curability of mouse l1210 leukemia by combination of 5 … · l1210 leukemia was induced in...

(CANCER RESEARCH 44, 652-656, February 1984]

Curability of Mouse L1210 Leukemia by Combination of 5-Fluorouracil,c/s-Diamminedichloroplatinum(ll), and Low Doses of y-Rays1

Claude Dionet2 and Pierre Verrelle

Centre Jean Perrin and INSERM UnitÃ©71, B.P. 392, Place Henri Dunant, 63011 Clermont-Ferrand Cedex, France

ABSTRACT

By combining 5-fluorouracil and c/s-diamminedichloro-plati-

num(ll) at drug levels which are ineffective when used alone, wehave cured L1210 leukemia in mice in a single treatment session.

It was also discovered that the doses of the drugs used in thiscombination can be decreased, with no corresponding decreasein their effectiveness, if they are administered in conjunction witha very low dose of radiation (7-rays), which, when used alone, is

ineffective. In the cells, the explanation for the synergic action ofradiation, 5-fluorouracil, and c/s-diamminedichloroplatinum(ll)can

be found in the action of each of the cytostatics at differentphases of the cell cycle, each cytostatic favoring the action ofthe others.

It is important to emphasize the order in which chemotherapyand radiotherapy are administered, as well as the time lapsebetween administration of the two treatments, maximum effectiveness having been obtained when radiotherapy was carriedout 8 to 24 hr after chemotherapy.

INTRODUCTION

One of the main lines of research in oncology is based oncombining different cytostatic agents (16, 23, 37), whether it canbe a combination of drugs (2), a combination of drugs andradiation (5, 8,21,17), or the use of radiosensitizers or hyper-

thermia combined with drugs or radiation (4, 9). The aim is toincrease the tumoricidal effect of such combinations while reducing the harmful side effects of each therapeutic agent (18, 19).The chosen approach to the problem of therapeutic effectivenesshas been to consider the cell kinetics (1,41 ). Some authors haveshown the potential of the tumoricidal effects of 5-FUra3 and

radiation (19), and numerous studies on the synergy of c/s-

platinum and radiation are in progress (14,38). It is possible thatthe effectiveness of a cytostatic agent (drug, radiation, etc.) islinked to the cytological type of the tumor (21). However, certaindrugs reputed to be inactive on a certain type of tumor sometimes prove to be active on that same tumor, depending on howthey are administered (21, 28) or if they are used in conjunctionwith other cytostatics (10).

In mouse L1210 leukemia, there is a sharp increase in thetumoricidal effects when c/s-DDP is combined with 5-FUra, andthe addition of a low dose of 7-rays allows the drug doses to be

decreased without leading to a corresponding decrease in thecytosatic effectiveness of the combination (13).

1This work was supported by INSERM CRL No. 813024.2To whom requests for reprints should be addressed.3The abbreviations used are: 5-FUra, 5-fluorouracil; cis-DDP, c/s-diamminedi-

chloroplatinum(ll); PLD, potentially lethal damage.Received February 2, 1983; accepted October 6, 1983.

MATERIALS AND METHODS

L1210 leukemia was induced in 6-week-old male C57BL/6 x DBA/2F, (thereafter called B6D2F!) mice by i.p. administration of 105 cells in

0.1 ml of ascitic liquid. The L1210 leukemia was transferred at weeklyintervals into B6D2F, mice at doses of 10s cells and was 100% lethal

afer a period of 9 to 10 days. The L1210 cells were obtained from theNational Cancer Institute (Bethesda, Md.), and kept in the Institut deCancÃ©rologieet d'ImmunogÃ©nÃ©tiquede Villejuif.

5-FUra (Produit Roche S.A., Neuilly-sur-Seine, France) stored awayfrom light or c/s-DDP (Cisplatyl, Laboratoire Roger Bellow, Neuilly-sur-

Seine, France) was administered by i.p. injection. When the chemotherapy was an association of the 2 drugs, they were given simultaneously.The 2 drugs were prepared immediately before use. The doses used areexpressed in mg of drug per kg of animal weight.

Irradiation of the peritoneal cavity was carried out with MCo at a rate

of 1 gray/min. The mice were confined in a plastic box to prevent themfrom moving. The top and bottom of the box were made of 5-mm-thickplastic so that the "build-up" would occur at the animals' skin. The

required dose was administered at the midline of the animal by 2 radiationfields, anterior and posterior. The irradiated area included all the abdominal cavity; only the head and the thorax above the diaphragm wereshielded. The administered dose was 2 grays, except in one experiment(Group 1) in which it was 1.25 grays. Each experimental group consistedof 6 animals. The control group consisted of N = K VÃ±animals where k

is the number of different groups and n is the number of animals pergroup (in this case, 6), N being raised to the nearest whole number.Quality control gave the following results: in the control group, 40% ofthe animals died on the 9th day, while the other 60% died on the 10thday. Median survival was therefore 10 days, and there were no "notakes" among the control mice. We used 450 mice.

Results are evaluated in terms of median survival. The survival of agroup is considered significant if it is greater than or equal to 135%, i.e.,in our case, greater than or equal to 13.5 days (NIH injunctions). Theanimals were considered cured when they survived for longer than 90days and seemed in good health. Administration of leukemia cells i.p.was carried out on Day 0, and treatment consisting of chemotherapy orradiotherapy was carried out 24 hr later on Day 1. In the case of acombination of the 2 kinds of treatment, it was begun on Day 1, and thetime lapse between radiotherapy and chemotherapy is given in detailunder "Results." In all cases, even in that of combined treatment, the

animals were radiated with 7-rays and/or given chemotherapy only once,

the aim of the treatment being to cure in a single administration.The following method was used to count cells in ascitic fluid. Three

ml of 0.9% NaCI solution were injected i.p. and then drawn off, and thetotal volume of liquid in the peritoneal cavity was measured. The micewere killed, and the peritoneal cavity was rinsed 3 times. Harvested cellswere then counted using a hemocytometer.

RESULTS

The results given in Table 1 show the effects of the differentcytostatic agents (c/s-DDP, 5-FUra, 7-rays) used separately. The

median survival of the control animals was 10 days. That ofGroups 1 and 2, treated only by radiation (1.25 and 2 grays,

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respectively) of the peritoneal cavity, was also 10 days, showingthe ineffectiveness of 7-rays alone. c/s-DDP used alone also had

very little effect; with 1 mg of drug per kg of animal weight(Group 3), survival was 11 days; with 10 mg per kg (Group 5), itwas 13 days, a result which was still not significant. Survivalrates of Groups 6, 7, and 8 show the low effectiveness of 5-

FUra used alone, which increased survival only to 16 days,thereby producing a significant result when the dose was increased to 200 mg/kg.

Table 2 shows the results obtained by combining 2 cytostatics.By combining 5-FUra and c/s-DDP in increasing doses, we

lengthened the survival time correspondingly. Combining 100mg 5-FUra per kg with 5 mg c/s-DDP per kg (Group 14) produceda survival time of 16 days, while combining 100 mg 5-FUra perkg with 10 mg c/'s-DDP per kg (Group 15) gave an infinite survival

time with most animals being cured (in the first experiment, 5 of6 animals survived; in the second experiment, 6 of 6 animalssurvived; in the third experiment, 5 of 6 animals survived).

Table 3 shows the survival rate when the 3 cytostatic agentswere combined. The survival of the 5-mg c/s-DDP per kg plus100-mg 5-FUra per kg group increased from 16 days (Group 14)to infinity when 2 grays of 7-rays (totally ineffective when admin

istered alone; Group 2 survival, 10 days) were added to thechemotherapy (Group 21).

Table 4 underlines the importance of the order in which 7-raysand chemotherapy are administered. For the same dose of 7-

Effect of 5-FUra, c/s-DDP, and Low Doses of -Â¡-RaysonL1210

rays (2 grays), and the same dose of chemotherapy (100 mg 5-FUra per kg plus 5 mg c/s-DDP per kg), the survival rate varied

greatly merely because of the order in which the treatmentswere administered. If 7-rays were administered 2 hr before or

after chemotherapy, survival increased to 19 and 22 days, respectively (Groups 18 and 19). On the other hand, if 7-rays were

administered at least 8 hr after chemotherapy (Group 20), theanimals were cured. This result did not change if the time lapsebetween chemotherapy and radiotherapy was within 24 hr(Group 21). However, the synergic effect is lost if radiotherapy

Table 1Survival of mice treated by one cytostatic agent

Median survival after treatment by one of the cytostatics used once on Day 1,24 hr after inoculation with L1210, expressed in days.

Days of death

Experiment 1 Experiment2

GroupControls1234S678TreatmentNone7-Rays,

1.25graysâ€¢y-Rays,2graysc/s-DDP,1mg/kgc/s-DDP,5mg/kgc/s-DDP,10mg/kg5-FUra,

50mg/kg5-FUra,100mg/kg5-FUra,200 mg/kgMedian101010111213121316Range9-10

(0/16)"9-10(0/6)9-13(0/6)10-12(0/6)11-13(1/6)12-18(1/6)12-15(0/6)13-14(0/6)16-27(0/6)Median1010101112121214Range9-10(0/18)9-10(0/6)9-10(0/6)9-12(0/6)11-14(0/6)11-14(0/6)10-14(0/6)14-17(0/6)

a Numbers in parentheses,number of survivors/total number of mice.

Table 2Survival of mice treated by combination of 2 cytostatic agents

Treatment was begun on Day 1.

Days of death


Group9101112131415Treatment7-Rays,2 grays, + 5-FUra,10mg/kg-y-Rays,

2 grays, + 5-FUra,50mg/kg7-Rays,

2 grays, + c/s-DDP,5mg/kgc/s-DDP,

1 mg/kg, + 5-FUra,10mg/kgc/s-DDP,

5 mg/kg, + 5-FUra,50mg/kgc/s-DDP,

5 mg/kg, -I-5-FUra,100mg/kgc/s-DDP,

10 mg/kg, +5-FUra,100mg/kgMedian11121212161600Range11-12(0/6)"10-14(0/6)10-16(0/6)11-14(0/6)14-24(1/6)15-22(0/6)(6/6)Median111313121717150000Range11-13(0/6)12-14(0/6)12-20(0/6)12-14

(0/6)15-20

(1/6)12-21

(1/6)13-24(2/6)"14-00

(5/6)20-00(5/6)"a

Numbers in parentheses,number of survivors/total number of mice.

TablesSurvival of mice treated by combination of 3 cytostatic agents

Group 14 is included for comparison.

Days of death


Group14

16

17

21Treatmentc/s-DDP,

mg/kgc/s-DDP,

mg/kg,c/s-DDP,

mg/kg,c/s-DDP,

mg/kg,5

mg/kg,1

mg/kg,+ -y-rays5 mg/kg,+ 7-rays5 mg/kg,+ -y-rays+

5-FUra,

+ 5-FUra,

+ 5-FUra,

+ 5-FUra,100

10

50

100Median16

12

1700Range15-22(0/6)"

12-14(0/6)

15-19(1/6)

(6/6)Median17

12

180000Range12-21

(1/6)

11-15(0/6)

14-24(1/6)16-00

(4/6)21-Â» (5/6)"

Numbers in parentheses, number of survivors/total number of mice.Third experiment.

FEBRUARY 1984 653



C. Dionet and P. Verrette

Table 4Survival of mice depending on the 3 cytostatics schedule: importance of the order of administration and of

the time lapse between radiotherapy and chemotherapy5-Fura and c/s-DDP are administeredsimultaneously.

Days of death


GroupTreatmentIB

2 hr7-Rays, 2 grays < Â»C"T1Q

2nrCTÂ« Â»-r-rays, 2grayson8 hrÂ¿u CT Â« Â»i-rays, 2grays01

24 hr' ' CT Â« >7-rays, 2grays18

hr22CT Â« >7-rays, 1.25grays0-3

48 hrCT < Â»i-rays, 2graysa

CT, chemotherapyof c/s-DDP, 5mg/kg,Miimhorc in ria rant hoc oc- ni imHar rtf 01 inMedian

Range19

17-27(1/6)"22

18-23(2/6)oo

19-00(4/6)oo

(6/6)oo

16-00(4/6)17

17-21(0/6)and

5-FUra, 100 mg/kg.Median

Range20

12-21(1/6)21

15-21(2/6)Â°<=

21-00 (5/6)Â°<= 17-oc(3/6)Â°Â°Â°

16-Â» (4/6)oo 21-00 (6/6)c

' Third experiment.

Table 5Survival of mice treated by 2 cytostatic agents: importance ot order and time lapse of administration

Treatment was begun on Day 1.

Days ofdeathExperiment

1Group91011242526272829Treatment2hr

FIT"< Â»5-FUra, 10mg/kg2hr

RT Â« Â»5-FUra,50mg/kg2hr

RT < Â»c/s-DDP, 5mg/kg8hr

c/s-DDP, 10 mg/kg < >RT24hrc/s-DDP,

10 mg/kg <>RT48

hrc/s-DDP,10 mg/kg Â«>RT8

hr5-FUra, 100 mg/kg Â« >RT24hr5-FUra,

100 mg/kg Â«Â»RT48

hr5-FUra,100 mg/kg <Â»RTMedian111212181417151515Range11-12(0/6)"10-14(0/6)10-16(0/6)14-21

(1/6)13-17(0/6)14-17(2/6)14-17(0/6)14-15(0/6)14-17(0/6)Experiment

2Median

Range11

11-13(0/6)13

12-14(0/6)13

12-20(0/6)

' RT, radiotherapy,2 grays.0 Numbers in parentheses,number of survivors/total number of mice.

is performed 48 hr after chemotherapy (Group 23). Group 22shows the possibility of decreasing -y-ray doses to 1.25 grays

while maintaining infinite survival if a period of 18 hr is maintainedbetween chemotherapy and radiotherapy.

The association of either 5-FUra or c/s-DDP alone with 7-rays

is unable to cure mice (Table 5).To gauge the effectiveness of the therapy with regard to the

tumor cell number, we stopped applying the curative chemotherapy on Day 1 and resumed it later (Days 2, 4, 6, and 8),while maintaining inoculation on Day 0. Results are shown inTable 6. The treatment is curative if applied up to Day 4 but isno longer so if applied on Day 6. We measured the cell numbereach day after inoculation of 105 cells on Day 0. On Day 4, theamount of cells was 8 x 106, which corresponds approximately

to the theoretical number if the cell cycle length is the same invivo as in vitro (i.e., 12 hr) (Table 6), considering the difficulty incollecting all the cells of the ascitic fluid.

TableÃ³Survival of mice depending on the day of treatment

Mediansurvival when the treatment (c/s-DDP,10 mg/kg, + 5-FUra, 100 mg/kg)is applied in a single session on different days after inoculation on Day 0 of 10'

cells.

Days of death Cell no. in the ascitic fluid

TreatmentonDay1

Day 2Day 4Day 6Day 8Median00

00X1910Range20-00

(5/6)"

(6/6)23-00 (5/6)18-21 (0/6)9-13(0/6)Measured1.5x10*

4 X1068 X1062 x10"5.3 x 10eTheoretical4

x10"1.6X 10"2.6 x 10'5 x10*8 x10"

8 Numbers in parentheses, number of survivors/total number of mice.

DISCUSSION5-FUra and c/s-DDP used alone and in a single treatment have

very little effect on L1210 leukemia (10, 25, 42). In this study,the doses used were mildly effective if the drugs were used




Effect of 5-FUra, cis-DDP, and Low Doses of y-Rays on L1210

individually. Nevertheless, the association of 5-FUra and cis-DDP

becomes curative for mice when the drugs are used simultaneously. By adding a low dose of radiotherapy (2 grays), it ispossible to maintain the curative effect of the 5-FUra-c/s-DDP

combination as long as radiotherapy is applied from 8 to 24 hrafter chemotherapy. To understand how the effectiveness of thiscombination functions, the action of the different cytostatics onthe cell cycle has to be taken into account, (a) 5-FUra is a

potentiator of radiotherapy (18,19,23). Its basic action is on theS phase of the cycle (21), the most radioresistant phase (6, 23).By killing the radioresistant cells, it increases the apparent effectiveness of radiotherapy, but its action on the S phase also givesit a true synergic action by hindering repair of PLD caused byradiation (23, 24, 30). The mechanism at the molecular level isthe interference of 5-FUra in the synthesis of thymidine (21, 36).To be active, the 5-FUra has to be transformed into fluoro-5-deoxyuridine monophosphate in the target cell. The fluoro-5-

deoxyuridine monophosphate inhibits the action of thymidinesynthetase and consequently the DNA synthesis. The incorporation of 5-FUra into RNA seems to be of less importance in therange of doses that we used (21, 36). (b) cis-DDP acts on theGÃ¬phase of the cycle (35). The greater effectiveness of c/s-DDPon plateau-phase cells in vitro, compared to exponential growth-

phase cells (7, 15, 20), may be due in part to the presence ofmore G, cells in the plateau-phase cultures. It must be notedthat plateau-phase cells in vitro are analogous to "quiescent"

cells in vivo (3, 22, 23, 31 ) and have slowed down metabolisms.To obtain maximum effectiveness for c/s-DDP, it is possible that

all cells must already be in the G! phase of the cycle. For L1210,cycle length is 12 hr, and d length is about 6 hours (21) as longas in vivo cell behavior is the same as that in vitro (Ref. 31 ;results in Table 6). Thus, within 8 hr, all cells have entered d.This is perhaps why it is necessary to wait to obtain maximumeffectiveness from the radiotherapy on cells thus sensitized. Weare now studying the minimum and maximum time lapses afterwhich radiotherapy must be administered, (c) Furthermore, lowdoses of radiation at sufficient dose rates (in the case of ourexperiments) cause the cell cycle to slow down temporarily byseveral hr (12, 27, 33, 40). This could be the explanation of acertain potentiation of the 7-ray followed by c/s-DDP sequence

(33, 39), since the latter acts more effectively on cells with aslowed down cycle (15). This last concept is important because,in the case of solid tumor treatment, the role of the radiationfollowed by c/s-DDP sequence could be of interest when it is

based on tumor radiobiological data and no longer solely on celldata as is the case with L1210 leukemia (our own work inprogress). The effectiveness of the action of the chemotherapycombination is the result of an as yet unexplained mechanism.The use of caffeine on cells treated with c/s-DDP leads to a

decrease in the shoulder of the survival curve. This can beattributed to the inhibition of a certain amount of repair of PLD(caused by c/s-DDP) (15). Consequently, the action of 5-FUracombined with c/s-DDP lies perhaps partly in PLD repair inhibi

tion. Extensive work is now in progress to investigate the molecular mechanisms of the action of radiation and c/s-DDP. It hasbeen established that c/s-DDP inserts itself into the DNA chain,

creating interstrand bonds which may explain a greater sensitivityto radiation (14, 26, 32, 43). Furthermore, c/s-DDP, when boundto other substances, will be less active than in free form (29, 34).It is possible that radiation plays a role in the release of activec/s-DDP. We now have work in progress on this subject. The

ability of radiation to be potentiated by 5-FUra and c/s-DDP

applied from 8 to 24 hr before is probably related to the metabolism of these 2 drugs. It has been shown that either one or theother drug is still efficient in vivo several hr after its administration(11,20,34).

In conclusion, 5-FUra acts more effectively on the S phase ofthe cycle and hinders repair of PLD due to radiation and perhapsrepair of PLD due to c/s-DDP. c/s-DDP has a maximal action onthe d phase of the cycle, and the delay of 8 hr necessary tooptimize the chemotherapy-radiotherapy sequence suggests theimportance of as great a number of cells as possible entering dphase. Finally, radiation has an optimal action in the G2, themitosis, and the late GT phases, and the slowing down of thecell cycle that it provokes may be favorable to a better action ofc/s-DDP. Each of the 3 cytostatics used has a different point ofimpact on the cell cycle phases, which may in part explain theeffectiveness of this triple combination. However, a fundamentalpoint of this effectiveness lies in the synchronization of the 3cytostatics.

ACKNOWLEDGMENTS

The authors are indebted to Professors Plagne, Rozan, and Meyniel and toDenise Godeneche for helpful discussions and comments. They wish to thankMaryse Rapp for her skilled technical assistance and Florence Maria and MichellaLabende for their help in preparing the manuscript.

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1984;44:652-656. Cancer Res Claude Dionet and Pierre Verrelle

-RaysγDoses of -Diamminedichloroplatinum(II), and Lowcis5-Fluorouracil,

Curability of Mouse L1210 Leukemia by Combination of

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