner, 1982c.)
`
`General Mechanism of Action. The antineoplas—
`tic agents
`fluorouracil
`(5-FU) and cytarahinc
`(AraC), the antiviral compound idoxuridine, and
`the antifungal agent flucytosine (Chapter 54) are
`the drugs in this group that ar'c established clini-
`cally. Other compounds arc under clinical investi-
`gation, as are potentially synergistic combinations
`of pyrimidine analogs and other types of inhibitors.
`Among the best-characterized agents in this class
`are the halogenated pyrimidines, a group that in-
`cludes such compounds as fluorouracil and idoxuri-
`dine. If one compares the van der Waals radii of the
`various substituents (Table 55-3), the dimension of
`the fluorine atom resembles that of hydrogen,
`whereas the bromine and iodine atoms are close in
`size to the methyl group. Idoxuridine has relatively
`little effect on the biosynthesis of thyrnidylic acid;
`like thymidine, however, it is converted enzymati-
`cally within cells to phosphorylated derivatives; it
`is also degraded to the corresponding base,
`iodouracil, which is converted to uracil and iodide.
`The phosphorylated forms of idoxuridine inhibit
`competitively the utilization of the analogous deriv-
`atives of thymidine and can lead, in appropriate cir-
`cumstances,
`to incorporation of the analog, as
`iododeoxyuridylic acid, into DNA in place of thy-
`midylic acid. These activities can suppress tempo-
`rarily the growth of both experimental and human
`neoplasms; in addition, incorporation of the iodo—
`or' bromo- analogs into DNA rende1's the latter
`more susceptible to the injurious effects of radia-
`tion.
`If the hydrogen on position 5 of the pyrimidine
`1'ing is replaced with fluorine, the chemical reactiv-
`ity of the ring is significantly altered, although the
`molecule, fluorouraeil. behaves as does uracil with
`several enzymes. Fluorine has an inductive (elec-
`tron-withdrawing) effect. which is reflected in a
`much lower pK,, with fluorouracil-containing com-
`pounds than with the natural compounds. The ioni-
`zation that occurs is as follows:
`
`
`
`r-....._..__.._._.....
`
`i.
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