JPH08169825A - Combined administration of anti-cancer medicine and anti-cancer medicine capable of being andministered jointly - Google Patents

Abstract

PURPOSE: To provide a combination of anti-cancer medicines more excellent than a conventional combination of anti-cancer medicines, having especially synergistic effects, that is, higher than an expected value of the combination of anti-cancer medicines by >=115%. CONSTITUTION: One or more medicines to be jointly administered selected from cisplatin, carboplatin, 5-FU, tegafur, carmofur, doxifluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin and 1-OHP are administered together. Especially administration of both cisplatin or 5-FU and 1-OHP shows destroying effects on tumor cells reaching twice an expected value depending upon conditions and is capable of remarkably contributing cancer treatment.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a combined administration method of anticancer agents having excellent combined effect and an anticancer agent which can be used in combination, and more specifically, a combined administration method of anticancer agents in which a synergistic effect of combination is exhibited by the combined administration, The present invention relates to a combination anticancer agent that can be used for carrying out the method, and a mixed anticancer agent prepared by mixing these anticancer agents.

[0002]

2. Description of the Related Art Anti-cancer agents are generally used in combination with other anti-cancer agents in order to enhance their effectiveness and prevent tumor cells from acquiring resistance to the agents. However, there is no special method for selecting the drug to be used in combination, and it is a general condition as a drug to be used in combination, that the drug to be used in combination is effective even when used alone, and side effects do not overlap with those of the concomitant drug. Under the prevailing conditions of, concomitant drugs have been selected as a result of experience by clinicians.

Tumor cells are killed when a reaction to recover from damage caused by a drug (anticancer drug) is induced in the cells and the repair mechanism is not fully exerted. However, it takes time to die (necessity of time administration). When two or more anti-cancer agents are used in combination, a cell biological reaction (synergistic effect) that is not observed when administered alone may occur. In this case, the unique mechanism of action of each anti-cancer agent (all have been elucidated) Not)) may compete or appear as an antagonistic reaction. In order to clarify these, it is necessary to perform various administrations in which the dose of the concomitant drug and the administration time are combined.

The present inventor has developed a rational technique for the combination of anticancer agents (CANCER CHEMOTHERAPY: Challenges for
the Future, vol.4, 1989; Molecular Bilology of DN
A Topoisomerases, Proceedings of the International
Symposium on DNA Topoisomerases in Chemotherapy,
1991), and demonstrated the effect of combined use of various anticancer agents. However, there are few combinations of anticancer agents that show a synergistic effect, and it is not possible to easily obtain a satisfactory combination effect of anticancer agents.

[0005]

SUMMARY OF THE INVENTION The present invention has been made to solve these drawbacks, and is a novel anticancer agent, cis-oxalato (1R, 2R-diaminocyclohexane) platinum (II).
The present invention has been accomplished by conducting various studies on the combined administration of (hereinafter referred to as 1-OHP) and a known anticancer agent, finding an optimal combined administration method.

[0006]

The present invention provides cisplatin, carboplatin, and 5-fluorouracil (hereinafter referred to as 5-
FU), tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone, and bleomycin in combination with 1-OHP. And a mixed anticancer agent prepared by mixing the concomitant agent with 1-OHP.

The details of the present invention will be described below. Tumor cells (cancer cells) have a higher proliferation rate than normal cells, and when the killing effect of tumor cells is equal to or less than the proliferation rate,
It only suppresses the progression of cancer and cannot be a fundamental treatment for cancer. Each anticancer drug has an optimal dose, and even if an anticancer drug is administered in a larger amount than the dose, the effect of killing tumor cells does not increase proportionally but only slightly. Moreover, the adverse effects such as damage to normal cells caused by the large amount of administration often appear more strongly, and it is hardly expected that the therapeutic effect is increased by the large amount administration of the single anticancer agent.

[0008] The conventional co-administration of anti-cancer agents eliminates the limitation of large-scale use of this single anti-cancer agent and expands the possibility of cancer treatment. Although its mechanism of action has not been fully elucidated, it has been pointed out that the use of a specific combination may significantly increase the killing effect of tumor cells. That is, by using the anticancer agent A and the anticancer agent B, an effect equal to or more than the sum (additive effect) of the tumor cell death rate when the anticancer agent A is used alone and the tumor cell death rate when the anticancer agent B is used alone ( Synergistic effect) may appear.

Suppressing the progression of cancer with an anti-cancer agent is not sufficient, and it is desirable to completely kill tumor cells.
For that purpose, it is necessary to kill the tumor cells at a rate faster than the growth rate of the tumor cells, and theoretically, if the rate of killing the tumor cells by the anticancer agent is higher than the growth rate, the tumor cells will eventually be completely killed. To do. However, due to the risk of metastasis of tumor cells and the risk of administering long-term toxic anticancer agents to patients, the emergence of anticancer agents capable of killing tumor cells in a short period of time is desired. For that purpose, a combination of anticancer agents in which the killing effect of tumor cells is synergistically increased by the use of two or more anticancer agents is essential, and the emergence of the combination of anticancer agents having this synergistic effect is decisive for current cancer chemotherapy. Contribute.

In particular, the present invention proposes a combination of anticancer agents having at least an additive effect of this synergistic effect, wherein 1-OHP represented by (Chemical Formula 1) is used as a target anticancer agent. One or more known anticancer agents are combined and administered in combination. With this combined administration, l-O
The anticancer effect of HP is synergistically or additively improved, and the combined administration can be expected to make a great contribution to cancer treatment.

[0011]

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The present inventors have found that cisplatin, carboplatin, 5-FU, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone,
Bleomycin, vincristine and vindesine in total 15
Known anti-cancer agents (combination agents) and l-OHP (targeting agents)
Attempts to measure the killing effect of tumor cells by co-administration with. In this combination, not only the combination of anticancer agents but also the administration method (simultaneous administration, additional administration) and dose (large dose,
Consider also small dose).

In evaluating the killing effect of tumor cells in each combination, the killing effect of the control (when no anticancer agent is used) is subtracted, and the killing effect of the combination of the pure concomitant drug and 1-OHP is calculated. The combined effect is calculated using the formula described below, and the value (%) calculated by this formula is 85 to 11
It is evaluated that there is an additive effect when it is 5%, less than the additive effect when it is less than 85%, and a synergistic effect when it exceeds 115%. ± 15% is the confidence limit or error.

As a result, as described in detail below, cisplatin, 5-FU, irinotecan, adriamycin,
About 8 kinds of etoposide, mitomycin, mitoxantrone and bleomycin in total, most of them have an additive effect or a synergistic effect regardless of the administration method and dose, and particularly the effect of the combination of cisplatin and 5-FU is remarkable, The combination of 5-FU and 1-OHP is the best. On the other hand, there are many combinations of vincristine and vindesine in which only an additive effect appears at best.

That is, in the combined administration of cisplatin and 1-OHP, when cisplatin was co-administered,
A synergistic effect was obtained with all combinations of OHP administered prior to cisplatin, and expected values (additive effect) depending on the conditions
2 times more effective in killing tumor cells. 5-FU and l-
When combined with OHP, 5-FU was administered under almost all conditions.
A synergistic effect can be obtained regardless of the dose and administration method, and, similar to the case of cisplatin, a tumor cell killing effect that is twice the expected value appears depending on the conditions. Of the combination drugs searched,
The best results were obtained, with 5-FU being the most recommended combination with l-OHP.

When irinotecan and l-OHP are used in combination,
A synergistic effect appears in all combinations with additional administration of -OHP. When adriamycin and l-OHP are used together, l-O
A synergistic effect appears in most combinations with HP boost.
When etoposide and 1-OHP are used in combination, a synergistic effect appears in most combinations in which l-OHP is additionally administered. The combined use of mitomycin and 1-OHP has a synergistic effect in many combinations in which 1-OHP is pre-administered. The combined use of mitoxantrone and 1-OHP has a synergistic effect in all combinations in which a small amount of mitoxantrone is used and l-OHP is additionally administered. The combined use of bleomycin and l-OHP has a synergistic effect in many combinations in which l-OHP is additionally administered on the 3rd or 4th day. Further, it is expected that carboplatin, tegafur, carmofur, doxyfluridine, and uracil have the same or slightly inferior effects as cisplatin and 5-FU. The combined effect of a single agent or a compounding agent (a mixture of tegafur and uracil) consisting of 5-FU and its derivative with 1-OHP also shows the effect of 5-FU and 1-OH.
It can be expected to be similar to the combined effect of P.

These effective concomitant agents are solely l-OH.
Further effects can be expected not only when used in combination with P, but also when two or more combined agents, for example, 5-FU and cisplatin are used in combination with 1-OHP. Vincristine and l-OHP
There is no combination showing a synergistic effect, and many combinations show an additive effect. In the combined use of vindesine and 1-OHP, there are no combinations showing a synergistic effect among the 14 kinds of combinations, and only 3 cases show an additive effect, which is the worst among the searched combination agents.

As described above, not only the type of concomitant drug, but also the size of the dose and the timing of administration influence the combined effect.
Although there is no clear standard for the dose, the timing of administration clearly affects the effect depending on each concomitant drug. For example, in the case of cisplatin, in most cases where 1-OHP is pre-administered and cisplatin is additionally administered, the effect is about double the expected value, whereas when cisplatin is pre-administered, only 1 out of 6 combinations is shown. Shows a synergistic effect, and the three types of combinations had a synergistic effect or less.

When administering a drug to a patient, simultaneous administration is preferable to staggered administration because the burden on the patient and the doctor is lightened, but 5-FU is expected to be 180 times the expected value by simultaneous administration.
% Or 150%, and from this point 5-FU and l
It can be seen that -OHP is a preferred combination. Note that the simultaneous administration of the present invention includes both the case where a plurality of anticancer agents are simultaneously administered with a time difference of zero and the case where there is a slight time difference in which a plurality of anticancer agents are continuously administered by separate administration operations. Administration is staggered administration. In the following examples of the present invention, the combination administration of the present invention was performed only on leukemia tumor cells, but the method of the present invention and the mixed anticancer agent of the present invention also exert synergistic or additive effects on other organ cancers. Expected to demonstrate. The route of administration of the anticancer agent may be oral, injection, vaginal or anal administration, and application to the skin, as is conventional. In the case of a combination in which the effect is obtained by simultaneously administering the above-mentioned 1-OHP and the concomitant drug, both drugs can be mixed to form a tablet, or can be enclosed in an ampoule for injection. In addition to mixing, 1-OHP can be integrated with a concomitant agent by chemical bonding and added to a tablet or enclosed in an ampoule.
When a time-lag administration is desired, both 1-OHP and the concomitant drug are separately prepared, and one of them is pre-administered and the other is additionally administered. The evaluation method for combined use of anti-cancer agents in the examples described below can be applied to combined use of anti-cancer agents other than the present invention, and is a useful method that can serve as an index for future evaluation methods for combined use of anti-cancer agents.

[0020]

[Examples] Next, examples relating to the combined administration of the anticancer agents according to the present invention will be described, but the present examples do not limit the present invention. The target tumor cells were human leukocyte cell line cells (RPMI-8402, manufactured by Gibco), and
Add 15% fetal calf serum (manufactured by Gibco) to increase the cell number to 10 ⁵
The cell suspension at the number of cells / ml was prepared in a 5 ml culture bottle (trade name: Sumilon, manufactured by Sumitomo Bakelite Co., Ltd.).
A large number of the same suspensions were prepared in this culture bottle, and as a concomitant drug, one of cisplatin, 5-fluorouracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone, bleomycin, vincristine and vindesine was selected. Was selected, and each of the following experiments was performed separately. In addition, the control
FIG. 1 shows the time course of addition of 1-OHP alone, addition of concomitant agent only, the following items (1) to (4)], and combined administration of concomitant agent and 1-OHP.

(1) As a control, no drug was added. (2) l-OHP alone was added on the first day. (3) A large amount of concomitant drug was added on the first day (1 μg / ml for cisplatin, 10 μg / ml for 5-FU, 0.05 μg / ml for adriamycin, 1 μg / ml for etoposide, and 0.05 μg / ml for vincristine as a comparison. , And vindesine 0.05 μg / ml). For irinotecan, the amount of irinotecan added was fixed at 10 μg / ml, and l-
The amount of OHP added was 5 μg / ml. (4) A small amount of concomitant drug was added on the first day (for cisplatin,
0.5 μg / ml, 5-FU 5 μg / ml, adriamycin 0.01 μg / ml, etoposide 0.5 μg / m
l, and vincristine 0.01 μg / ml for comparison,
And vindesine 0.01 μg / ml). Regarding irinotecan, the amount of irinotecan added was fixed at 10 μg / ml, and the amount of 1-OHP added was 1 μg / ml.

(5) 1-OHP and a large amount of combination agent [item (3)
The same amount as below, and the same below] were simultaneously added on the first day. (6) 1-OHP and a small amount of the combination agent [the same amount as in item (4), the same applies below] were simultaneously added on the first day. (7) l-OHP was added on the first day, and a large amount of concomitant drug was added on the second day.
Added on the day. (8) l-OHP was added on the first day, and a small amount of the concomitant drug was added on the second day.
Added on the day. (9) l-OHP was added on the first day, and a large amount of concomitant drug was added on the third day.
Added on the day. (10) l-OHP was added on the first day, and a small amount of concomitant drug was added on the third day.
Added on the day.

(11) l-OHP was added on day 1 and a large amount of concomitant drug was added on day 4. (12) 1-OHP was added on the 1st day, and a small amount of concomitant drug was added on the 4th day.
Added on the day. (13) Add a large amount of concomitant drug on the first day and add l-OHP to the second day.
Added on the day. (14) Add a small amount of concomitant drug on the 1st day and add l-OHP to the 2nd day.
Added on the day. (15) Add a large amount of concomitant drug on the first day and add l-OHP on the third day.
Added on the day. (16) Add a small amount of concomitant drug on the 1st day and add l-OHP to the 3rd day.
Added on the day. (17) Add a large amount of concomitant drug on the 1st day and add l-OHP on the 4th day.
Added on the day. (18) Add a small amount of concomitant drug on the 1st day, and add l-OHP to the 4th day.
Added on the day.

In each of these experiments, 5% was added to each suspension.
After adding carbon dioxide gas and culturing at 37 ° C for 6 days, 24 hours (2nd day) and 48 hours (3rd day) from the first drug administration (1st day)
Sun), 72 hours later (4th day), 96 hours later (5th day), 120
The number of dead cells per constant number (1000) of cells was measured after time (day 6) and 144 hours (day 7).
In the measurement, a sample was sampled from the culture solution, placed in a cell observation plate (ZOG-1 manufactured by Elecon Chemical Co., Ltd.), and the cells were observed with an inverted microscope with a fluorescent device of 1500 times (manufactured by Nikon Co., Ltd.) to obtain 1000 cells. The number of dead cells per hit was counted. The number of dead cells was counted three times in one experiment, and the percentage and standard deviation were calculated.

From these measured values, the combined efficiency OE (ratio of expected value and measured value) was calculated using the following formula. OE (%) = A / [C ₀ + (B−C ₁ ) + (D−C ₂ )] × 100 In the formula, A is the measured value of dead cells on the 7th day obtained by the combination, and C ₀ is Cell killing value on day 7 with the control cells of (1) above,
B is the cell killing effect (%) during the number of days exposed to 1-OHP, C ₁ is the cell killing effect (%) of the control cells of the above (2) at the same number of days as B, and D is the combination agent. C ₂ is the cell killing effect (%) during the same number of days, and C ₂ is the cell killing effect (%) of the control cells of the above (3) at the same number of days as D.

The calculated values for each concomitant drug are summarized in FIG. In the figure, ● ▲ ■ is a large dose of concomitant drug, ○ △ □ is a small dose of concomitant drug, ● ○ is simultaneous administration, ▲ △ is prior administration of l-OHP, ■ □ is prior administration of concomitant drug, and subscripts 2 to 4 are This is the date of administration of the additional drug. From FIG. 2, the effects as described above are observed for each combination agent. The effects are summarized in Table 1. In the figure, ● indicates synergistic effect, ○ indicates additive effect, and Δ indicates less than additive effect.

[0027]

[Table 1]

[0028]

INDUSTRIAL APPLICABILITY The present invention provides one or more combination agents selected from cisplatin, carboplatin, 5-fluorouracil, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin. , Cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is used in combination for administration of an anticancer agent (claim 1).
As is clear from the examples, when 1-OHP and an existing anti-cancer agent are combined and administered to tumor cells, the effect on the death of the tumor cells in almost all cases is an additive effect to the case of 1-OHP alone. And often produce a synergistic effect.

The increase in the killing effect of tumor cells by the combined administration of anti-cancer agents has important meaning especially in the vicinity of antagonizing the growth rate of tumor cells, and even a slight increase in the killing effect promotes a significant therapeutic effect. Will be given.
According to the method of combined administration of anticancer agents of the present invention, the killing effect is dramatically increased, especially by appropriately selecting the combination of anticancer agents, and it can make a great contribution to many cancer treatments.

The 1-OHP and the concomitant drug may be administered simultaneously (claim 2) or one of them may be additionally administered (claim 4), and the administration timing may be appropriately determined depending on each combination. However, co-administration is desirable to reduce the burden on patients and doctors, and 5-FU (claim 3), which is about twice as effective as expected, is a particularly effective concomitant drug.

The concomitant anticancer agent used for carrying out the method of the present invention is selected from cisplatin, carboplatin, 5-FU, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin 1 or It is a combination of two or more concomitant drugs and 1-OHP (claim 5), and the use of the concomitant anticancer drug produces the above-mentioned remarkable therapeutic effect on cancer. In the case of a combination of anticancer agents, which is preferably administered at the same time, 1 or 2 of 1-OHP and each combination agent is used.
When the above is mixed to form a tablet or provided in an ampoule for injection and provided (Claim 6), it is particularly desirable because the trouble of the combined administration can be saved.
It may be coordinated by a chemical bond (claim 7).

[Brief description of drawings]

FIG. 1 is a diagram showing a time course of a control and a combined administration of a concomitant drug and 1-OHP.

FIG. 2 is a diagram showing calculated values of the killing effect under each condition of combined administration of the concomitant drug and 1-OHP in the example.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61K 31/70

Claims (7)

[Claims] 1. A cis-oxalate containing one or more concomitant agents selected from cisplatin, carboplatin, 5-fluorouracil, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin. (1R, 2R-diaminocyclohexane) platinum (II) is used in combination for administration of an anticancer agent. 2. A concomitant drug is cis-oxalate (1R, 2
The method of claim 1, wherein the method is co-administered with R-diaminocyclohexane) platinum (II). 3. 5-Fluorouracil is converted into cis-oxalate (1R, 2R-diaminocyclohexane) platinum (I
The method according to claim 2, which is co-administered with I). 4. A combination drug and cis-oxalate (1R,
The method according to claim 1, wherein any of 2R-diaminocyclohexane) platinum (II) is additionally administered. 5. Cisplatin, carboplatin, 5-fluorouracil, tegafur, carmofur, doxyfluridine, which can be administered in combination with cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II),
One or more anticancer agents selected from uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin. 6. One or more concomitant agents selected from cisplatin, carboplatin, 5-fluorouracil, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin are combined with cis-oxalate. (1R, 2R-diaminocyclohexane) platinum (II) mixed and prepared, The mixed anticancer agent characterized by the above-mentioned. 7. A combination of one or more selected from cisplatin, carboplatin, 5-fluorouracil, tegafur, carmofur, doxyfluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin is cis-oxalate. (1R, 2R-diaminocyclohexane) An anticancer agent characterized by being coordinated to platinum (II) by a chemical bond.