Pharmac. Ther. Vol. 52, pp. 35-84, 1991
`Printed in Great Britain. All rights reserved
`
`Specialist Subject Editor: E. HAMEL
`
`0163-7258/91 SO.OO + 0.50
`© 1992 Pergamon Press pic
`
`THE CLINICAL PHARMACOLOGY AND USE OF
`ANTIMICROTUBULE AGENTS IN CANCER
`CHEMOTHERAPEUTICS
`
`ERIC K. ROWINSKY and Ross C, DONEHOWER
`Division of Pharmacology and Experimental Therapeutics, The Johns Hopkins Oncology Center,
`600 North Wolfe Street, Baltimore, Maryland 21205, U.S.A.
`
`Abstract-Although there has been a rapid expansion of the number of classes of compounds with
`antineoplastic activity, few have played a more vital role in the curative and palliative treatment of cancers
`than the antimicrotubule agents. Although the vinca alkaloids have been the only subclass of antimicro(cid:173)
`tubule agents that have had broad experimental and clinical applications in oncologic therapeutics over
`the last several decades, the taxanes, led by the prototypic agent taxol, are emerging as another very active
`class of antimicrotubule agents. After briefly reviewing the mechanisms of antineoplastic action and
`resistance, this article comprehensively reviews the clinical pharmacology, therapeutic applications, and
`clinical toxicities of selected antimicrotubule agents.
`
`CONTENTS
`
`~harmac. Ther. Vol. 52, pp. 35-84, 1991 0163-7258/91 $ )rinted in Great Britain. All rights reserved © 1992 Pergamc ;pecialist Subject Editor: E. HAIvtEL Division of Pharmacology and Experimental Therapeutics, The Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, Maryland 21205, U.S.A. Abstract--Although there has been a rapid expansion of the number of classes of compounds wi{ antineoplastic activity, few have played a more vital role in the curative and palliative treatment of cance than the antimicrotubule agents. Although the vinca alkaloids have been the only subclass of antimicr( tubule a~ents that have had broad exnerimental and clinical an,alication~ in oncolo~it~ tharar~utic.~ nv THE CLINICAL PHARMACOLOGY AND USE OF ANTIMICROTUBULE AGENTS IN CANCER CHEMOTHERAPEUTICS :,/.:. 2,7.3. 2.7.4. 2.7.5. 3. Taxanes 3.1. Taxol 3.1.1. 3 1.2. z.z. ~wecnanlsms oi acnon 2.3. Mechanisms of resistance 37 2.4. Vincristine 38 2.4.1. Clinical pharmacology 38 2.4.2. Dose and schedule 39 2.4.3. Clinical applications 40 2.4.4. Toxicities 43 2.5. Vinblastine 46 2.5.1 Clinical pharmacology 46 2.5.2, Dose and schedule 46 2.5.3. Clinical applications 46 Loxicities of selected antimicrotubule agents. CONTENTS duction t Alkaloids 3eneral Vlechanisms of acti( PP L5.4. Toxicities ¢indesine L6.1. Clinical pharmacology L6.2. Dose and schedule L6.3. Clinical trials L6.4. Toxicities qinorelbine (Navelbine) L7.1. Preclinical L7.2. Clinical pharmacology Dose and schedule Clinical trials Toxicities Mechanisms of action 3.1.2. Preclinical antineoplastic activity 3.1.3. Mechanisms of resistance 3.1.4. Clinical pharmacology 3.1.5. Dose and schedule 3.1.6. Clinical trials ERIC K. tubule agents that have had broa the last several decades, the taxan( class of antimicrotubule agents. resistance, this article comprehen: clinical toxicities 1 Intrndl~Ptlcm and Ross C. DONEHOWER with ~alliative treatment of cancers Icro- d and clinical applications m oncologic therapeutics over )rototypic agent taxol, are emerging as another very active reviewing the mechanisms of antineoplastic action and the clinical pharmacology, therapeutic applications, and 36 36 36 37
`
`1. Introduction
`2. Vinca Alkaloids
`2.1. General
`2.2. Mechanisms of action
`2.3. Mechanisms of resistance
`2.4. Vincristine
`2.4.1. Clinical pharmacology
`2.4.2. Dose and schedule
`2.4.3. Clinical applications
`2.4.4. Toxicities
`2.5. Vinblastine
`2.5.1 Clinical pharmacology
`2.5.2. Dose and schedule
`2.5.3. Clinical applications
`2.5.4. Toxicities
`2.6. Vindesine
`2.6.1. Clinical pharmacology
`2.6.2. Dose and schedule
`2.6.3. Clinical trials
`2.6.4. Toxicities
`2.7. Vinorelbine (Navelbine)
`2.7.1. Preclinical
`2.7.2. Clinical pharmacology
`2.7.3. Dose and schedule
`2.7.4. Clinical trials
`2.7.5. Toxicities
`3. Taxanes
`3.1. Taxol
`3.1.1. Mechanisms of action
`3.1.2. Preclinical antineoplastic activity
`3.1. 3. Mechanisms of resistance
`3.1.4. Clinical pharmacology
`3.1.5. Dose and schedule
`3.1.6. Clinical trials
`
`36
`36
`36
`37
`37
`38
`38
`39
`40
`43
`46
`46
`46
`46
`49
`50
`50
`51
`51
`52
`53
`53
`54
`54
`54
`55
`56
`56
`56
`57
`58
`58
`59
`59
`
`Abbreviations: ALL = acute lymphocytic leukemia; ANLL = acute nonlymphocytic leukemia; AUC = area under the
`time-versus-concentration curve; DNA = deoxyribose nucleic acid; GM-CFC = granulocyte-macrophage colony-forming
`cell; GTP = guanosine
`triphosphate; HSR = hyp~rsensitivity reaction; MAPs = microtubule-associate proteins;
`NCI = National Cancer Institute; NVB = vinorelbine (Navelbine); SIADH = syndrome of inappropriate secretion of
`antidiuretic hormone; tl = half-life; VBL = vinblastine; VCR = vincristine; VDS = vindesine.
`
`35
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`36
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`E. K. ROWINSKY and R. C. DoNEHOWER
`
`3.1.7. Future directions
`3.1.8. Toxicities
`3.2. Taxotere (RP 56976)
`.
`3.3. Novel antimicrotubule agents in preclinical development and conclusIOn
`References
`
`61
`62
`65
`65
`66
`
`l. INTRODUCTION
`
`Microtubules are among the most strategic sub(cid:173)
`cellular targets of anticancer chemotherapeutics. Like
`DNA, microtubules are ubiquitous to all cells.
`Although they are primarily recognized as being
`important in mitotic functions, microtubules also
`play critical roles in many interphase and mainten(cid:173)
`ance functions in cells such as maintenance of cell
`shape and scaffolding, intracellular transport, se(cid:173)
`cretion, and possible relay of signals between cell
`surface receptors and the nucleus (Edelman, 1976;
`Dustin, 1980; Crossin and Carney, 1981; Otto et al.,
`1981). Interestingly, antimicrotubule agents are all
`structurally complex natural products or semi(cid:173)
`synthetic compounds. They are among the most
`important of anticancer drugs and have significantly
`contributed to the therapy of most curable neoplasms
`such as Hodgkin's and non-Hodgkin's lymphomas,
`germ cell tumors and childhood leukemia (Loehrer et
`al., 1988b; DeVita et al., 1989; Hellman et al., 1989;
`Henderson et al., 1990). They are also extremely
`useful in the palliative treatment of many other
`cancers. Despite their promise, only a few anti micro(cid:173)
`tubule agents have been developed over the last
`decade and only two vinca alkaloids, vincristine and
`vinblastine, are officially approved for use and are
`widely available for oncologic therapy in North
`America and Europe. However, there has recently
`been a resurgence of interest in these compounds.
`This has led to the identification and development of
`several novel vinca alkaloids like vinorelbine (Navel(cid:173)
`bine), as well as new classes of antimicrotubule agents
`such as taxanes, dolostatins, and rhizoxin which
`possess novel mechanisms of cytotoxic action, unique
`antitumor spectra in vitro and/or in the clinic, and
`potentially improved therapeutic indices. This review
`will focus on those vinca alkaloids and taxanes in
`which ample clinical and preclinical experience exists.
`
`36 E.K. ROWINSKY and R. C. DONEHOWER 3.1.7. Future directions ( 3.1.8. Toxicities ( 3.2. Taxotere (RP 56976) 3.3. Novel antimicrotubule agents in preclinical development and conclusion References Since the 1960s, only two vinca alkaloids, (VCR) and vinblastine (VBL), have been I.~x~,o ~a 1~. x]. ,tt,t~.y O./,~ ~VII/,IJV~K,'~t vt important in mitotic functions, microtubules also nucleus (the catharanthine portion) and a ( play critical roles in many interphase and mainten- dole nucleus (the vindoline portion). VCR ante functions in cells such as maintenance of cell are structurally identical with the excepti shape and scaffolding, intracellular transport, se- substitutent attached to the nitrogen of the cretion, and possible relay of signals between cell nucleus where VCR possesses a formyl [ surface receptors and the nucleus (Edelman, 1976; vm hae a m~thvl ...... T-T ...... V("l~ 1. INTRODUCTION vincr offi Microtubules are among the most strategic sub- approved for the treatment of malignant disord( cellular .............. targets of anticancer chemotherapeutics. Like the United States. Both VCR and VBL are ] Will IUI,;U~ UII LIIU~I; VlllUi:t iall~.i:l, ll.)lU5 i~llltl ti:tAi:tllU~ Ill V|N~N[ which ample clinical and preclinical experience exists. ~nl~lulmm o,i 2. VINCA ALKALOIDS ~ CL~ .... its future is uncertain, utner vmca amaloms With useful in the palliative treatment of many other antitumor activity include vinleurosine and vinro- cancers. Despite their promise, only a few antimicro- sidine; however, further clinical development of these tubule agents have been developed over the last decade and only two vinca alkaloids, vincristine and vinblastine, are officially approved for use and are widely available for oucologic therapy in North ~~-"~ America and Europe. However, there has recently been a resurgence of interest in these compounds. ~" ............... A third pounds. They are among the most desacetyl v nticancer drugs and have significantly rivative an( the therapy of most curable neoplasms duced into dn's and non-Hodgkin's lymphomas, has demon rs and childhood leukemia (Loehrer et cies, most i ¢ita et al., 1989; Hellman et al., 1989; only been aL, 1990). They are also extremely its future " the identification and development of inca alkaloids like vinorelbine (Navel- new classes of antimicrotubule agents es, dolostatins, and rhizoxin which aechanisms of cytotoxic action, unique :tra in vitro and/or in the clinic, and roved therapeutic indices. This review those vinca alkaloids and taxanes in A 2.1. GENERAL lkaloids are natural or semisynthetic ich are present in minute quantities in haranthus roseus G. Don (formerly an.), commonly called the periwinkle. s were originally screened by pharma- DNA, microtubules are ubiquitou Although they are primarily recog Dustin, 1980; Crossin and Carney, l! 1981). Interestingly, antimicrotubule structurally complex natural prod synthetic com t important of a contributed to such as Hodgkin's c,~rrn ~'Pll t,mn 65 65 66 vincristi officia disorders the United States. Both VCR and VBL are lar~ ells. dimeric compounds with similar but complex str~ ring tures (Fig. 1). They are composed of an ind¢ dihydroi and V[ ation of t en of the vindoli group al VBL has a methyl group. However, VCR and V[ al., differ dramatically in their antitumor spectrum aJ all clinical toxicities. :mi- A third vinca alkaloid analog, vindesine (VD vinblastine carboxyamide), a synthetic and human metabolite of VBL, was intr clinical trials in the 1970s. Although V[ demonstrated activity against several maligna notably non-small cell lung cancer, it h available for investigational purposes m tain. Other " alkaloids wi /
`
`Since the 1960s, only two vinca alkaloids, vincristine
`(VCR) and vinblastine (VBL), have been officially
`approved for the treatment of malignant disorders in
`the United States. Both VCR and VBL are large,
`dimeric compounds with similar but complex struc(cid:173)
`tures (Fig. I). They are composed of an indole
`nucleus (the catharanthine portion) and a dihydroin(cid:173)
`dole nucleus (the vindoline portion). VCR and VBL
`are structurally identical with the exception of the
`substitutent attached to the nitrogen of the vindoline
`nucleus where VCR possesses a formyl group and
`VBL has a methyl group. However, VCR and VBL
`differ dramatically in their antitumor spectrum and
`clinical toxicities.
`A third vinca alkaloid analog, vindesine (VDS;
`desacetyl vinblastine carboxyamide), a synthetic de(cid:173)
`rivative and human metabolite of VBL, was intro(cid:173)
`duced into clinical trials in the 1970s. Although VDS
`has demonstrated activity against several malignan(cid:173)
`cies, most notably non-small cell lung cancer, it has
`only been available for investigational purposes and
`its future is uncertain. Other vinca alkaloids with
`antitumor activity include vinleurosine and vinro(cid:173)
`sidine; however, further clinical development of these
`
`2. VINCA ALKALOIDS
`
`2.1. GENERAL
`
`The vinca alkaloids are natural or semisynthetic
`compounds which are present in minute quantities in
`the plant Catharanthus roseus G. Don (formerly
`Vinca rosea Linn.), commonly called the periwinkle.
`The compounds were originally screened by pharma(cid:173)
`ceutical chemists because of their use as hypoglycemic
`agents in several parts of the world. However, their
`hypoglycemic activity turned out to be of miniscule
`importance compared to their cytotoxic properties.
`
`FIG. 1. Structures of vincristine and vinblastine (A);
`vindesine (B).
`
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`Antimicrotubule agents in cancer chemotherapy
`
`37
`
`agents has been abandoned due to their exceptional
`toxicities (Creasey, 1975). Recently, semi-synthetic
`derivatives of VBL, specifically vinorelbine (Navel(cid:173)
`bine; NVB) and vinzolidine, have also entered clinical
`development and appear to be exciting for several
`reasons. These compounds, especially NVB, have
`demonstrated activity in neoplasms that are refrac(cid:173)
`tory to conventional agents. In addition, both NVB
`and vinzolidine are oral preparations in contrast to
`all other available vinca alkaloids which can only be
`administered by parenteral routes.
`The clinical pharmacology, toxicology, and clinical
`applications of the vinca alkaloids, VCR, VBL, VDS,
`and NVB, will be discussed in this section. Relevant
`aspects of vinzolidine's clinical pharmacology and
`early phase 1/11 trials have been published (Budman
`et al., 1984; Kreis et al., 1986; Taylor et al., 1990;
`Budman et al., 1991). Extensive reviews of the
`identification, isolation, and characterization of the
`vinca alkaloids are also available (Johnson et aI.,
`1963; Neuss et al., 1964; Creasy et al., 1975).
`
`The binding of the vinca alkaloids to tubulin, in
`turn, prevents the polymerization of these subunits
`into microtubules. The subunits then form highly
`ordered paracrystalline arrays of tubulin that are
`often termed 'paracrystals' (Bryan, 1972b; Manfredi
`and Horowitz, 1984a) which contain one mole
`of bound drug per mole of tubulin (Bensch and
`Malawista, 1969). The net effects of these processes
`include the blockage of the polymerization of tubulin
`into microtubules which may eventually lead to
`the inhibition of vital cellular processes and cell
`death.
`Although most evidence indicates that mitotic ar(cid:173)
`rest is the principal cytotoxic effect of the vinca
`alkaloids, there is also evidence suggesting that the
`lethal effects of these agents may be attributable
`in part to effects on other phases of the cell cycle.
`The vinca alkaloids appear to be cytotoxic to non(cid:173)
`proliferating cells in vitro and in vivo in both G 1 and
`S cell cycle phases (Madoc-Jones and Mauro, 1968;
`Strychmans et al., 1973; Rosner et al., 1975).
`
`Antimicrotubule agents in cancer chemotherapy igents has been abandoned due to their exceptional The binding of the vinca alkaloids to tu oxicities (Creasey, 1975). Recently, semi-synthetic turn, prevents the polymerization of these terivatives of VBL, specifically vinorelbine (Navel- into microtubules. The subunits then fort fine; NVB) and vinzolidine, have also entered clinical ordered paracrystalline arrays of tubulin levelopment and appear to be exciting for several often termed 'paracrystals' (Bryan, 1972b; ] • easons. These compounds, especially NVB, have and Horowitz, 1984a) which contain o of bound drug per mole of tubulin (Bet Malawista, 1969). The net effects of these 1 include the blockage of the polymerization and NVB, will be discussed in this section. Relevant rest is the principal cytotoxic effect of I aspects of vinzolidine's clinical pharmacology and alkaloids, there is also evidence suggestinp early phase I/If trials have been published (Budman lethal effects of these agents may be aU et al., 1984; Kreis et al., 1986; Taylor et al., 1990; in part to effects on other phases of the Budman et al., 1991). Extensive reviews of the The vinca alkaloids appear to be cytotoxi identification, isolation, and characterization of the nroliferatin~ cells/n vitro and/n vivo in bol demonstrated activity in neoplasms that are refrac- Bensch tory to conventional agents. In addition, both NVB proc~ and vinzolidine are oral preparations in contrast to of tut all other available vinca alkaloids which can only be into microtubules which may eventually leac the inhibition of vital cellular processes and meiosis, secretion, intracellular transport, and axonal products by virtue of increased amounts transport. Many of the unique pharmacologic inter- brane phosphogiycoproteins (P-glycoprot, actions of drugs with microtubules are due to a as the P-170membraneglycoprotein that fu dynamic equilibrium between microtubules and tubu- a drug efflux pump (Hamada et al., 1987). lin dimers (Bryan, 1974; Dustin, 1980). Critical mess- tial number of unrelated compounds, incl ages in the cell, including those related to cell cycle cium channel antagonists (Tsuruo, 1983; B 17OU}. k/tlll;l IJIUl.;llq;ll|l~.tll ~;ll~;t,l.~ tltO.t IIIIVI~ ~l~ll [1;- I;ll, Ul;l till; ttl[.,lUitl UI ~ttt ~IIIJUIIIL~ LIt tUUUIIII, IGiO.ldlll~ ported for the vinca alkaloids include: (a) compe- to decreased vinca alkaloid binding (Cabral et al., tition for transport of amino acids into cells; (b) 1986; Brewer and Warr, 1987). The second, more well inhibition of purine biosynthesis; (c) inhibition of characterized mechanism of resistance involves the RNA, DNA, and protein synthesis; (d) disruption of general multi-drug resistance (mdr) phenotype that lipid metabolism; (e) inhibition of glycolysis; (f) confers broad resistance to many unrelated classes of alterations in the release of antidiuretic hormone; (g) large, bulky natural product antineoplastic agents inhibition of release of histamine by mast cells and including the antitumor antibiotics, vinca alkaloids, enhanced release of epinephrine; and (h) disruption in colchicine, and taxoi, and the epipodophyllotoxins . MECHANISMS OF ACTION lkaloids induce cytotoxicity by direct Resistanc th tubulin which is the basic protein rapidly in rotubules (Johnson et aL, 1963; Olm- date, two r ~y, 1973; Luduena et al., 1977; Dustin, scribed. Th, iochemical effects that have been re- either the a f the cell membrane and membrane (Juliano an nprehensive reviews on these various 1978; Beck cen published (Creasy, 1975, Beck, Inaba et ai 1985; Beck, s are ubiquitous in eukaryotic cells et al., 1987; e performance of many critical func- Moscow an ; maintenance of cell shape, mitosis, type posses race net microtubule polymerization. Warr, 1987 s exert their antimicrotubule effects by antagonists Le on tubulin that is distinctly different 1986), antit ag sites of colchicine, podophyllotoxin, amiodarom an, 1972a; Owellen et al., 1972; Wilson Earuyama, ~attacharyya and Wolff, 1976; Huang 1989), and bine develo~ reasons. administered by parenteral routes. The clinical pharmacology, toxicolc applications of the vinca alkaloids, V( identification, isolation, and charactc vinca alkaloids are also available (: 1963; Neuss et al., 1964; Creasy et a 2.2. The vinca alkalo interactions with ~UDU[II1 form highl that m Man fret one mol an )rocess( mli lead t ce ieal death. ~)S, Although most evidence indicates that mitotic a] the vinc ,~esting that t~ attributab cell cycl~ rtotoxic to not the proliferating cells/n vitro and vivo in both GI an al., S cell cycle phases (Madoc-Jones and Mauro, 1961 Strycbmans et al., 1973; Rosner et aL, 1975). 2.3. MECHANISMS OF RESISTANCE race to the vinca alkaloids develops fairl vitro in the presence of these agents. "[ mechanisms of resistance have been d~ The first mechanism involves mutations i alpha or beta subunits of tubulin leadin
`
`The vinca alkaloids induce cytotoxicity by direct
`interactions with tubulin which is the basic protein
`subunit of microtubules (Johnson et aI., 1963; Olm(cid:173)
`stead and Borisy, 1973; Luduena et al., 1977; Dustin,
`1980). Other biochemical effects that have been re(cid:173)
`ported for the vinca alkaloids include: (a) compe(cid:173)
`tition for transport of amino acids into cells; (b)
`inhibition of purine biosynthesis; (c) inhibition of
`RNA, DNA, and protein synthesis; (d) disruption of
`lipid metabolism; (e) inhibition of glycolysis; (f)
`alterations in the release of antidiuretic hormone; (g)
`inhibition of release of histamine by mast cells and
`enhanced release of epinephrine; and (h) disruption in
`the integrity of the cell membrane and membrane
`functions. Comprehensive reviews on these various
`effects have been published (Creasy, 1975, Beck,
`1984).
`Microtubules are Ubiquitous in eukaryotic cells
`and vital to the performance of many critical func(cid:173)
`tions including maintenance of cell shape, mitosis,
`meiosis, secretion, intracellular transport, and axonal
`transport. Many of the unique pharmacologic inter(cid:173)
`actions of drugs with microtubules are due to a
`dynamic equilibrium between microtubules and tubu(cid:173)
`lin dimers (Bryan, 1974; Dustin, 1980). Critical mess(cid:173)
`ages in the cell, including those related to cell cycle
`traverse, influence net microtubule polymerization.
`Vinca alkaloids exert their antimicrotubule effects by
`binding to a site on tubulin that is distinctly different
`from the binding sites of colchicine, podophyllotoxin,
`and taxol (Bryan, 1972a; Owellen et al., 1972; Wilson
`et al., 1975; Bhattacharyya and Wolff, 1976; Huang
`et al., 1985). The vinca alkaloids bind to specific sites
`on tubulin with a binding constant of 5.6 x lO-s M
`(Na and Timasheff, 1986) and initiate a sequence
`of events that lead to disruption of microtubules.
`
`2.2. MECHANISMS OF ACTION
`
`2.3. MECHANISMS OF REsISTANCE
`
`Resistance to the vinca alkaloids develops fairly
`rapidly in vitro in the presence of these agents. To
`date, two mechanisms of resistance have been de(cid:173)
`scribed. The first mechanism involves mutations in
`either the alpha or beta subunits of tubulin, leading
`to decreased vinca alkaloid binding (Cabral et al.,
`1986; Brewer and Warr, 1987). The second, more well
`characterized mechanism of resistance involves the
`general multi-drug resistance (mdr) phenotype that
`confers broad resistance to many unrelated classes of
`large, bulky natural product antineoplastic agents
`including the antitumor antibiotics, vinca alkaloids,
`colchicine, and taxol, and the epipodophyllotoxins
`(Juliano and Ling, 1976; Wilkoff and Dulmadge,
`1978; Beck et aI., 1979; Riordan and Ling, 1979;
`Inaba et al., 1984; Conter and Beck, 1984; Gupta,
`1985; Beck, 1987; Fojo et al., 1987a,b; Greenberger
`et al., 1987; Hamada et al., 1987; Choi et al., 1988;
`Moscow and Cowan, 1988). Cells with mdr pheno(cid:173)
`type possess an increased capacity to expel natural
`products by virtue of increased amounts of mem(cid:173)
`brane phosphoglycoproteins (p.glycoproteins) such
`as the P-170 membrane glycoprotein that functions as
`a drug efflux pump (Hamada et al., 1987). A substan(cid:173)
`tial number of unrelated compounds, including cal(cid:173)
`cium channel antagonists (Tsuruo, 1983; Brewer and
`Warr, 1987), phenothiazines and other 'calmodulin
`antagonists' (Tsuruo et al., 1983; Akiyama et al.,
`1986), antiarrhythmic agents such as quinidine and
`(Tsuruo et al., 1984;
`Inaba and
`amiodarone
`Earuyama, 1988), cephalosporins (Gosland et al.,
`1989), and cyclosporin A (Slater et al., 1986) have
`been demonstrated to reverse drug resistance related
`to the mdr phenotype. Interestingly, the ability of the
`calcium channel blocker verapamil or cyclosporin A
`to reverse mdr resistance does not appear to be
`
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`38
`
`E. K. ROWINSKY and R. C. DoNEHOWER
`
`related to either calcium channel antagonism or
`immunomodulation since inactive isomers are con(cid:173)
`siderably more active in reversing this type of resist(cid:173)
`ance (Gruber et al., 1988; Twentyman, 1988).
`
`2.4. VINCRISTINE
`
`38 E.K. ROWINSKY and R. C. DONEHOWER related to either calcium channel antagonism or highest (0.740+0.3171/kg-hr), and VDS immunomodulation since inactive isomers are con- mediate value (0.252 4:_ 0.1001/kg-hr) (Nel siderably more active in reversing this type of resist- 1980; Nelson, 1982). It has been postu ance (Gruber et aL, 1988; Twentyman, 1988). VCR's longer terminal half-life and low clearance rate compared to other vinca might account for its greater neuroto~ There has been a considerable intere administration of VCR on protracted c :_.i~..~: .... '1.~.~1..1~^ '1-~_..1 __ ~L-- 1.'1._1111-_~ JI ........... 1" ....... o ............... 1 ~ ......... d .................. \ ......... , .... , ...... d ....... to a lack of sensitive assays capable of measuring vinca alkaloids appears to be dependent n minute plasma concentrations which result from the drug concentration, but on duration of wide distribution of mg doses of these agents. Early (Jackson and Bender, 1979; Hill and Wh~ animal and human studies used radiolabeied vinca Ferguson et al., 1984; Ludwig et al., 1984 alkaloids, with further separation of parent drug and 1990). VCR concentrations in the range of metabolites bv high-oressure liouid chromato~,raohv only brieflv achieved after intravenous b crest i~ conti~ Relative to their broad clinical use, there are infusion schedules based on the likelihood that limited data available about the pharmacology of the schedules more closely simulate optimal in vitro in children (Sethi and Kimball, 1982). When the the spleen appears to concentrate VCR tt pharmacologic behavior of VCR has been studied extent than any other tissue (Owellen and using 3H-VCR coupled with purification by HPLC, 1972; Castle et al., 1976). In the monkey, alpha, beta, and terminal t½ have been determined to with the highest VCR concentration ha, be 0.85, 7.4, and 64 min, respectively (Bender et al., pancreas (El Dareer et al., 1977). Althougl 1977). In one comparative pharmacokinetic study of been demonstrated to rapidly enter the c, ~J,~.,I, lll t;l ul., 12OIU, Ot.'l, lll O,111.1 I'~.IIIIUO.II~ 1701, 11~'l~Ull, ~,UIIk,II,dlI.IO.I, IUII~ U~,IU','V .(., IIIVl I..l~l.t.,lk~Ull O*llld I./~,lll,.ll,~l~ 1982; Hacker et al., 1984; Rahmani et al., 1985; 1979). Interestingly, a 0.5 mgintravenous bolus injec- Labinjoki et al., 1986; Ratain and Vogelzang, 1986, tion of VCR followed by a continuous infusion at 1987). doses of 0.5 to 1.0 mg/m2/day for 5 consecutive days Following standard doses of VCR administered as has typically produced steady-state VCR concen- a bolus intravenous injection, peak plasma VCR trations ranging from 1 nM to 10 nM and half-lives levels approach 0.4/~M (Bender et al., 1977). VCR's after discontinuation of the infusions have ranged plasma distribution is characterized by triexponential from 10.5 hr (1.0 mg/m 2) to 21.7 hr (0.5 rag/m:) kinetics with a distribution (alpha) half-life (t½) of less (Jackson et al., 1981b). Although peak VCR plasma on el at., 15p/~; uwellen ana raartKe, el at., !'35U ecently, studies using sensitive radio- to conditiq (RIA) and enzyme-linked immuno- though, tr [ELISA) methods, which may be able required to tlolar concentrations, have been able lymphobla, hese problems (Nelson et al., 1979, ment is req ! al., 1980; Jackson et al., 1980, 1981a; at 10 nM ~lb; Sethi and Kimball 1981; Nelson, concentrati ng to extensive and rapid tissue bind- concentrati t½ values have been reported to range have gener; min and terminal t½ values have varied bolus inject ffoundly, from 23 _ 17 to 85 ___ 65 hr greater tota , 1977b; Nelson et al., 1980; Jackson concentrati Sethi et al., 1981b; Nelson, 1982). The tisst lcokinetic parameters have been noted gated in sev d VDS, VCR had the longest terminal vous systen hr, versus 24.8 + 7.5 hr for VBL and with VCR ~or VDS (Nelson et al., 1980; Nelson, brospinal fl parent volumes of distribution (V a) Dareer et c high (Vdcentral of 0.328 -t- 0.106 1/ks dogs, monk 8.42_ 3.17 I/ks for VCR), indicating penetrates 2.4. VINCRISTINE 2.4.l. Clinical Pharmacology vinca alkaloids in humans compared of antineoplastic agents. This has pri by high-l: t 1 (HPLC) (Castle et al., 1976; Bender e et al., 1977; E1 Dareer et al., 1977; 1977a,b; Jackson et al., 1978 Owell 1985). More recentl, immunoassays sorbent assay ( to detect picomolar l"~elson et ~ostulated tt lower plasl alkalo ~toxic effe (Nelson et al., 1980; Nelson 1982). in 1 contmuc th~ Y F vitro cc sses ditions required for cytotoxicity compared to bo due schedules (Jackson, 1990). The cytotoxicity of t not only treatmc elan, 191 1984; Jacksc 100 nM phy only y bolus inj~ 2ulp tions and levels typically decline to less than 10 nM al., 2 to 4 hr approaching 1 nM by 48 to 72 hr (Nels tke. et al., 1980; Jackson et al., 1981b). When compar conditions required for cytotoxicity in vit treatment with 100riM VCR for 3 hr kill 50% of L1210 murine or CEM hum >hoblastic leukemias, whereas 6 to 12 hr of trel :luired to achieve this degree of cytotoxic and no lethal effects occurs with V( concentrations below 2riM (Jackson and Bend
`
`highest (0.740 ± 0.317 I/kg-hr), and VDS an inter(cid:173)
`mediate value (0.252 ± 0.100 I/kg-hr) (Nelson et al.,
`1980; Nelson, 1982). It has been postulated that
`VCR's longer terminal half-life and lower plasma
`clearance rate compared to other vinca alkaloids
`might account for its greater neurotoxic effects
`(Nelson et al., 1980; Nelson 1982).
`There has been a considerable interest in the
`administration of VCR on protracted continuous
`infusion schedules based on the likelihood that these
`schedules more closely simulate optimal in vitro con(cid:173)
`ditions required for cytotoxicity compared to bolus
`schedules (Jackson, 1990). The cytotoxicity of the
`vinca alkaloids appears to be dependent not only on
`drug concentration, but on duration of treatment
`(Jackson and Bender, 1979; Hill and Whelan, 1980;
`Ferguson et aI., 1984; Ludwig et al., 1984; Jackson,
`1990). VCR concentrations in the range of 100 nM are
`only briefly achieved after intravenous bolus injec(cid:173)
`tions and levels typically decline to less than 10 nM by
`2 to 4 hr approaching I nM by 48 to 72 hr (Nelson
`et al., 1980; Jackson et aI., 198Ib). When compared
`to conditions required for cytotoxicity
`in vitro,
`though, treatment with 100 nM VCR for 3 hr is
`required to kill 50% ofLI21O murine or CEM human
`lymphoblastic leukemias, whereas 6 to 12 hr of treat(cid:173)
`ment is required to achieve this degree of cytotoxicity
`at 10 nM and no lethal effects occurs with VCR
`concentrations below 2 nM (Jackson and Bender,
`1979). Interestingly, a 0.5 mg intravenous bolus injec(cid:173)
`tion of VCR followed by a continuous infusion at
`doses of 0.5 to 1.0 mg/m2/day for 5 consecutive days
`has typically produced steady-state VCR concen(cid:173)
`trations ranging from I nM to 10 nM and half-lives
`after discontinuation of the infusions have ranged
`from 10.5 hr (1.0 mg/m2)
`to 21.7 hr (0.5 mg/m2)
`(Jackson et al., 1981b). Although peak VCR plasma
`concentrations achieved with continuous infusions
`have generally been lower than levels achieved with
`bolus injections, continuous infusions have produced
`greater total drug exposure above a critical threshold
`concentration (Jackson et al., 1981 b).
`The tissue distribution of VCR has been investi(cid:173)
`gated in several animal species. In the dog and the rat,
`the spleen appears to concentrate VCR to a greater
`extent than any other tissue (Owe lien and Donigian,
`1972; Castle et al., 1976). In the monkey, the tissue
`with the highest VCR concentration has been the
`pancreas (EI Dareer et al., 1977). Although VCR has
`been demonstrated to rapidly enter the central ner(cid:173)
`vous system of primates after intravenous injection,
`with VCR levels above 1 nM maintained in cere(cid:173)
`brospinal fluid for longer than 72 hr in one study (EI
`Dareer et al., 1977), most investigations using rats,
`dogs, monkeys, and humans have indicated that VCR
`penetrates poorly through the blood-brain barrier
`(Castle et al., 1976; EI Dareer et al., 1977; Jackson
`et al., 1980, 198Ia). In humans, cerebrospinal fluid
`levels have been 20- to 30-fold lower than concurrent
`plasma concentrations and have never exceeded
`
`2.4.1. Clinical Pharmacology
`
`Relative to their broad clinical use, there are
`limited data available about the pharmacology of the
`vinca alkaloids in humans compared to other classes
`of antineo