mutagenicity of several classes of antitumor agents to ... · plasmid pkm101 (1). ' this work was...

[CANCER RESEARCH 38, 2148-2156, July 1978]0008-5472/78/0038-0000$02.00

Mutagenicity of Several Classes of Antitumor Agents to Salmonellatyphimurium TA98, TA100, and TA921

Yuko Seino,2 Minako Nagao, Takie Yahagi, Akio Hoshi, Takashi Kawachi, and Takashi Sugimura

Biochemistry [Y. S., M. N., T. Y., 7. K., T. S.] and Pharmacology [A. H.Â¡Divisions, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104,Japan

ABSTRACT

The mutagenic activities of antitumor agents, including5 antibiotics, 19 antimetabolites, 5 alkylating agents, 2alkaloids, 1 enzyme, and 1 adrenal steroid hormone, weretested on Salmonella typhimurium TA100, TA98, and TA92.

Four of these, busulfan, carbazilquinone, 1-(4-amino-2-methy Ipy rim idine - 5 - yl)met hyI- 3-(2-ch loroethy l)-3 -n itroso-

urea hydrochloride, and pipobroman were shown for thefirst time to be mutagenic. Further, the known mutagenic-ities of five others, daunomycin hydrochloride, Adriamy-cin hydrochloride, mitomycin C, 6-mercaptopurine, andcyclophosphamide, were confirmed.

INTRODUCTION

Many chemotherapeutic agents are now widely usedclinically for treatment of cancers and leukemias and sometimes for prophylaxis of recurrent cancer after surgicaltreatment.

However, a phenomenon known as Haddow's paradox

(5) is that some cancer chemotherapeutic agents are carcinogenic to laboratory animals and also induce chromosomal aberrations in cultured mammalian cells. Thus, it isimportant to know whether chemotherapeutic agents arecarcinogenic.

Recently, it has become widely accepted that many mu-tagens are carcinogens (15, 16, 24). Therefore, in this workwe tested the mutagenic activities in S. typhimurium strainsTA100, TA98, and TA92 of various kinds of chemotherapeutic agents now in use or being tested for use in treatment ofhuman cancer. The compounds tested were antibiotics,antimetabolites, alkylating agents, alkaloids, an enzyme,and a hormone.

MATERIALS AND METHODS

Microbes. S. typhimurium strains TA100, TA98, and TA92were kindly supplied by Dr. Bruce N. Ames, University ofCalifornia, Berkeley, Calif. TA100 and TA98 are uvrB andrfa (deep rough) mutants (1). TA92 has the capacity forexcision repair and an intact lipopolysaccharide barrier(LPS+) (1). TA100 and TA92 both contain the same base-

pair change mutation, and TA98 contains a frameshiftmutation at his locus (1). All these strains carry R-factorplasmid pKM101 (1).

' This work was supported Â¡npart by Grants-in-Aid for Cancer Research

from the Ministry of Education, Science and Culture and the Ministry ofHealth and Welfare, Japan, and by the Princess Takamatsu Cancer ResearchFund.

2 To whom requests for reprints should be addressed.

Received April 14, 1977; accepted March 22, 1978.

Chemicals. Adriamycin hydrochloride, 5-fluorouracil, mitomycin C, and L-asparaginase were obtained from KyowaHakko Kogyo Co., Ltd., Tokyo, Japan. Cyclophosphamideand vinblastine sulfate were purchased from Shionogi &Co., Ltd., Osaka, Japan; Methotrexate and busulfan werefrom Takeda Chemical Industries. Ltd., Osaka, Japan; 1-/3-D-arabinofuranosylcytosine and cyclocytidine were fromKohjin Co., Ltd., Tokyo, Japan. 6-Mercaptopurine and 8-azaguanine were from Sigma Chemical Co., St. Louis, Mo.;ACNU3 and carbazilquinone were from Sankyo Co., Ltd.,Tokyo, Japan; and actinomycin D was from Nippon Merck-Banyu Co., Ltd., Tokyo, Japan. Bleomycin hydrochloridewas from Nippon Kayaku Co., Ltd., Tokyo, Japan; daunomycin hydrochloride was from Meiji Seika Kaisha, Tokyo,Japan; and FT-207 was from Taiho Pharmaceutical Co.,Ltd., Tokyo, Japan. Alkylcarbamoyl derivatives of 5-fluorouracil were synthesized at Mitsui Pharmaceuticals, Inc.,Tokyo, Japan. Vincristine sulfate was from Eli Lilly & Co.,Indianapolis, Ind., and pipobroman was from DainipponPharmaceutical Co., Ltd., Osaka, Japan. Prednisolone wasfrom Sanwa Research Institute, Tokyo, Japan. Glucose 6-phosphate, glucose-6-phosphate dehydrogenase (EC1.1.1.49), and ATP were from Sigma; NADH and NADPHwere from Oriental Yeast Co., Ltd., Tokyo, Japan; anddimethyl sulfoxide, spectrophotometric grade, was fromWako Pure Chemical, Inc., Osaka, Japan.

Eight compounds for drug use contained some vehicle,and the amounts of these compounds were expressed asfjiQof active principle. The names of these compounds andthe amounts in 1 vial, 1 ampul, or 1 tablet were as follows:daunomycin-HCI (20 mg principle; actual weight, 120 mg/vial), Adriamycin-HCI (10 mg principle; actual weight, 50mg/vial), bleomycin-HCI (15 mg potency; actual weight, 8mg/ampul), actinomycin D (0.5 mg principle; actual weight,20.5 mg/vial), mitomycin C (0.996 mg principle; actualweight, 1 mg/vial), cyclophosphamide (500 mg principle;actual weight, 725 mg/vial), L-asparaginase (10,000 ID;actual weight, 33 mg/vial), and prednisolone (5 mg principle; actual weight, 153 mg/tablet).

Mutation Test. The mutation test was carried out by ourmodification (20) of the method of Ames ef al. (1). The testchemical in 0.1 ml dimethyl sulfoxide or H,0 was placed ina tube and mixed with 0.5 ml S-9 mix (150 /u.lof the S-9fraction of rat liver pretreated with polychlorinated bi-phenyl, 2 /nmol NADPH, 2 Â¿imolNADH, 2.5 /Â¿molglucose 6-phosphate, 0.25 unit glucose-6-phosphate dehydrogenase,4 /Limol MgCIo, 16.5 /nmol KCI, and 50 /Â¿molsodium phosphate buffer, pH 7.4 and 0.1 ml of culture of the bacterial

3 The abbreviations used are: ACNU, 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride; FT-207, 1-(2-tetra-hydrofuryl)-5-fluorouracil.

2148 CANCER RESEARCH VOL. 38

on April 2, 2021. © 1978 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

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tester strain (1 to 2 x 108 cells). Without metabolic activa

tion 50 /Â¿molsodium phosphate buffer, pH 7.4, in 0.5 mlwere used instead of S-9 mix. The mixture was preincu-bated at 37Â°for 20 min and then mixed with 2 ml top agar(0.7% agar and 0.6% NaCI) at 45Â°and spread on a minimal-glucose agar plate containing 0.1 /Â¿moleach L-histidine andbiotin. Plates were incubated at 37Â°for 2 days, and thenhis+ revertant colonies were counted.

RESULTS AND DISCUSSION

The trivial names and structures of the 5 antibiotics, 19antimetabolites, 5 alkylating agents, and other compoundstested are shown in Tables 1,3,5, and 7, respectively, withthe results of mutagenicity tests on them and informationon their carcinogenicities.

Antibiotics. Results on the mutagenicities of the antibiotics are listed in Table 2. The mutagenicities of daunomycinhydrochloride (16), Adriamycin hydrochloride (16), and mi-tomycin C (17), which had been reported previously, wereconfirmed. Daunomycin hydrochloride and Adriamycin hydrochloride intercalate DNA (33), resulting in inhibition ofDMA-dependent DNA and RNA polymerases (32). Thesecompounds were highly mutagenic to TA100 and TA98without S-9 mix, the latter showing more mutagenicity inTA98 than in TA100. Addition of S-9 mix reduced theactivity. Clear dose-response activities of these compoundswere obtained, as shown in Table 2. These compoundshave potent actions in producing malignant transformation

Mutagenicity of Antitumor Agents

in vivo and in vitro and mutation in mammalian cells in vitro(14). Bleomycin hydrochloride was not mutagenic to TA100or TA98, with or without S-9 mix, but it is known to causeDNA strand breakage (26). Actinomycin D, which bindspreferentially to dG-dC pairs of DNA (13) and inhibits DNA-dependent RNA synthesis (12), was not mutagenic to TA100or TA98 with or without S-9 mix. The in vivo carcinogenicityof actinomycin D in rats has been reported (30). Actinomycin D is also reported to have very weak mutagenic activityon mammalian cells cultured in vitro (14). Mitomycin C wasnot mutagenic to TA100 or TA98 but was weakly mutagenicto TA92, especially without S-9 mix, as shown in Table 2.Mitomycin C produces interstrand cross-linking of double-stranded DNA (27). In this case uv repair-deficient straincells were killed and did not yield any mutants (19). TA92,which has uv repair capacity, gave more reversants than didthe spontaneous revertants. Mitomycin C produces tumorsin vivo (30). Bleomycin hydrochloride and actinomycin Dwere not mutagenic but were toxic to TA100 and TA98, aswas mitomycin C. But these compounds were not mutagenic to TA92 (Table 2).

Antimetabolites. Results on antimetabolites are listed inTable 4. 5-Fluorouracil, an inhibitor of thymidylate synthe-tase, was not mutagenic to TA100 or TA98 with or withoutS-9 mix, as shown in Table 4. 5-Fluorouracil had a stronglethal effect on cells at a concentration of 5 /Â¿g/platewithout S-9 mix. FT-207 also was not mutagenic to TA100or TA98 with or without S-9 mix. These 2 compounds werealso not mutagenic to TA92 with or without S-9 mix.

Table 1Trivial names, structures, mutagenicities, and carcinogenicities of antibiotics

Trivial name Structure Mutagenicity Carcinogenicity

Daunomycin-MCIAdriamycin-HOI

+ (14)+ (14)

Bleomycin-MCI

Actinomycin D

OH NH2

Ft: â€”CH3, daunomycinâ€”CHjOH, Adriamycin

Glycopeptide

Peptide Peptide

CO CO

+ (30)

Mitomycin CÂ° + (30)

Mitomycin C is mutagenic to S. typhimurium TA92.

JULY 1978 2149



V. Se/no ef al.

Table 2

Results of mutation tests on antibioticshis* revertants/plate

TA100Drug"Daunomycin-HCIAdriamycin-HCIBleomycin-HCIActinomycin

DControl''Mitomycin

CControl*"/itg/plate0.0830.17

0.420.830.020.050.10.20.5125100.941.884.79.418.82.46.112.20.011.02.5510+

S-9mix144160

16314710913015215927030317018516899111125129106125100661471471107075103131-

S-9mix286295

20214410630923498723620670190143100010390451321150000122TA98+

S-9mix24273362242827223155106423443252320221218172130212121221719-S-9mix340852

1555136810232355610347762606445017187001815181626000017TA92fWo+

rowortantc/+

S-9mix4648494945282014484840806139-S-9 mix nmol*2800

(8,-)c3130(8,

-)393732

02892434

0323690120

43(2,-)1377226

" Drug contained some vehicle, and the amount of the drug was expressed as /*g of active principle.6 The number of his' revertants per nmol was calculated from the data obtained under the most active conditions in the linear dose-

responsible range and a yield of 100 colonies more than the background yield.c Tester strain TA98; -, without S-9 mix; 2, TA92.rt Average of values in 20 experiments. The numbers of revertants were: 117 to 183 of TA100 with S-9 mix, 89 to 169 of TA100 without S-

9 mix, 19 to 38 of TA98 with S-9 mix, and 14 to 26 of TA98 without S-9 mix.e Average of values in 2 experiments.

Twelve alkylcarbamoyl derivatives of 5-fluorouracil(namely, 1-methyl, 1-ethyl, 1-propyl, 1-isopropyl, 1-butyl, 1-ferf-butyl, 1-pentyl, 1-hexyl, 1-cyclohexyl, 1-phenyl, 1-hep-tyl, and 1-octyl-carbamoyl-5-fluorouracil) were all nonmu-tagenic to TA100 and TA98 with or without S-9 mix. All ofthese derivatives were cytotoxic at doses of 2.5 to 5 Â¿Â¿g/plate. Therefore, these compounds were also tested inTA92 and were found not to be mutagenic, as shown inTable 4. These alkylcarbamoyl derivatives of 5-fluorouracilare not yet used clinically, although their antitumor activities against experimental tumors in mice were demonstrated by Hoshief al. (9, 10).

6-Mercaptopurine, an inhibitor of purine synthesis, wasweakly mutagenic to TA100 without S-9 mix, as shown inTable 4. This drug was reported to be mutagenic to S.typhimurium strains TA1535 and /?/sG46 by the liquidmethod (8). The noncarcinogenicity of this compound wasreported (25). Methotrexate, which inhibits the bio-syntheses of purine and thymine from formate, gave negative results on TA100 and TA98 at doses of up to 312 Â¿ig/plate. It had a slight lethal effect on the cells. Methotrexatewas also reported to be nonmutagenic to S. typhimuriumTA1535.TA1536, TA1537, TA1538, and hisG46 by the liquidmethod (8). A weak carcinogenicity of this compound on

experimental animals has been reported (22), but it has alsobeen reported not to be carcinogenic (23) and to cause nochromosomal aberrations in mammalian culture cells (7).Thus, further studies are required to determine whether it isreally carcinogenic.

8-Azaguanine, an inhibitor of guanylic acid synthesis,was not mutagenic to TA100, TA98, orTA92 with or withoutS-9 mix (Table 4). It had no effect on cell survival of TA100or TA92 at doses of up to 50 Â¿Â¿g/platebut killed TA98 at adose of 25 /xg/plate. This compound is noncarcinogenic(6).

1-/3-D-Arabinofuranosylcytosine and cyclocytidine werenot mutagenic at doses of up to 30 and 25 mg/plate,respectively (Table 4). Arabinofuranosylcytosine is knownto interfere with DNA polymerase (18) and to be incorporated into DNA (31), and it induced chromosomal aberrations both in vivo (2) and in vitro (4, 11).

Alkylating Agents. Five alkylating agents were all foundto be mutagenic in this system, as shown in Table 6.Cyclophosphamide was mutagenic to TA100 with S-9 mixbut was not mutagenic to TA98. This compound was reported to be mutagenic (8, 16) and carcinogenic (29).Busulfan was mutagenic to TA100 with or without S-9 mixbut not to TA98. Busulfan was reported to be carcinogenic





Table 3Trivial names, structures, mutagenicities, and carcinogenicities of antimetabolites

Trivial name Structure Mutagenicity Carcinogenicity5-Fluorouracil

FT-207

Carbamoyl derivatives of 5-fluorouracilfl: Methyl

EthylPropylIsopropylButylfert-ButylPentylHexylCyclohexylPhenylHeptylOctyl

6-Mercaptopurine

d

CONH-R

SH

N-N>CH

- (25)

Methotrexate

8-Azaguanine

NH2 CH3 COOH

OH

+ (22), - (23)

-(6)

1-/3-D-Arabinofuranosylcytosine

Cyclocytidine

HO

HO

HOÃ‡H2o'01

!H2

D

NH2CT

JULY 1978 2151



Y. Se/no ef al.

Table 4Results of mutation tests on antimetabolites

his*revertants/plateTA100Antimetabolite5-FU6FT-2071

-Methylcarbamoyl-5-FU1-Ethylcarbamoyl-5-FU1

-Propylcarbamoyl-5-FU1-lsopropylcarbamoyl-5-FU1

-Butylcarbamoyl-5-FU1-ferf-Butylcarbamoyl-5-FU1

-Pentylcarbamoyl-5-FU1-Hexylcarbamoyl-5-FU1

-Cyclohexylcarbamoyl-5-FU1-Phenylcarbamoyl-5-FU1

-Heptylcarbamoyl-5-FU/ug/plate15105025502501510502.5510502.5510500.52.510500.52.55500.52.510500.52.55500.52.55100.515100.52.510500.52.51050+

S-9mix183134121133132131871771531730145165142100158189137012913419497162170150140110126142160170162171154120107114148132149146138121151131671741461510-S-9mix82000991010125000125000133000103000154960010000011812500710001041150011000095000TA98+S-9mix3032380371403549270272722028323101425204024232922122124036193021262916243037353127172203319290-S-9mix13000710110001470010000900021000120002100010000151100900012000TA92+S-9mix3332003421221921176261615120201112623181263017227283032129221330222732425232251330225171712-S-9mix19000151391900016000120001800017000100001300019000130001300018000his*revert-

ants/nmol"o0ooogooooo




Mutagenicity of Ant/tumor Agents

Table ^-Continuedh/sf revertants/plate

TA100 TA98 TA92

Antimetabolite1

-Octylcarbamoyl-5-FU6-MercaptopurineMethotrexate''8-Azaguanine1

-/3-o-ArabinofuranosylcytosineCyclocytidineControl6/Â¿g/plate0.52.510502505007501,0001042083121025501,0005,00010,00025,00030,0005,00010,00020,00025,000+

S-9mix13013513001141101279014217216910912612312714515813513112791132150147-S-9mix80000276313282231657785117139127921341251321419077105135132+S-9mix28223102232242436353744373637302834282919313830-S-9 mix + S-9 mix - S-9 mixants/nmol"8

33150310013001102021

nner9UUb63335

02120

2114036 19003318313022

019202225

037U2216

39 26" The number of his* revertants per nmol was calculated from the data obtained under the most active conditions in the linear dose-

responsible range and a yield of 100 colonies more than the background yield.6 5-FU, 5-fluorouracil.c Tester strain TA100 without S-9 mix.d Drug contained some vehicle, and the amount of the drug was expressed as /xg of active principle.e Average of values in 20 experiments. The numbers of revertants were: 117 to 183 of TA100 with S-9 mix, 89 to 169 of TA100 without S-

9 mix, 19 to 38 of TA98 with S-9 mix, and 14 to 26 of TA98 without S-9 mix.

(28). ACNU, which is now being tested clinically, wasmutagenic to TA100 with or without S-9 mix but was notmutagenic to TA98 at doses of up to 50 /xg/plate. Carba-zilquinone was mutagenic to TA100 with or without S-9 mix.Pipobroman was mutagenic to TA100 without S-9 mix butwas not mutagenic to TA98.

Vinca Alkaloids. Results on Vinca alkaloids, includingvinblastine sulfate and vincristine sulfate, are shown inTable 8. These compounds were not mutagenic to TA100 orTA98 with or without S-9 mix at doses of up to 500 Â¿/.g/plate,as shown in Table 8. Moreover, a dose of 500 /Â¿g/platehadno apparent lethal effect on the bacterial cells. Thesealkaloids were reported to inhibit the growth of cells inculture (21), but no data on their carcinogenicities areavailable.

Enzyme. u-Asparaginase was not mutagenic to eitherstrain with or without S-9 mix (Table 8). Moreover, it had nolethal effect at doses of up to 3 mg/plate.

Adrenal Steroid Hormone. Prednisolone was not mutagenic to either strain with or without S-9 mix (Table 8), andit was not lethal at doses of up to 33 /Lig/plate. Thiscompound was not tested at concentrations greater than 33Â¿ig/plate.

In this work we tested the mutagenicities of various kinds

of antitumor agents. Some of them are now in clinical use,and some, such as various alkylcarbamoyl-5-fluorouracilderivatives, are now being tested in animals. Among 33compounds tested 9 were found to be mutagenic; thesewere daunomycin hydrochloride, Adriamycin hydrochlo-ride, mitomycin C, 6-mercaptopurine, cyclophosphamide,busulfan, ACNU, carbazilquinone, and pipobroman. Themutagenicities of daunomycin hydrochloride (3, 16), Adriamycin hydrochloride (3, 16), 6-mercaptopurine (3, 8), andcyclophosphamide (3, 8, 16) were reported, and the lack ofmutagenicity found with methotrexate (3, 8) and actinomy-cin D (3) were confirmed in this study. Recently, Benedictef a/. (3) reported that uracil mustard was mutagenic toTA1535 without S-9 mix. Uracil mustard has a bis(2-chlo-roethyl)amino group. This bis(2-chloroethyl)amino groupmay alkylate DMA and induce mutation. On the other hand,5-fluorouracil and its alkylcarbamoyl derivatives seem tohave no alkylating activity.

Certain substances used in cancer chemotherapy areendowed with mutagenic potential. There is a demonstrated correlation between mutagenicity in this bacterialtest system and potential for causing cancer in laboratoryanimals. Therefore, the development of new chemothera-peutic agents that have no mutagenicity in such bacterial

JULY 1978 2153



Y. Se/no et al.

Table 5

Trivial names, structures, mutagenicities, and carcinogen/cities of alkylating agents

Trivial name Structure Mutagenicity Carcinogenicity

Cyclophosphamide

Busulfan

ACNU

Carbazilquinone

Pipobroman

C1CH,CH2 2 + (29)

(28)

2|>'>r^CHCH2Ã–CONH2

H2C 0 L

0

OCH3

0

Table 6

Results of mutation tests on alkylating agentshis+ revertants/plate

TA100AgentCyclophosphamide1'BusulfanACNUCarbazilquinonePipobromanControl0Â¿ig/plate70175

525700100500

7501000510

2550102575100250500

7501000+

S-9mix158309

437401160390

5781132140178

234500198251273317127147

157196147-

S-9mix90110

106133137267

5781038182218

262366365602641420176218

260313132TA98hle>

+ruxjartontc/+

S-9mix1627

22253524

35493028

2338294066293535

303830-

S-9 mixnmol"132

0.26(0,+)c034

0.14(0,+)521^

2.33 (0,-)302648

-, AQ m,89 7'48


Table 7Trivial names, structures, and mutagenicities of Vinca alkaloids, an enzyme, and an

adrenal steroid hormone

Trivial name Structure Mutagenicity

Vinblastine sulfateVincristine sulfate

H3CO COOCrhCOOCH3

H

L-Asparaginase

Prednisolone

R: -CH3 Vinblastine

-CHO Vincristine

CH2Ã›HIC=0

Table 8Results of mutation tests on Vinca alkaloids, an enzyme, and an adrenal steroid hormone

his* revertants/plate

TA100Vinblastine

sulfateVincristine

sulfateL-Asparaginase6Prednisolone*Control0^g/plate100250500100250500500

(152IU)1500(455IU)3000(909IU)8.31733+

S-9mix1249392113104149146148165135145123147-S-9mix102129113121127126134156135125145144132TA98+S-9mix25292632332629232537393530-S-9mix9141418181615262334332316his*revert-

ants/nmol"0000

" The number of his+ revertants per nmol was calculated from the data obtained under the most active conditions inthe linear dose-responsible range and a yield of 100 colonies more than the background yield.

'' Drug contained some vehicle, and the amount of the drug was expressed as /*g of active principle.c Average of values in 20 experiments.

test systems would be most desirable because of the possibly decreased risk of latent drug-induced cancer in thepatient undergoing chemotherapy.

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1978;38:2148-2156. Cancer Res Yuko Seino, Minako Nagao, Takie Yahagi, et al.

TA98, TA100, and TA92Salmonella typhimuriumMutagenicity of Several Classes of Antitumor Agents to

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