The Effect of the Sequence of Administration of Cytoxan and Methotrexate on the Life-Span of L1210 Leukemic Mice

[CANCER RESEARCH 32, 200-207, February 1972)

The Effect of the Sequence of Administration of Cytoxan and Methotrexate on the Life-span of L1210 Leukemic Mice

Marc J. Straus, Nathan Mantel, and Abraham Goldin Drug Research and Development, Chemotherapy [M. J. S., A. G.J, and Biometry Branch, National Cancer Institute [N. M.J, Bethesda, Maryland 20014

SUMMARY studies have generally involved either cyclic chemotherapy, in which the drugs are rotated, or the utilization of a drug until The purpose of this study was to determine whether the there is clinical deterioration, followed by administration of sequence of administration of two chemotherapeutic agents, the next agent. Neither system has provided a definitive cytoxan (Cyt) and methotrexate (MIX), would alter advantage in therapy (1, 3â€”5,14). antileukemic effectiveness. CDF! mice were inoculated i.p. Experimental models for the study of synergistic with 10s L1210 ascites tumor cells. In one experiment, mice relationships of combinations of 2 drugs have been used in a were treated with one dose of MTX 2 days after tumor number of laboratories (8â€”10, 19, 23, 24). More recently, inoculation (Day 2) and one dose of Cyt on Day 4 or 6. sophisticated designs for seeking enhanced chemotherapeutic For each group of mice in this study there was a effect with combinations of 3 drugs (13) and for sequential corresponding group that received the same doses of the drugs chemotherapy (15, 21â€”23)have been devised. There have also but for which the order of administration was reversed; i.e., been studies to determine whether it is possible to identify Cyt was given on Day 2 and MTX was given on Day 4 or 6. combinations of drugs that will be synergistic and which When the doses of Cyt and MTX were 80 and 30 mg/kg, combinations may be effective in remission induction or respectively, significantly longer survivals were noted when remission maintenance (11). However, there have been few Cyt was administered prior to MTX. systematic studies designed to determine the optimal sequence In other experiments, MTX was administered in a series of in sequential chemotherapy. doses at 2- or 4-day intervals to L1210 mice. When a high dose On the basis of experimental results obtained by Laster et of Cyt (120 mg/kg) was substituted for a regularly scheduled al. (17), it was suggested (17, 18) that the utilization of an dose of MTX, the earlier the substitution, the longer was the alkylating agent prior to an antimetabolite would result in survival. No effect of replacement was noted when Cyt (40 increased chemotherapeutic effect. Goldin et al. (11) have mg/kg) was substituted for MTX. When a higher dose of MTX suggested the use of a reciprocal design (Drug A -> B, Drug (36 mg/kg) replaced a dose of MTX (4 mg/kg), earlier B -Â»â€¢A),as one means for determining the influence of drug substitution appeared to increase survival. scheduling on the effectiveness of drugs in sequential therapy. The advantage to therapy of a high priming dose may reflect Straus et al. (20) showed that the use of priming doses of MTX a prior observation that the percentage kill of tumor cells of resulted in increased survival of mice with leukemia L1210. cell cycle stage-specific agents such as MTX is greater for The study reported here was designed to determine whether smaller populations of tumor cells. Early administration of a the sequence in which effective chemotherapeutic agents are high priming dose of Cyt or MTX apparently lowers the tumor given may alter the life-span of LI210 leukemic mice and cell population so that scheduled doses of MTX can kill tumor whether the specific dose levels of the drugs play an important cells more effectively. role in determining an optimal sequence. Specifically, we proposed to determine whether the time of administration and dose of the alkylating agent Cyt1 relative to the time of INTRODUCTION administration and dose of the antimetabolite MTX would alter therapeutic effectiveness. It was considered that the The trend of protocol designs of cooperative cancer results of such a laboratory study might provide insight into chemotherapy groups has been in the direction of utilization the kinetics of drug action which in turn might enable of greater numbers of drugs in combination and in the use of clinicians to plan more effective sequences when administering more complex schedules. In acute lymphocytic leukemia there more than 1 drug. has been a higher frequency of remission induction with combinations of drugs than with single agents (11, 14). Similarly, in Class III and IV Hodgkin's disease, combinations MATERIALS AND METHODS of agents have increased the frequency of remission (2). Many studies have included the use of 4 or more agents (5, 11, 16). Stock tumor of lymphoid leukemia L1210 was carried i.p. Clinically, it has not been established whether combinations of in DBA/2 male mice. Ascites tumor cells were counted in a drugs are best given together or sequentially (14). Sequential 'The abbreviations used are: Cyt, cytoxan; MTX, methotrexate; MST, mean survival time; CCSN, cell cycle stage nonspecific; CCSS, cell Received May 13, 1971 Â¡acceptedOctober 7, 1971. cycle stage specific.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1972 American Association for Cancer Research. The Sequence of Administration of Drugs in L1210 hemocytometer and diluted in Hanks' balanced salt solution to A single dose of Cyt, 120 mg/kg, administered on Day 2 1 X IO6 cells/ml, and the suspension was kept in an ice bath. increased the MST to 14.2 days. MTX, 3 mg/kg, administered Tumor cell suspensions (1 X 10s; 0.1 ml) were injected i.p. on Day 2 increased the MST to 8.9 days. When MTX was into CDF, (BALB/cAnCr X DBA/2Cr) F, male mice, administered every other day, from Day 2 to 16, the MSTwas weighing 18 to 25 g. Mice were randomized and housed in 15.8 days. plastic cages in a constant temperature facility and provided Of the groups of mice scheduled to receive MTX, 3 mg/kg, with water and laboratory chow ad libitum. every other day from Day 2 to 16, the group with the MTX (amethopterin; NSC 740) was prepared every 4 days earliest Cyt substitution, 120 mg/kg (Day 2) survived the from Lot No. 1260x8105 from Lederle Laboratories, Pearl longest; MST, 23.4 days. There was 1 mouse "cured" in this River, N. Y., and was refrigerated in an opaque jar. It was group of 20 mice, which was counted as a 60-day survivor. The dissolved in 2% sodium bicarbonate and injected i.p. Cyt group with the next earliest Cyt substitution (Day 4) survived (cyclophosphamide; Mead Johnson Laboratories, Evansville, 2nd longest; MST, 21.7 days. The MST of mice scheduled to Ind., Lot No. 2, man 121;NSC 26271) was freshly prepared at receive Cyt on Day 16 was 16.4 days, which approximates the each injection period. It was dissolved in 0.85%NaCl solution 15.8-day MST of mice that received MTX every other day. The and injected i.p. Both drugs were administered in a volume of earlier the substitution was made, the longer the mice lived. 0.01 ml/g body weight. This is indicated by a plot of MST's of all of the groups of mice (Chart 1). When a dose of Cyt, 40 mg/kg, was similarly substituted for RESULTS MTX (Chart 2), the group of mice receiving Cyt substitution earliest had an MST of 17.6 days. This was not significantly Cross-overExperiment Involving a Single Treatment with longer than the MST of the last group, 16.8 days, which had MTX and Cyt in L1210. Mice were inoculated with 10s received Cyt on Day 16. The MST of mice that received a single dose of Cyt on Day 2 was about 1 day longer than that L1210 ascites cells on Day 0. The MST of untreated control of the mice receiving a single dose of MTX. A plot of MST's mice was 8.0 days. Mice in Groups 1 and 2 were treated with suggestsa possible advantage in earlier Cyt substitution. MTX, 3 mg/kg, on Day 2. Group 1 then received Cyt, 40 When Cyt (120 mg/kg) was substituted for a higher dose of mg/kg, on Day 4, and Group 2 received Cyt, 40 mg/kg, on Day MTX (4 mg/kg; Chart 3) the advantage in substituting Cyt 6. The MST of these groups were 10.6 and 11.1 days, respectively (Table 1). Two other groups received the same Table 1 doses of the drugs, but the order of administration was reversed ("cross-over" Groups 1 and 2), i.e., Cyt was given on Effect of altering the sequence of I dose of Cyt and MTX on the life-span of L1210 leukemic mice Day 2 and the MTX was given on Day 4 or 6. The MST's of CDF, mice, 18 to 25 g, were inoculated with 10s L1210 ascites cells the initial and cross-over groups were similar. When MTX, 30 on Day 0. MTX and Cyt were inoculated i.p. in mg/kg doses. There mg/kg, was administered to mice on Day 2 and Cyt, 40 mg/kg, were 15 to 20 mice/group. The MST of untreated control mice was 8.0. was administered on Day 4 or 6, the MST's were also similar to those of mice treated on the respective cross-over schedules Injection of MTX or Cyt (mg/kg) (Groups 3 and 4). The above schedules were repeated, with 80 in place of 40 b Mouse survival mg of Cyt per kg. When MTX, 3 mg/kg, was administered to time"10.6 mice on Day 2, followed by Cyt, 80 mg/kg, on Day 4 or 6 group1234567891011121314151617181920Day2MTX 4Cyt 6Cyt time10.4 (Groups 5 and 6), the MST's of these groups were similar to 3MTX 40Cyt Â±0.411.1 Â±11.5 those of their respective cross-overgroups. 3MTX 40Cyt Â±0.411.6 Â±11.0 Both groups of mice that had received MTX, 30 mg/kg, on 30MTX 40Cyt Â±0.711.8+ +11.016.216.419.518.30.50.50.30.30.50.61.20.3 Day 2 and Cyt, 80 mg/kg, on Day 4 or 6 had MST's of 16.4 30MTX 40Cyt 0.615.6 days (Groups 7 and 8). The corresponding groups of mice on 3MTX 80Cyt Â±0.416.3 cross-over schedules had MST's that were significantly longer. 3MTX 80Cyt Â±0.416.4 30MTX 80MTX Â±1.016.4 Mice that received injections of a single dose of Cyt, 40 30MTX 80MTX Â±0.48.8 mg/kg, on Day 2, 4, or 6 showed no significant difference in 3MTX Â±0.38.4 MST. Mice receiving Cyt, 80 mg/kg, on Day 2,4, or 6 also had 3MTX Â±0.28.9 constant MST's, as did mice receivingMTX, 3 or 30 mg/kg, on 3MTX Â±0.210.9 30Cyt Â±0.69.4 either of those days. Similar schedules with higher doses of 30Cyt Â±0.29.7 Cyt in combination with MTX resulted in frequent toxic 30Cyt Â±0.39.4 deaths. 40Cyt Â±0.29.5 40Cyt Â±0.39.8 Sequential Chemotherapy Experiments Involving a Single 40Cyt Â±0.414.6 Modification in the Regularly Scheduled Treatment of L1210. 80Day Â±0.414.2 The data of 3 experiments are summarized in the charts: 1 in 80Day Â±0.716.0Â± Charts 1,2, 6, and 7; 1 in Chart 4; and 1 in Charts 3, 5, and 8. 80Survival 0.9Cross-over"- In Chart 1, the basic group of mice received MTX(3 mg/kg) 0 Mean Â±S.E. every other day from Day 2 to 16 after leukemic inoculation. b The order of injection of the drugs was reversed. Example: in In the other groups of mice, Cyt was substituted for MTXon Group 1, CYT, 40 mg/kg, was administered on Day 2 and MTX, 3 the day indicated. Tumor-bearing control mice died on Day 8. mg/kg, on Day 4.

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Â£ 5 UNTREATED DAY 2 DAY 2 2 4 6 8 10 12 14 16 NO SUBSTITUTION CONTROLS CYT MTX DAY OF CYTOXAN SUBSTITUTION MTX 40 mg/kg 3 mg/kg 3 mg/kg MTX, q2d, days 2-16, except40 mg/kg CYTon day of substitution 3 mg/kg, q2d days2-16 Chart 2. early was more evident. The MST of the group that received significant difference in the MST's of the individual groups. the Cyt substitution on Day 2 was 25.9 days, with 1 mouse The MST's of groups receiving a single dose of MTX, 36 or 4 cured. Delaying the substitution to Day 4 lowered the MST 4 mg/kg, differed by only 1 day. days, to 22.1 days. The MST of the group with a Day 16 Cyt, 120 mg/kg, was again (as in Chart 3) substituted on substitution was 15.8 days. The MST of mice that received a different days for MTX, 4 mg/kg (Chart 5). However, after the single dose of Cyt, 120 mg/kg, was about 6 days longer than last day of substitution, each group continued to receive MTX, that of mice that received a single dose of MTX, 4 mg/kg. 4 mg/kg, every other day until death. Again, the group that When MTX, 36 mg/kg, was substituted at various times for received Cyt on Day 2 survived the longest; MST, 29.0 days. MTX, 4 mg/kg, a plot of MST's suggests some advantage in There was progressive decrease in MST with increasing delay in earlier substitution (Chart 4). However, there was no Cyt substitution. Thus, the MST of the group that received

202 CANCER RESEARCH VOL. 32

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1972 American Association for Cancer Research. The Sequence of Administration of Drugs in L1210 substituted at various times for MTX, 15 mg/kg, the MST's of Cyt earliest was 13.7 days longer than that of the group scheduled to receive Cyt last. the mice were not altered, regardless of the day of substitution Utilizing a similar design, we increased the interval between (Chart 7). The MST of mice that received a single dose of Cyt, doses to 4 days (Charts 6 to 8). When Cyt, 120 mg/kg, was 40 mg/kg, on Day 2 was slightly less than the MST of mice substituted for MTX, 15 mg/kg, and was administered every that received MTX, 15 mg/kg, on Day 2. 4th day from Day 2 to 14, there was an advantage in early When the dose of MTX was increased to 20 mg/kg (Chart substitution (Chart 6). 8), the MST of the group of mice receiving a dose of Cyt, 120 When the dose of Cyt was decreased to 40 mg/kg and mg/kg, on Day 2 was 25.7 days. This was the longest survival

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Ã® 5 UNTREATED DAY 2 DAY 2 2 4 6 8 IO 12 14 16 NO SUBSTITUTION CONTROLS CYT-120 MTX 15 DAY OF CYTOXAN SUBSTITUTION MTX mg/kgday mg/kgday 15mg/kgMTX,q4d,days2-14, except120mg/kgCYTondayof substitution 15mg/kgq4d, daysZ-14 Chart 6. time observed in the 3 experiments involving treatment witn as Cyt and the other being a CCSS agent such as MTX, then MTX every 4th day. When substitution was delayed until Day the optimal sequence of administration of the drugs would be 18, the MST was reduced to 12.5 days. to give the CCSN agent first, provided that it is given in a high enough dose. Thus, when 1 dose of Cyt and 1 dose of MTX were DISCUSSION administered in sequence to groups of L1210 leukemic mice, the mice that received Cyt prior to administration of MTX had The current studies suggest that if one is to use 2 classes of longer MST's than did mice on cross-over schedules when the agents in sequential chemotherapy, 1 being a CCSN agent such doses of Cyt and MTX were high. The single dose of Cyt (80

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1972 American Association for Cancer Research. The Sequence of Administration of Drugs in L1210 mg/kg) in this instance increased life-span more than did the replacement was noted. When a high loading dose of a CCSS single dose of MIX (30 mg/kg). agent (MTX, 36 mg/kg) was substituted for a low dose (MIX, Similarly, when 1 of a series of doses of MIX was replaced 4 mg/kg), earlier substitution increased chemotherapeutic by a high dose of Cyt (120 mg/kg), the earlier was the effectiveness. substitution, the longer was the MST (Charts 1, 3, 5, 6, and 8). A number of studies have suggested a rationale for improved This effect was noted with several dose levels of MIX and with survival with sequential schedules. Increased survival has been intervals of 2 and 4 days between treatments. obtained in sequential chemotherapy studies when a priming When a low dose of Cyt was used for substitution which was dose of 1 drug was followed by a series of treatments with a equally effective with the single dose of MIX, no effect of 2nd drug (12). The principle involves the use of priming

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therapy to decrease the number of tumor cells, and this in turn Combination Antimetabolite Therapy in Acute Leukemia: permits the drug that is used sequentially to be more effective 6-Mercaptopurine and Methotrexate. Blood, 18: 431-454, 1961. (7). 4. Frei, E., Ill, Karon, M., Levin, R. H., Freireich, E. J., Taylor, R. J., Priming dose schedules of MIX were demonstrated to Hananian, J., Selawry, O., Holland, J. F., Hoogstraten, B., Wolman, increase its antileukemic effectiveness (20). In a series of I. J., Abir, E., Sawitsky, A., Lee, S., Mills, S. D., Bergert, E. O., Jr., experiments, it was indicated that MTX, a CCSS agent, Spurr, C. L., Patterson, R. B., Ebaugh, F. G., James, G. W., Ill, and Moon, J. H. The Effectiveness of Combinations of Antileukemic exhibited a decreasing percentage of kill of tumor cells as the Agents in Inducing and Maintaining Remission in Children with population of tumor cells increased. Kinetic considerations Acute Leukemia. Blood, 26: 642-656, 1965. suggested that the priming dose of MTX may lower the tumor 5. Freireich, E. J., Karon, M., Flatow, F., and Frei, E., HI. Effect of cell population sufficiently for subsequent doses of the drug to Intensive Cyclic Chemotherapy (BIKE) on Remission Duration in kill tumor cells more effectively. Schabel has suggested that, in Acute Lymphocytic Leukemia. Proc. Am. Assoc. Cancer Res., 6: sequential therapy, utilization of an alkylating (a CCSN agent), 20, 1965. prior to administration of an antimetabolite (CCSS agent) 6. Goldin, A. Preclinical Methodology for the Selection of Anticancer would result in increased chemotherapeutic effect. Treatment Agents. In: H. Busch (ed.), Methods in Cancer Research, Vol. 4, with the alkylating agent would constitute priming therapy. pp. 193-254. New York: Academic Press, Inc., 1968. 7. Goldin, A. Factors Pertaining to Complete Drug-induced Remission He proposed, also, that with progressive tumor growth the of Tumor in Animals and Man. Cancer Res., 29: 2285-2291, sensitivity to antimetabolites decreases. Laster et al. (17) treated CA-755 tumor-bearing mice with a single dose of Cyt 1969. 8. Goldin, A., Greenspan, E. M., and Schoenbach, E. B. Studies on (CCSN agent) followed by daily doses of 6-mercaptopurine the Mechanism of Action of Chemotherapeutic Agents in Cancer. (CCSS agent) and noted a higher percentage of cures. VI. Synergistic (Additive) Action of Drugs on a Transplantable In the current experiments, the priming dose of Cyt or MTX Leukemia in Mice. Cancer, 5; 153-160, 1952. apparently also lowered the tumor cell population so that the 9. Goldin, A., and Mantel, N. The Employment of Combinations of percentage of tumor cell kill of subsequent doses of MTX Drugs in the Chemotherapy of Neoplasia: A Review. Cancer Res., (CCSS agent) was increased. 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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1972 American Association for Cancer Research. The Effect of the Sequence of Administration of Cytoxan and Methotrexate on the Life-span of L1210 Leukemic Mice

Marc J. Straus, Nathan Mantel and Abraham Goldin

Cancer Res 1972;32:200-207.

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