ADVANCES IN
`CANCER RESEARCH
`
`Edited by
`ALEXANDER HADDOW
`Chester Beatty Research Institute
`Institute of Cancer Research
`Royal Cancer Hospital, London, Englan d
`
`SIDNEY WEINHOUSE
`Fels Research Institute
`Temple University Medical School
`Philadelphia, Pennsylvania
`
`Volume 7
`
`1963
`
`ACADEMIC PRESS INC.
`
`NEW YORK AND LONDON
`
`1 of 119
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`Q
`
`D·
`
`Col'YKIGH T © L96;l
`BY
`ACADEMIC PRESS me.
`All Rights R eserved
`
`No part of this book may be reproduced i11
`r111y form by photos/at, microfilm, or any
`other means, without written permission
`from the miblisher11.
`
`Ac.~DEMIC PRESS I Nc.
`111 FIFTH A VEN lTE
`K..:w YOR K 3, Nmv Yo1tK
`
`L ibrary or Congress Catalog Card Number : 52-13360
`
`United Kingdom Edition
`Published by
`
`AcAOEM1c PnEss INc. (LoNooN) LTD.
`BERKELEY SQuARt: HousE
`],ONDON, vV. I
`
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`Co:-iTnrnuTons i ·o VoLUMt" 7 .
`
`CONTENTS
`
`Avian Virus Growths and Their Etiologic Agents
`J. \Y. Bt:ARll
`
`I. lnlrodurlion .
`I I. Spectrum of Disea8e Manifestation
`Ill . Fartors l nflucncing Ho~t Response
`IV. Attributes of the ..\gent11
`\'. Cell Growth and Virus .'ynthesis i11 Vit ro
`VJ. lTltrastrm·tuni l Morpholoii:.v
`Vll. Cyto1·hC'mi11try
`VIII. Comnw11t11
`R<'fcrent·rs
`
`Mechanisms of Resistance to Anticancer Agents
`R. \Y. BHO<'KMAN
`
`l. 111trod11l'!ion .
`Ir. Mctaholi:<n1 of PurinN1
`ll L Metabolism of P~·rimiclinrs
`I\'. :\ucleir Acid ._ynthe,.is
`\I. Purinl' .\ naloi;cis .
`VI. Pyrimidmr Ann lo._,.,.
`V ll . Glutmn inr A 11t>1gonil:!lli
`Vl II. FoJir At:id An11log<i
`IX.
`leroids
`X. Alkylating Agents
`XI. Antibiotics
`Refer<'llt'l'>l
`
`\ '
`
`2
`4
`28
`45
`70
`0
`109
`114
`118
`
`130
`131
`134
`137
`139
`167
`183
`192
`200
`203
`209
`214
`
`Cross Resistance and Collateral Sensitivity Studies in Cancer Chemotherapy
`DoRR1 J. H uTcn1soN
`
`LiH of Abbrr,·iatiom; .
`I. [ot rochwlion
`.
`II. Hi$lOry 11ml Sropr of 1111• \\'ork
`III. Aoti111ct11holilcs .
`I\'. Possible Antimetaholite"
`, ._ Alkylating ..\gents .
`teroids
`\I I.
`VII. Misccllanromi Compounds
`VIII . M echanisms 11nd Altcrnlions
`£X. Collatcrul Sensitivity
`.
`X. Critique and Coosideralion:(cid:173)
`References
`
`vii
`
`236
`238
`2311
`256
`308
`314
`321
`:l24
`330
`330
`331
`343
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`\'Ill
`
`CONTEN'l'8
`
`Cytogenetic Studies in Chronic Myeloid leukemia
`W. M. CouRT BROWN ANO I s uet:L M. T ouoH
`
`I. Introduction
`II. Chroni c Myeloid Lcukemin .
`III. T echnical Considerations .
`IV. Th e Normal Ruma n Karyolypc
`V. The Abnormal Chromosome of C hroni c- Mycloid Lc• ukemia
`VI. The Frequency of the Ph' Chromo~omC' in l lntr<'ated Patient:!
`VIL The Effect of Trealm r al .
`VIII. The FN'quency of Ph' + vc Ce lls in Previously T rcaled P atients in the
`Chronic Phase
`LX. The R elative Frequencies of P h' + ve Cells in Blood and Marrow
`X. Th e Findings in the Acute Transfonnation
`XI. General Discussion
`Addendum
`Rrfcrenc:es
`
`351
`352
`353
`355
`357
`361
`364
`
`361
`365
`366
`375
`380
`380
`
`Ethionine Carcinogenesis
`E~UfA:SUEL FARB&R
`
`I. In troduct ion .
`U. Chemistry
`III. Natural Occurrence
`IV. Acute Biologica l Effects
`V. Chronic Biological Effects
`VI. Metabolism of Ethi onine .
`VII. C11rcinogenesis
`R eferences
`
`Atmospheric Factors in Pathogenesis of lung Cancer
`PAUL K oTIN ANO HANS L. FALK
`
`.
`I. Introduction
`II. General Epidrmiolof(ical Consid rrulion~
`III. Experimental Considerations
`IV. Bioassay Studies
`V. Clinical Lunrc Cam·r r .
`VI. Etiology of Lung Cnn\·er .
`R eferences
`
`Progress with Some Tumor Viruses of Chic ken s and Mammals:
`The Problem of Passenger Viruses
`<1 . N~:onONJ
`
`.
`L 1u trod ud io11
`1 r. ClaickPn Tum or Vi1·11~l'K
`U L Rnhbi t. Tum or Viruses
`
`383
`384
`385
`385
`414
`422
`440
`465
`
`475
`477
`485
`5-0'l
`504
`506
`509
`
`51 5
`5 17
`527
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`CONTENTS
`
`IV. Mom:e Tumor Viruses
`V. Summary and Conclusions
`References
`
`AUTHOR INDEX
`
`SUBJECT I NDEX
`
`ix
`
`529
`552
`552
`
`563
`
`591
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`CROSS RESISTANCE AND COLLATERAL SENSITIVITY
`STUDIES IN CANCER CHEMOTHERAPY * t
`
`Dorris J. Hutchison
`
`Resistance Studiu Section, Division of Experimental Chemot herapy, Sloan -Ketteri ng
`Institute for Cancer Research, ond Sloon-Kettering Division, Graduate School of
`Medical Sciences, Cornell Un iversi ty Medical College, New York, New York
`
`236
`238
`239
`247
`250
`252
`256
`256
`275
`279
`299
`308
`308
`308
`314
`314
`315
`315
`321
`321
`324
`324
`327
`327
`327
`327
`
`List of Abbreviations
`I. Introduction .
`H . H istory 1ind Scope of t he Work
`coplasms
`A. Animal
`B. Tissue Cultures
`C. Microorganisms
`ITI. .\ntirnetaboli tes
`.
`A. Folic Acid Antagonists
`B. Amino Acid Antagonist'!
`C. Purine Antagonists
`D. Pyrimidine Antagonii<ts
`JV. P!k.;sible Anlimctabolites .
`A. Mitomycin C .
`B. Formamidc, N-M elhylfo rm umidc (NMF), uncl Urethan .
`C. Olher Po:<..~i hlc Antimctaholi tcs
`V. Alky lating Agc•nts
`A. P-ChlorO<'lhyl Derivath•cs
`B. Ethylenimines
`n . toroids
`.
`A. Corticoidi,;
`B. Androgens
`VIL Miscellaneous Compounds
`A. Potfu35lium Arsenite
`B. Colchicinc and D erh•fllivcs
`C. Glyoxul Bi:;guanylhydrazone (GOH )
`D. Guanidinc Derivatives
`*This work was requested and supported by the Cancer Chcmothem py National
`Service Center, National Cancer Institut.e, National Institutes of H ealth, Contract
`No. A-43-ph-2445.
`t T his work is dedicated to the memory of Dr. Cornelius P. Rhoads in gratitude
`for his guidance. r wan t to acknowledge \viU1 si nc·crc appreciation the support and
`<"011lin11ing inl l'rl'sl of Dr. C. Chrsll'r Stock, ns well m; the di~r11>t.~ions with, nnd ro l(cid:173)
`laborntion of. Dr. M. l~a rl Balis :ind Dr. R. W11ll111·1• Brotk rn:111, :mcl lo !hank thus!'
`i11vP>1I i!(al or:-1 who 111·uvidr d I heir unpuhlisheu <lnl11 , t iii' 1 •P r:<o11111•l of tire HPsisl anl'C'
`'loan-1\cllcring Instilule, aml l\lrs. Ccorgc 13. B row11 for
`'ludie · &>ct ion of the
`n.ssistance with thi compilation.
`
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`236
`
`DORRIS .T. HUTCHISON
`
`Vlll. l\!frchanisms and Alterations
`IX. Collateral Sensitivity
`X. Critique and Considerations
`Hcrrren<"cs
`
`L1 T OF A1mRE\'lATIONS
`
`330
`330
`331
`343
`
`9-AFH
`AMP
`4-A PP
`AZAAD
`AZAHX
`AZAX
`AZT
`AZU
`AZ R
`Aminopterin
`Adcnoptcl'iu
`Aninopterin
`Amcthopterin
`Amino-an-fol
`BCM
`BU
`BW 49-210
`CE
`CF
`CP
`2,6-DAP
`DCM
`DDMP
`
`D~l EP
`D-54-HCl
`DON
`Dccaclron
`
`(Tho:;c in µarenthe::;cs arc in the recommended ahbrc\'inlions
`but have not been used in the literature rrvicwcd.)
`9-a-FluorohydrocortiliOOc
`Adeno ine-5'-phosphatc
`4-Aminopyrazolo- l 3,4d]-pyrimidine
`8-Azaadenine (Aza-Ade)
`8-Azahypoxanthine (Aza-Hyp)
`8-Azaxanthine (Aza-Xan)
`6-Azathymine (Aza-Thy)
`6-Azauracil (Aza-Ura)
`rd)
`6-Azauridinc (Aza-
`4-Aminopteroylglutamic acid
`4-Amino-9,10-dimcthy lpteroylglutamio acid
`4-Amino-9-mcthylpteroylglutamic acid
`4-Amino-10-mcthylpteroylglutamic acid
`4-Aminoptcroyla partic acid
`3'-Bromo-5'-chloroamethopterin
`5-Bromouracil <B-l.;ra)
`3'.4'-Dimethoxybcnzylpyrimidine
`1-(2-Chloroethyl )-3-nitro-1-ni trosoguanicline
`Citrovorum factor (5-formylfolate-H.)
`1- (3-Chloropropyl )-3-nitro-l-nitrosoguanidine
`2,6-Diaminopurinc
`3',5'-Dichloronmcthoptcrin
`2,4-Diamino-5- (3' ,5' -di ch lorophenyl )-6-mcthy !(cid:173)
`pyrimidine
`2,4-Diamino-5- (3'-chloropbenyl)-6-ethylpyrimidine
`1,2-Dihydro-2,2-dimethyl-5-triazine
`6-Diazo-5-oxo-L-norleucine
`Pregna-l ,4-dienc-3,20-dione,9a-fluoro-11(3,-17a,21-
`trihydroxy-l 6a-methyl-
`Ethionine
`FoJic acid (folate)
`2-Fluoroadcninc (F-Adc)
`2-FluoroadenoRinc (F-Ado)
`
`ETH
`FA
`FAcl
`FAS
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`CROSS RES!S'l' AN CE AND COLLA'rERAL SENS1T(V1TY
`
`237
`
`J;'C
`FCDR
`FCR
`FO
`FP A
`FU
`FUDR
`FUR
`GAH
`GOH
`GMP
`HN2
`HN3
`Halotestin
`
`IDUR
`IMP
`Kethoxal
`Mcthioprim
`
`6-MP
`NG
`NMF
`NSC-38280
`
`NSC-48841
`
`OPDA
`Prednisonc
`TDA
`TEM
`THA
`THAM
`THFA
`Thfo-TE PA
`TG and TH
`U-17323
`
`UMP
`VLB
`XMP
`
`5-Fluoroeyto:::inc (lf-CyLI
`5-Fluorodeoxycyticline (F-dCyd)
`5-Fluorocyticline (F-Cyd)
`5-F luoroorotic acid (F-Orotic)
`p-Fluorophenylalanine (F-Phe)
`5-Fluorouracil (F-Ura)
`5-Fluorodeoxyuridine (F-clUri)
`5-Fluorouridine (F-Uri)
`Glutamic acid hydrazide (Glu-NHNH2 )
`Glyoxal bisguanylhydrazone
`Guanosine-5'-phosphate
`Nitrogen mustard
`Tris-,8-chloroethylamine
`Androst-4-en-3-one,9a-fluoro-l l ,8, 17,8-clihy<lroxy-
`17-methy l-
`5-Jododeoxyuridine <I-dUri )
`Inosine-5'-phosphate
`,8-Ethoxy-a-ketobuteraldchyde
`2-Metby lmerca pto-4-amino-5-hydroxymethy ](cid:173)
`pyrimidine
`6-Mercaptopurinc
`l-Methyl-3-nitro-I-nitrosoguanidine
`N-Metbylformamide
`2-Chloro-4',4" -bis (imidazolin-2-y I )-terephthalanide,
`dihyclrocbloride
`Malononitrile{p-l bis (2-cbloroethyl ) amino] benzyl(cid:173)
`idene}-
`o-Phenylcnediamine
`Pregna-1 ,4-diene-3, 11,20-trione, 17 a,21-di bydroxy-
`2-Ethy lamino-1,3,4-thiadiazolc
`Triethylenemelamine
`Tetrabydroamethopterin
`Tetrahydroaminopterin
`Tetrahydrofolic acid (Folate-H4)
`Trietbylenethiophosphoramide
`6-Thioguanine (Thio-Gua)
`9a-Pregna-l ,4-diene-3,20-dione,9-fluoro-l l/3, l 7-
`dihydroxy-6a-methyl, 17-acetate
`Uridine-5'-phosphate
`Vincaleukoblastine sulfate
`Xan thosine-5' -phosphate
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`23
`
`DORRI · .J. 11 UTCll ISON
`
`I. Introduction
`That. therapy of cancer with chemicals is not new can be seen in the
`comprehensive literature survey prepared by Dyer {1949); this area of
`cancer research ha been extended and expanded vince the second World
`\Var, and it i · nn area in which many in,•estigators arc still striving lo
`find totally effective chemotherapeutic agents for ome kinds of cancer.
`That progre " ha· been made i apparent from comparison of the follow(cid:173)
`ing quotations. In 1949, Dyer stated, "There is no evidence in the litera(cid:173)
`ture to indicate that a pecific tumor de·troying agent has been found.
`While there is little reason to expect the discovery of a single chcmicnl
`agent which ";ll destroy either all or many kind of cancer, there seem'
`to be no chemical known, which, when administ-ercd ystemically, will
`cau e complete rcgre:don of even one kind of cancer and
`till pPrmit
`survival of the host." Ten years later Gellhorn (1959) stated, "There
`are two neoplastic di case in which convincing evidence ha been offered
`to indicate lhe use of an antitumor drug as a part of the definitive and
`curative regimen. This includes the rare childhood tumor retinoblastoma.
`'J'he combination of radiotherapy and chemotherapy with one of the
`alkylating agents
`[nitrogen mustard
`(HN2),
`triethylcnemelaminc
`(TEl\l ), or triethylenethiopho phoramide (Thio-TEPA) j makes it po~­
`sible to reduce the radiation dosage, with concomitant decrea ·e in X-ray
`damage to the normal ocular tissue' and no sacrifice of the cure rate.
`The other neoplastic disea e which can be cured by chemotherapy i ·
`choriocarcinoma in women. The folic acid (FA) antagonists have been
`found to be particularly dramatic in their effect on thi · also rare
`neopla ·m."
`The response of patients with neoplastic di eases to chemotherapeutic
`agents i oflen highly variable despite the identical histological pattern
`of the tumor (Bierman and Mar hall, 1960). Furthermore, Zubrod {1960)
`writes that cancer represents many diseases and is perhap a term with
`no more specificity than fever. There are many cancers in man and there
`are many more cancers in experimental animals. How can the results of
`the thousand · of variable' be matched ~o that advantage can be taken of
`a nimal tumor responses to drugs? ome of the positive and negative rela(cid:173)
`tion hip have been presented by Burchenal {1956b), Karnof ky (1958),
`and Gell horn (1959).
`Some pertinent que tion must be rai cd concerning chemotherapy of
`cancer: Is the lack of profoundly effective chemicals due to natural
`cellular resi tance, to a low sensitivity of neoplastic cells to the majority
`of available chemicals, to the lack of a differential en itivity between
`tumor and normal cells, or to the emergence of drug-resistant populations
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`CROSS RES ISTANCE ANO COLLATERAL SENS ITIVITY
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`239
`
`from a previou ly su ceptible population of neoplastic cell ? P robably
`all of these contribute to the problem in one way or another.
`
`II. History and Scope of the Work
`Drug resistance is not a new phenomenon; indeed, it i a old as the
`field of chemotherapy, pel'haps older. King Mithridatc · of P ontus (12~
`63 B.C.), in fear of being poi oned by hi enemies, conditioned himself
`to then known poisons to such good effect that, when he wnntcd to commit
`suicide by this means, he wa unable to do so (Duggan, 1959). Ehrlich
`described the inhibitory effect of pararosaniline on trypano ome and at
`the same time presented information on the emergenc<.' of resistant cells
`from the e culture
`(Schnitzer and Grunberg, 1957).
`ince then , resist(cid:173)
`ance ha accompanied chemotherapy like a faithful shadow, and the
`history of chemotherapy i · also the history of drug resistance.
`In connection with the problem o f drug resistance, • hear (1959) com(cid:173)
`mented, " The trouble wi th this general problem i
`that it bristle· with
`too much re istance of too many different types. If, however, we arc going
`to overcome them, it is nccessa.ry that we learn the nature of their re(cid:173)
`sistance."
`~Iuch information ha been gained about drug re i tance in micro(cid:173)
`organisms; the mechanisms presented to explain resistance in microbial
`systems natura lly have been carried over to t he field of cancer chemo(cid:173)
`therapy as working hypothc ·e . Po~ ·ible explanations ha,·e been detailed
`by Wys
`( 1950, 1957), D avis and l\laa
`(1952), Law (1956), Nichol
`(1957 ), and Rhoads (1959). When these arc grouped by categories as is
`done below, the ·imila1·ity of idcat1 is immediately a pparent from their
`all but identical terminology:
`
`P ORSIBLE !\1ECHANISMS OF R ESISTANCE
`I. Cytological changes.
`2. Decreased penetration of the drug.
`Reduction in the tran port of an inhibitor to a u cepti ble enzyme.
`Decrea ed cellular permeability to the inhibitor.
`Reduced uptake of the drug associated with an al tered permeability
`or a reduced binding capacity.
`3. Increa eel de truction of the drug (or conversion t-0 an inacth·e com-
`pound ).
`fnnctivnLi011 of llH• drul-( rn· dt•1·n•w:;cd acli\•ation of lli1· dr11~.
`Ability to hind llw drug in 1t11 inal'livc form.
`D c,·dopment. of an eniymc with increai::cd nhility lo com·t•rt or in(cid:173)
`activate the drug (increased destruction of the inhibitor).
`
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`240
`
`DORRIS J. HUTCH! O~
`
`4. Increa ·cd concentration of an enzyme using a mclabolite.
`Increase in the amount or the efficiency of the enzyme usmg the
`metabolite.
`Quantitative alteration in the sub trate, enzyme, or product system.
`5. Decreased quantitative requirement for a product of the metabolite.
`6. Increased concentration of a metabolite antagonizing the drng.
`Increased formation of a competing metabolite.
`Increased availability of the normal metabolite, either because the
`resistant cells make it more efficiently or because it is liberated more
`rapidly to an active form in the resistant strain.
`7. Enzyme changed in some quality such as relative affinity for drug.
`D ecrease in the relative affinity of the su ceptiblc enzyme for the
`the
`compared with the affinity for
`chemotherapeutic agent, a
`appropriate metabolite.
`Enzyme with decrea ed relative affinity for the drug compared with
`the metabolite.
`D evelopment of changes in enzyme affinity for the drug compared
`with the metabolite.
`ing the metabolite.
`8. AlternatiYe metabolic pathway bypa
`Development of an alternative pathway.
`Utilization of exogenous metabolites which are products of the in(cid:173)
`hibited reactions.
`Utilization of an altered metabolic pathway with concomitant elimina(cid:173)
`tion of the sensiti,·e anabolic route.
`Decreased conversion of the administered compound to an active form.
`
`Each of these explanations, regardless of the terminology used by
`individual investigators, has been implicated in the variety of studies on
`resistance to cancer chemotherapeutic drugs. The l'elative case of ob(cid:173)
`taining a drug-resistant population is shown by this sul'Vey. A major
`responsibi lity falls upon the investigator to prove within the system
`under investigation that his results arc unequivocal and that they demon(cid:173)
`strate a specific change or changes that result in resistance. A detailed
`presentation of the few proven mechanism can be found in a review by
`Brockman (1963).
`Regardless of the point from which one might attempt to approach
`drug resi tance as an entity, one will always be confronted by a multiplic(cid:173)
`ity of underlying problem . . Drug r<'sistance mu t be approached from
`many aspects if one hopes to find I\ means of clas ification whfoh wiU
`allow t.lie marshaling of an amorphoui:; mn~s of material aC'cording to the
`development of clrug resistance, the characwri ·lies of drug-fast organisml',
`and the mechanism of drug rcsi tance ( chnitzer and Grunberg, 1957).
`
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`CUOSS RE.SISTANCE ANO COLLATERAL SENSITIVITY
`
`241
`
`'fho cmcr~cnce of a rel'.lisLanL µopulat,ion of n·ll:-: i,.; dcpt·ndt'11L 11pu11
`several factors: the number of cells initially present, sensitiYity of these
`cells, frequ ency of their expo ure to the drug, conc<>ntration of the drug,
`and length of exposure to each concentration of drug. Propertic of the
`cellular populations, ~uch as normal mutation rate and homogeneity, aR
`the mode of action and stability of the drug, will have considerable
`well a
`influence on the phenomenon. This phenomenon of resistant cells in popu(cid:173)
`lations of neoplastic cell has been con idered theoretically and from ac(cid:173)
`tual observations in man and experimental animals. Klein and Klein
`(1957}, Druckrey ( 1959), and m e in ( 1961 ) have discussed experimen ta I
`approache · to the problem of demonstrating re istant cell line .
`toll
`(1959) pre ented results on clinical obserYations and lamented that o far
`it had been impossible to prevmt the emergence of a resistant population
`in certain human cancer,.;. kipper et al. (1957b) presented definitive data
`on the curability of mouse leukemia with anwtltopterin. The fact that
`animals receiving a sufficiently small numbC'r of IC'ukemic cells could he
`cmed suggested the possibility of curing cancer if therapy could be
`started soon enough. Potter (1959 ). working with another neoplasm, pre(cid:173)
`sented somewhat ·imjlar data with 6-diazo-5-oxo-L-norlcucine (DO~ l.
`It ha been stated hopefully by a number of clinic·al investigators that
`certain neoplasms, such as acute leuke1rua of childhood, could be cmcd if
`cells refractory to the chemotltcrnpcutic drug did not appear. The subtle
`differences between leukemic cells and certain normal cells do not allow
`ibly
`the u e of do cs ·ufficiently high to eradjcatc the neoplastic cell . Po
`the appearance of resi tant ncopla tic cells may be due to one or more of
`the biological phenomena ,,·hich haYe been amply demon trated in the
`field of microbiology: (1) mutation {spontaneous or induced ). (2) trans(cid:173)
`formation , (S) transduction, (4) recombination, or (5) adaption, but data
`available on human and animal neoplasms in t his area do not yet permit
`the implication of all of the e phenomena as a means for explaining the
`emergence of drug-resistant population . Law ( 1952 I and Klein (19.59)
`reported spontaneous mutations to amethopterin re-i ·tance in the L 1210
`mouse leukemia and genetic transformation of re ' i tance character· ha~
`been repor ted (Hoshino, 1961 ; Blumenthal et al., 1960, l 961 ), hut much
`more evidence is needed in this area to prove the actual genetic trami(cid:173)
`formation.
`i a young and rapidly
`Cancer chemotherapy on a systematic ba i
`progres ing field. As was indicated earlier, it evolYed on a large scale only
`after World War II. The achieYements in the therapy of infectiou dis(cid:173)
`eases with antibiotics and other chemotherapeutic agents have stimulated
`the continued hut less dramatic advancements in the therapy of cancer
`with chemicals. Numerous ideas are direct exton. ions from the chcmo-
`
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`242
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`DOHRIR .J. UUTCHli'iO"'
`
`thcrnpy of infectious diseases, even though it is well k110\\·11 Uiut lmsiu
`difft•rcnces cxi ·t between the two ~y ·tcms. Tt has been amµly demon(cid:173)
`:slrat.cd that tmder ce1-t.ain conditions cancer cells, like haclcrial cells, sat(cid:173)
`i fy the cla sical postulate of Koch in regard to isolation, cultivation,
`rl'infection, and reisolation of the causative agent (Rhoad, 1955). The
`prime difference appears to lie in the origin, i.e., the extrinsic 01· intrinsic
`nature of the invading cell. Thus, a cancer cell originates from tissue of
`the individual, while the microbe is extrinsic and, as such, is markedly
`more stimulatory to the immune mechanisms of the host. This profound
`difference in the nature of the two types of disease suggests tlrnt, if chemo(cid:173)
`therapy of cancer is to be totally effective, 100% of the neoplastic cells
`mu t be destroyed.
`The literature in the field of cancer chemotherapy and re istance to
`chemotherapeutic drugs begin in 1944. This review coYers work reported
`between 1944 and 1962. An attempt has been made to enumerate and cat(cid:173)
`egorize all the examples of cancer chemotherapeutic drug-resistant sys(cid:173)
`tems selected and reported during this period of time. For the sake of
`completene s several drugs made possible by progress in biochemistry arc
`included even though they have not and probably never wi ll be used clin(cid:173)
`ically, because results obtained in certain experimental systems have been
`invaluable in delineating some of the normal and abnormal rresi tancel
`metabolic pathways in the cells (Mandel, 1959; Brockman, 1961).
`The literature on rcsi ·tance to cancer chemotherapeutic agents is ex(cid:173)
`tremely dive1"e. All drugs to which re istance in animal neopla m , tis ue
`culture', and microorganisms ha been reported are Ii led in Table I. In
`ummarizing these data we note that 352 re istant mutants from 66 dif(cid:173)
`ferent biological sy terns have been mentioned. Some have been described
`at length whereas other$ have been more or less casual observations. In
`the sections on chemotherapy with specific drugs all of the resistant mu(cid:173)
`tants will be included. Of the Tl compounds which have served as
`selecting agents, only a type drug from each group or class will be con(cid:173)
`sidered in detail. Ranked according to total numbers of resistant systems
`the c are: amethopterin, aza 'crine, 6-mercaptopurine (6-1\IP), 8-aza(cid:173)
`guanine, 5-fluorouracil (Fl"), N-methy 1 formamide C>.TMF), 3'-bromo-5' -
`chloroamethopterin (BCl\I) 1 nitromin, 1- (3-chloropropyl) -3-nitro-1-nitro_
`soguanidine (CP), formamide, DON, 2,6-diaminopurine
`(2,6-DAP),
`mitomycin C, and actinobolin. All the other chemicals listed in T able I
`have served as agents for the selection of fewer than six diverse systems.
`For further orientation and to indicate the general scope of this problem,
`the biological systems for wbich several mutants (more than 5) have been
`obtained are Streptococcu,s /aecalis, L1210, Escherichia coli 9637, Escher(cid:173)
`ichia. coli. S, Ehrlich carcinoma, Bacillus subtilis, plasma cell neoplasm
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`CROSS RESlS'rANCE ANO COLLATERAL SENS!TIVI'J'Y
`
`243
`
`TABLE I
`CHE~IOTHERAPEUTIC DRUGS AND RESISTANT BJOLOGICAL SYS'l'EMS
`
`Biological systems
`
`Chemotherapeutic drug
`
`Tissue
`Animal
`neoplasms cultures Microbes
`
`Totals
`
`ANTJ METAllOl.JTES
`Polle acid ant.agonists
`Pteroylglutamates
`Amethopt.erin (Methutrexate)
`Aminopterin
`Aninopterin
`Adenopterin
`3',51-Dichloroamethopterir1 (DCM)
`3'-Bromo-5'-chloroamethopt.erin
`(BCM)
`
`2G
`1
`1
`2
`3
`9
`
`Diamioopyrimidioes
`2,4-Diamino-5-(3 ',5' -dicbloropheny l )-
`6-methylpyrimidine (DDMP)
`2,4-Diamioo-5-(3'-chlorophenyl)-6-
`ethylpy rimidioe (Dara.prim)
`(DMEP)
`3',4'-Dimetboxybenzylpyrimidine
`(BW 49-210)
`
`Dih ydrotriazines
`l ,2-Dihyclro-2,2-dimctJ1yl-s-triazine
`(D-54-HCl)
`
`Amino acid antagonista
`Glutamine analogs
`Azaserine
`6-Diazo-5-oxo-.L-norleucine (DON)
`Glutamic acid hydrazide (GAR)
`
`Other amino acid analogs
`p-FluorophenylalaniM (FPA)
`Ethiooine
`Allylglycine
`
`Purine antagonists
`Mercaptopurines
`6-Mercaptopurine (6-MP)
`6-Thioguanine (TC)
`
`Azap11ri11es
`8-Azaguaninc
`8-Azaguauosiue
`8-Azaxa.ntbine (AZAX)
`
`9
`5
`
`ll
`3
`
`2
`
`10
`4
`
`;j(j
`6
`
`2
`
`3
`
`7'2.
`11
`1
`2
`3
`9
`
`2
`
`3
`
`1
`
`1
`
`15
`3
`I
`
`2
`1
`
`13
`2
`
`10
`
`2
`
`24
`8
`1
`
`2
`I
`I
`
`:n
`5
`
`15
`J
`2
`
`7
`
`:1
`1
`
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`244
`
`DORRIS J. HUTCHISON
`;
`
`TABLE I (Continue<l)
`
`ChemoU1crapeutic drug
`
`8-Azaadeninc (AZAAD)
`8-Azahypoxanthinc (AZAJ:IX)
`
`Other purine analogs
`Purine
`2-Fluoroadeuine (F Ad)
`2-Fluoroadeoosine (FAS)
`2,6-Diaminopurine (2,6-DAP)
`6-Chloropuriue
`Aminonucleoside of puromycio
`
`Pyrimidine antagonists
`Fluorinated pyrimidll1es
`5-Fluoroorotic acid (FO)
`5-Fluorouracil (FU)
`5-Fluorouridine (FUR)
`5-Fluorodeoxyuridine (FUDR)
`5-Fluorocytosine (FC)
`5-Fluorodeoxycytidine (FCDR)
`
`Azapyriroidines
`6-Azauracil (AZU)
`6-Azauridine (AZUR)
`6-Azatbyroioe (AZT)
`
`Other pyrimidine analogs
`Amiee tin
`
`PossraLE ANTIMETABOLlTES
`Formamide
`N-Methylformaroide (NMF)
`Uretban
`Thiadiazole (TDA)
`Miracil D
`Actinobolfo
`Actinomycin D
`Mitomycin C
`NSC-38280
`
`ALKYLATINO AGENTS
`tl-Chloroetbyl derivat,ives
`Nit.rogen mustard (HN2)
`Acetyl p-phcnylcnecli;~minc mustMtl
`Nitromin
`
`Biological systems
`
`Tissue
`A1.1imal
`neoplasms cultures Microbes
`
`Tut<tls
`
`1
`
`3
`
`1
`1
`
`J.
`
`l
`l
`
`1
`2
`1
`6
`1
`
`2
`IJ
`
`2
`2
`
`3
`
`1
`
`1
`
`!)
`8
`5
`
`5
`2
`5
`1
`
`~{
`
`3
`
`l
`2
`
`1
`2
`1
`~
`
`2
`24
`3
`2
`2
`2
`
`3
`2
`1
`
`2
`
`9
`10
`5
`l
`l
`6
`3
`8
`
`5
`l
`9
`
`1
`
`13
`1
`
`1
`
`2
`
`1
`1
`l
`
`3
`
`2
`I
`6
`
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`CROSS RESlS'rANCE AND COLLATERAL SENSITIVITY
`
`245
`
`TAHL.E l (C1mtin11ed)
`
`Biological systems
`
`Chemotherapeutic drug
`
`Tissue
`Animal
`neoplasms cultures Microbes
`
`Totals
`
`l
`2
`2
`1
`
`5
`l
`
`:3
`
`l
`1
`
`Alanine mustard
`Phenylalanine mustard (Sarcolysin)
`Cytoxau
`Chlorambucil
`Ethylenimines
`Triethyleuemelamine (TEM)
`Triethylenethiophosphoramidc
`(Thio-TEPA)
`
`81'EROIDS
`Corticoids
`Cortisone
`9-a-Fluorohydrocortisone (9-AFH)
`Hydrocortisone
`Androgens
`Testosterone
`Dihydrotestosterone
`4-Androstene-3, 17-dione
`
`MlSCELLANEOOS COMPOUNDS
`Potassium arsenite
`Colchicine
`Colcemid
`N-Metbylcolchicamide
`Glyoxal bisguanylbydrazone (GGH)
`l-Metbyl-3-nitro-1-nitrosoguanidine
`(NG)
`J-(3-Chloropropyl)-3-nitro-J-
`nitrosoguanidine (CP)
`l-(2-Chloroethy 1)-3-ni tro-1-
`nitrosoguanidiue (CE)
`
`1
`2
`2
`1
`
`5
`J
`
`:3
`
`l
`~$
`
`I
`1
`2
`
`6
`
`3
`
`2
`
`6
`
`1
`
`Totals
`
`128
`
`35
`
`189
`
`352
`
`70429, Diplococcus pneumoniae, Yoshida fibrosarcoma, "L" cells, L euco(cid:173)
`nostoc citrovorum, Lactobacillus casei, and Escherichia coli B. The data
`are diffuse, and are summarized for anjmal neoplasms, tissue cultmes, and
`microorganisms in a series of tables.
`In order that an analysis of both the systems and the development of
`cancer chemotherapy can be made, these resistant Jines arc presented in
`chronologica l sequences within the general classification of chemothcra-
`
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`246
`
`DORRIS J. HUTCHISON
`
`pt·uti1· agl'nl,; .. \II tlll' rht·111otl1er'ttpcutic data arc lahulalc.·d with rl'fcn•nct•,.,
`attording to the n•,;ponsc of the resi~tc111L line rclatin• lo that of tlw sensi(cid:173)
`ti,·c wild (parl·nt) type as follows: n·,;pou ·c :mrnc as parent, lint•, <:ross
`resistance, and collaternl sensitivity. Cross resistance means that a popu(cid:173)
`lation resi tant to a given drug is no longer susceptible to another com(cid:173)
`pound while the parent population remain susceptible to both. Collateral
`·en iti,;ty is defined a
`the greater usceptibility of a resistant popula(cid:173)
`tion, in comparison with the parent population, to another compound. The
`parent population, therefore, is less ·u ·ceptible than the resistant popula(cid:173)
`tion to the action of the ·econd chemotherapeutic agent. The reference
`cited in these table arc organized ·o that the fir ·t one in the erie for
`any gi,·en re istant line is the one in which there is a description of the
`selection of the resistant. strain. Chemotherapy data may or may not be
`in the paper. All other references cited contain some detailed data on
`comparative responses to one or several chemotherapeutic agents. Where
`known, the level of resistance of each train is al o included.
`Kumerou review on cancer chemotherapy have appeared and each
`has contained different groups of compounds. Since lhere is no conven(cid:173)
`tional outline to follow, it seemed advisable to present a listing and group(cid:173)
`ing of chemicals to which re istancc ha been observed in one of the
`previously mentioned biological ystcms. The chemc used (Table l) is
`imilar to that of Burchenal (1956a) and Gelhorn (1959). Again, it, should
`be emphasized that the chemicals Ii ted are those that have been u ed for
`the selection of experimental resistant systems. No attempt will be made
`to cover the field of clinical chemotherapy. The variou.- resistant sy 'tcms
`in three biological group (animal neopla ms, tis uc cultures, and micro(cid:173)
`organism ) readily indicate the amount of work with each type com(cid:173)
`pound. The first observation of resistance to a cancer chemotherapeutic
`agent was made by Heilman and Kendall (1944), who described a mouse
`lymphosarcoma resistant to cortisone. Six years passed before other re(cid:173)
`sistant neoplasms were ob erved (Burchenal et al., 1950; Law and Boyle,
`1950). Then, within a few mouths, Burchenal et al. (1951a) reported the
`6J·st selection of a bacterium resistant to an anticancer drug. ubse(cid:173)
`quently, Fischer (1958) selected the first tissue culture )ine resistant to
`an anticancer drug. The sequence and number of reports on re i ·tant lines
`is an obvious barometer of the clinical and/ or biochemical "value" of the
`specific compound.
`The u e of microorganisms as model systems in the study of drug re(cid:173)
`sistance has a number of proponents and opponents; nevertheless, one
`must consider the basic contributions developed from the field of micro(cid:173)
`biology. The real value of uch studie has not yet been fully exploited,
`but such contribution a
`the demon tration of a genetic basis for resist-
`
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`CROSS RESJ STANC~; A~D COLLATERAL SEN TTT\'lTY
`
`247
`
`:111<·e (l> l'l'.W, 1!)57; . 'irut11ak ('( 111 .• HlliOa,h) and i111Tc·a:-:1•d
`:<cw.;ifi,·ity
`(" colla ternl scnl'iilivily"
`' r.y l>nl:;ki and Bry:;on, 19fi2) 1 log<'tlw r with t.111·
`use of microorgani:;111:s a::; ::icrcN1ing sy~tt·m::; (~<:l tahcl , 1958; G ut hrie et al.,
`1958; Schabel and P itti llo, 196 L; H utch ison et al., 1962b) have attracted
`much intere t and added to our knowledge.
`
`A. AN I.M AL 1'\ EOPLA MS
`The 32 ani mal neoplasms from which 128 resistant su blines have been
`selected arc listed in T able II. Al ·o included are host animal, type o f neo(cid:173)
`plasm, chemotherapeutic agents u,ed, and number of strains resistant to
`
`TA BLE II
`REs1sTAN<;t; ro CHEMOT1tERAP£uT1c D Rt:Gs rn Ai>rn AL )/'EOPL.AsMs
`
`Animal neoplasm
`
`Chemothcrape11lic drug
`
`Number
`of
`resistant
`strains
`
`Total
`uumbcr
`of
`resistant
`strains
`
`AK.
`LymphO<'y1ic leukemia (mouse) Amethopterin
`
`L12 10
`Lymphocytic leukemia (mouse) Amethopterin
`Aninopterin
`Adcnopterin
`DCM
`BCl\f
`Aza.serine
`6-MP
`TG
`8-Azuguanine
`FU
`Miracil D
`Aclinobolin
`Cytoxan
`GGH
`
`Line I
`Lympbor.ytic leukemia (mouse) Amcthopterio
`
`llE8186
`Lymphoid leukemia (mouse)
`
`Amethopterin
`
`L.5178
`I.ymphocytic leukemia (mouse) A methopterin
`Ci-MP
`
`4:.t
`
`3
`
`12
`J
`1
`3
`9
`1
`4
`2
`2
`3
`1
`1
`
`1
`
`1
`
`1
`
`2
`
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`

`248
`
`DOHIUS .1. H U 'fCll I. ON
`
`TABL'E U (Cu11ti 11uecl)
`
`.\nimal neoplasm
`
`Chemotherapeutic drug
`
`IA 9-16
`Lymphocytic leukemia (mouse) Amcthopterin
`
`P288
`Lymphocytic leukemia (mouse) Amclhopterin
`
`1~3054
`J4ymphoid leukemia (mouse)
`
`Adcnopterin
`
`B-82
`Lymphocytic leukemia (mou8<') Aminonucleoside of
`puromycin
`FU
`Amiee tin
`TDA
`
`Leukemia. 15
`Lymphoid leukemia (mouse)
`
`Potassium ursenite
`
`P388
`Lymphocytic leukemia (mouse) Amcthopteri