HK1067039B - A combination comprising combretastatin and anticancer agents - Google Patents

Description

Compound medicine containing COMBRETASTATIN and anticancer agent

The present invention relates to a therapeutic combination drug for the treatment of cancer comprising a 1, 2-stilbene derivative and an anticancer agent such as a taxane, an alkylating agent, an antimetabolite, a vinca alkaloid, an epipodophyllotoxin, and an antibiotic.

The present invention relates to the combined use of 1, 2-stilbene derivatives and other anticancer drugs for the treatment of cancer, in particular solid tumors, to the use of such combinations in improved anticancer therapy, and to the use of these active ingredients in the treatment (therapy), inhibition and amelioration of tumors.

Currently, there are a wide variety of chemotherapeutic agents used for the treatment and inhibition of tumors, particularly malignant solid tumors. Although these therapeutic agents all have tumor-reducing effects, it is often impossible to achieve a cure with these known therapeutic agents due to the cancer gaining tolerance to the therapeutic agent, tumor recurrence, and the like. Therefore, more excellent antitumor agents are required.

1, 2-stilbene derivatives having cis-1, 2-stilbene as a basic skeleton are known to have strong mitosis inhibitory activity and cytotoxicity, but most of the 1, 2-stilbene derivatives cannot be used as agents because of their low water solubility.

Recently, it has been found that certain 1, 2-stilbene derivatives having inhibitory activity on tubulin polymerization also have improved water solubility. This includes the phosphorylated prodrug of Combretastatin-a4 (see U.S. patent 5,561,122) and the 1, 2-stilbene derivatives disclosed in U.S. patent 5674906. The clinical use of these 1, 2-stilbene derivatives seems to be increasingly promising.

An object of the present invention is to develop an excellent antitumor agent, in particular, a pharmaceutical preparation capable of improving the effectiveness of a 1, 2-stilbene derivative, and particularly, to develop and provide an antitumor agent showing excellent safety and effectiveness in treating malignant tumors.

It has been found that 1, 2-stilbene derivatives, when administered with another anticancer agent such as a taxane, an alkylating agent, an antimetabolite, an epipodophyllotoxin, an antibiotic and a vinca alkaloid, have improved therapeutic effects in inhibiting tumor growth.

Among them, the substances which can be used in combination or complex with 1, 2-stilbene derivatives are taxanes such as paclitaxel, taxotere (taxotere) or their analogues; alkylating agents, such as cyclophosphamide, ifosfamide (isosfamide), melphalan, hexamethylmelamine, thiotepa or dacarbazine; antimetabolites, such as pyrimidine analogs, e.g., 5-fluorouracil, cytarabine capecitabine (capecitabine), and gemcitabine (gemcitabine) or analogs thereof, such as 2-fluorodeoxycytidine; folic acid analogs such as methotrexate, idatrexate or trimetrexate; spindle poisons including vinca alkaloids such as vinblastine, vincristine, vinorelbine and vindesine or their synthetic analogues such as navelbine (navelbine), or estramustine and taxanes (taxoid); epipodophyllotoxins, such as etoposide or etoposide; antibiotics, such as daunorubicin, doxorubicin, bleomycin or mitomycin, enzymes, such as L-asparaginase, topoisomerase inhibitors, such as topotecan or pyridine benzindole derivatives, and agents, such as procarbazine, mitoxantrone and biological response modifiers or growth factor inhibitors, such as interferons or interleukins.

Taxanes (e.g., paclitaxel and taxotere) and vinca alkaloids (e.g., vincristine and vinblastine), are recognized as antimicrotubule agents that interfere with cell division by disrupting the normal function of cellular microtubules. Alkylating agents (e.g., cyclophosphamide, ifosfamide, melphalan, hexamethylmelamine, thiotepa, or dacarbazine) typically produce cytotoxic activity by alkylating DNA, thereby directly interfering with the reproductive cycle of the cell. Antimetabolites exert cytotoxic activity by substituting pseudonucleotides into cellular DNA, thereby interfering with enzymes necessary for cell division or inhibiting DNA replication. Epipodophyllotoxins, such as etoposide and etoposide, are inhibitors of topoisomerase. Antibiotics, such as doxorubicin and daunorubicin, are also thought to act by inhibiting topoisomerase II.

It has now been found that the combination of these various anti-cancer agents with 1, 2-stilbene derivatives is particularly effective in the treatment of many solid tumours. Among the effective 1, 2-stilbene derivatives are combretastatin A-4 and derivatives of this compound, (Z) -1- (3-amino-4-methoxyphenyl) -2- (3, 4, 5-trimethoxyphenyl) ethylene, which may be referred to as SN 38. Both compounds show strong mitotic inhibitory activity, cytotoxicity and inhibit tubulin polymerization.

combretastatin A-4 has the following formula:

SN38 has the following formula:

this combretastatin is almost insoluble in water and can be used in the form of salts, such as hydrochloride, acetate, phosphate, mesylate and amino acid salts.

The manufacture of 1, 2-stilbene derivatives, which may be in the form of pharmaceutically acceptable salts, hydrates and solvates, as well as the manufacture of pharmaceutical compositions for oral and/or parenteral use containing the above compounds, inert pharmaceutically acceptable carriers and/or diluents thereof, is disclosed for SN38 and prodrugs in us patent 5,525,632, 5,731,353 and 5,674,906. These patents disclose that 1, 2-stilbene derivatives, including combretastatin SN38 when used alone, have an in vivo cancer-inhibiting effect, and are incorporated herein by reference.

Recently, it has been found that combretastatin z in combination with an anti-cancer agent selected from the group consisting of taxanes, alkylating agents, antimetabolites, vinca alkaloids, epipodophyllotoxins, and antibiotics, significantly reduces the development of tumor volume, an effect significantly greater than would be expected if each compound was administered alone to a mammal infected with a tumor.

Accordingly, the present invention is intended to provide a novel antitumor agent, for example, an anticancer chemotherapeutic drug (cancer chemotherapeutic agent) containing two types of active ingredients, i.e., a 1, 2-stilbene derivative and another anticancer compound, simultaneously or independently.

The present invention relates to an antitumor agent comprising a 1, 2-stilbene derivative and an anticancer agent.

The invention also encompasses combination therapies in which a 1, 2-stilbene derivative and another anti-cancer agent are prepared as two separate pharmaceutical formulations and administered to a patient in need of treatment simultaneously, semi-simultaneously, separately or separated by a period of time.

The tumors against which the antitumor agents of the present invention are administered include all types of tumors that occur in animals, particularly humans. Preferably, the antitumor agent of the present invention can be used for inhibiting proliferation of tumor cells in human. The antitumor agent of the present invention is a pharmaceutical preparation in which at least two compounds are used for curing (treating) or inhibiting tumors.

The administration form of the antitumor agent is not particularly limited. Anticancer agents can be routinely administered by intravenous, parenteral and oral means. The invention also includes an antitumor agent consisting of a combination of two compounds having distinctly different administration forms.

The 1, 2-stilbene derivative used in the present invention has cis-1, 2-stilbene as a basic skeleton and exhibits in vivo tubulin polymerization inhibitory activity and/or antitumor activity. The 1, 2-stilbene derivatives of the invention also include prodrugs which can be converted in vivo into the 1, 2-stilbene derivatives. All forms of suitable pharmaceutically acceptable derivatives, such as salts, esters, amides, solvates (solvated products) and hydrates thereof, may be used as the 1, 2-stilbene derivative in the present invention, provided that these derivatives exhibit antitumor activity when used in vivo.

Prodrugs of SN38 are preferably amino acid salts.

A representative 1, 2-stilbene derivative is represented by one of the following general formulae (I) or (II).

The amino acids are exemplified by alpha-amino acids, beta-amino acids and y-amino acids. Examples of preferred amino acids include glycine, alanine, leucine, serine, lysine, glutamic acid, aspartic acid, threonine, valine, isoleucine, ornithine, glutamine, asparagine, tyrosine, phenylalanine, cysteine, methionine, arginine, alanine, tryptophan, proline, histidine and the like. In particular, threonine and serine are preferable from the viewpoint of the effect and safety of the drug. Although any of these amino acids may have the L-, D-or DL-form, the L-form is preferred.

As described above, the 1, 2-stilbene derivative of the present invention is a compound whose structure has a cis-1, 2-stilbene skeleton and exhibits tubulin polymerization inhibitory activity and/or antitumor activity. Examples of such 1, 2-stilbene derivatives are combretastatin-A4 and SN38 or CPT-11, which are disclosed in prior art publications, such as U.S. Pat. Nos. 4,996,237, 5,561,122 and 5,430,062, the prior art 1, 2-stilbene derivatives described in these patent publications, and combretastatin of formula (II) described in U.S. Pat. Nos. 5,525,632 and 5,731,353, may be used for the 1, 2-stilbene derivatives of the present invention, as long as they conform to the definition of the 1, 2-stilbene derivatives in the present invention.

The above-mentioned 1, 2-stilbene derivatives can be produced by conventional techniques, including the processes disclosed in the above-mentioned known publications.

Among the 1, 2-stilbene derivatives of the present invention are salts, esters and other derivatives of 1, 2-stilbene and derivatives which can be converted in vivo into 1, 2-stilbene derivatives, provided that these 1, 2-stilbene derivatives exhibit the above-mentioned target activities in animals.

Among the compounds represented by the above general formula (II), are compounds represented by the following formula (IIa):

the compound of formula (IIa), or CPT-11, is soluble in water and may be in the form of a salt, such as the hydrochloride, acetate, mesylate, and the like.

When the antitumor agent of the present invention is to be used, the 1, 2-stilbene derivative may be combined with a compound selected from the group consisting of: taxanes, alkylating agents, antimetabolites, vinca alkaloids, epipodophyllotoxins and antibiotics, and are administered to patients, animals, particularly humans, in need of cure, mitigation of tumors, especially humans suffering from tumor cell proliferation, in order to inhibit proliferation of said tumor cells.

The invention also relates to a pharmaceutical composition containing the composite medicament according to the invention.

The products comprising such codrugs may be administered simultaneously, separately or separated by a period of time, in order to obtain maximum effectiveness of the codrugs; for each administration, the mode of administration may vary from rapid administration to continuous perfusion over the course of the administration.

Therefore, for the purpose of the present invention, the codrug is not exclusively limited to a codrug obtained by physically combining constituent ingredients, but also includes codrugs that allow independent administration, which can be administered simultaneously or in a separated time form.

One of the preferred embodiments of the present invention is the administration of an amount of compound IIa effective to inhibit the proliferation of tumor cells in combination with taxotere, doxorubicin or vincristine to inhibit the proliferation of tumor cells.

"inhibiting proliferation of tumor cells" refers to inhibiting proliferation of tumor cells that are susceptible to treatment, wherein said treatment comprises administering to, for example, a human suffering from tumor cell proliferation an effective amount of a 1, 2-stilbene derivative, such as combretastatin IIa, and a taxane compound, such as paclitaxel, taxotere and derivatives thereof. In acceptable cases, such administration may inhibit proliferation of tumor cells or reduce the measurable size of the tumor. In the best cases, the tumor is completely regressed.

As mentioned above, the method of administering the antineoplastic agent of the present invention to humans is not particularly limited, so that it can be administered orally or parenterally by intravenous, subcutaneous or intramuscular route. For improved effectiveness, parenteral administration via intravenous and subcutaneous routes of administration, i.e., by infusion and the like, is preferred. In the method of administration of the pharmaceutical preparation according to the present invention, the 1, 2-stilbene derivative and the taxane compound may be administered simultaneously, or the two compounds may be administered in an optional order. The actual required method and sequence of administration will vary depending on the individual preparation of 1, 2-stilbene used and the individual preparation of the other anticancer compound used (e.g. taxotere, doxorubicin or vinca alkaloids), the individual tumor cells being cured and the individual host being treated. The optimal method and sequence for administering the 1, 2-stilbene derivative and the supplementary anticancer compound under the conditions given in advance can be chosen appropriately by the person skilled in the art with the aid of routine techniques and the information contained in the present description.

The antitumor agent of the present invention sufficiently serves as the pharmaceutical preparation of the present invention containing two active ingredients, which are contained independently in different pharmaceutical preparations and used in the form of a combined drug. It should be noted that pharmaceutical preparations containing other agents (third and fourth medicinal ingredients, etc.) such as other antitumor agents are of course also within the scope of the present invention as long as these pharmaceutical preparations contain the active ingredients used in the present invention.

As suitable pharmaceutically acceptable carriers and diluents used in the antitumor agent of the present invention, carriers used for preparing pharmaceutical preparations known to those skilled in the art and the like can be suitably used. The antineoplastic agents of the present invention may be administered parenterally, as discussed above. In this case, the antineoplastic agent is formed into an intravenous infusion bag along with a pharmaceutically acceptable carrier by a variety of different methods known to those skilled in the art. Preferably, the medicaments are prepared, for example, in unit dosage form and as lyophilized preparations by conventional techniques and, upon administration, are reconstituted in water or other suitable infusion liquid.

The ratio of the two components in the pharmaceutical preparation of the antitumor agent of the present invention may vary within wide limits depending on many factors, such as the desired amount to be administered, and on the pharmaceutically acceptable carrier used. As for the amount or combination in administering the 1, 2-stilbene derivative as the pharmaceutical preparation of the antitumor agent of the present invention, it is preferable to use the 1, 2-stilbene derivative in an amount of about 0.01 to 1000 and particularly about 0.1 to 100 parts by weight of the 1, 2-stilbene derivative to 1 part by weight of the auxiliary anticancer compound present in the pharmaceutical preparation of the antitumor agent of the present invention. Therefore, when the pharmaceutical preparation containing two active ingredients of the present invention is to be administered to a patient, the pharmaceutical preparation is administered in an amount capable of achieving the above-defined administration range.

If the pharmaceutical preparations are to be administered stepwise, the above-defined administration ranges can be set as the average ratio of the individual pharmaceutical preparations.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments thereof. It should be noted that they are given by way of example only and are not intended to limit the present invention.

The effectiveness of a codrug can be demonstrated by determining its therapeutic synergy. Codrugs exhibit therapeutic synergy if their therapeutic effect is superior to that of one or the other of the constituent components used at the optimal dose (t.h. corbett et al, Cancer Treatment Reports, 66, 1187 (1982)).

The effectiveness of a codrug can also be demonstrated by comparing the maximum tolerated dose of the codrug with the maximum tolerated dose of each of the individual constituent ingredients in the study being addressed. This effectiveness can be quantified, for example, by log₁₀Cell kill rate, which can be determined by the following formula:

log₁₀killed cells ═ T-C (days)/3.32 × T_d

Wherein T-C represents the time taken for the cells to grow, which is the average time, in days, required for the tumors of the treatment group (T) to reach a predetermined value (e.g., 1g) and the tumors of the control group (C) to reach the same value, and T_dThe time necessary for doubling the tumor volume in the control group is expressed in days. (T.H.Corbett et al, Cancer (Cancer), 40, 2660.2680 (1977); F.M.Schabel et al, Cancer drug development (Cancer drug development), part B, Methods for Cancer research (Methods in Cancer research), 17, 3-51, New York, Academic Press Inc. (1979)). If log₁₀A cell kill rate greater than or equal to 0.7 is considered active. If log₁₀The cell kill rate was greater than 2.8 and the product was considered very active.

Log when the combination drug is used at its own maximum tolerated dose₁₀Killed cells, log greater than the best constituent when administered alone₁₀The cytocidal value, in which the individual constituents are present in a dose not exceeding their maximum tolerated dose, generally represents a therapeutic synergy.

In the present invention, a 1, 2-stilbene derivative, such as combretastatin, in an amount sufficient to inhibit tumor proliferation may be used together with another anticancer agent, such as a taxane compound, an alkylating agent, an antimetabolite, a vinca alkaloid, an epipodophyllotoxin, and an antibiotic, and administered to a mammal in need of curing, alleviating, or inhibiting tumor proliferation, particularly a human suffering from tumor cell proliferation, so as to inhibit the growth of tumor cells.

By "inhibiting proliferation of tumor cells" is meant inhibiting proliferation of tumor cells that are susceptible to treatment comprising administering to a human suffering from proliferation of tumor cells an effective amount of combretastatin and an effective amount of a second anti-cancer compound as described below. In acceptable cases, such administration may inhibit proliferation of tumor cells or reduce the measurable size of the tumor. In the best cases, the tumor is completely regressed.

As mentioned above, the method of administering the antitumor agent of the present invention to a mammal to be treated is not particularly limited. They may be administered orally or parenterally, for example by intravenous, subcutaneous or intramuscular route. To enhance effectiveness, combretastatin is preferably administered parenterally, e.g., intravenously and subcutaneously, by infusion, and the like. In the method of administering the pharmaceutical preparation according to the present invention, combretastatin may be administered simultaneously with another anticancer agent, or the two compounds may be administered in an alternative order. In practice, the method and sequence of administration will vary depending upon the individual formulation of combretastatin used, the individual formulation of the second anti-cancer agent, the individual tumor cells being cured, and the individual host being treated. The optimal method and sequence for administering combretastatin and the second anti-cancer agent may be suitably selected by those skilled in the art using routine techniques and the information contained in the present specification.

An effective tumor proliferation inhibiting amount of combretastatin and an anticancer agent selected from the group consisting of taxanes, alkylating agents, antimetabolites, vinca alkaloids, epipodophyllotoxins, and antibiotics, refers to a cure unit that inhibits proliferation of tumor cells that are susceptible to administration in a human suffering from tumor cell proliferation. The actual unit of cure required will vary depending on the individual dosage form of combretastatin used, the individual dosage form of the adjunctive anti-cancer agent used, the individual tumor cells being cured and the individual host being treated. The optimal healing unit under the conditions given in advance can be suitably selected by the person skilled in the art with the aid of the healing test unit and the information contained in the present description.

The antitumor agent of the present invention is a pharmaceutical preparation containing at least combretastatin and one of the anticancer compounds as described above, so that the two active ingredients can be contained in the pharmaceutical preparation in the form of a mixture. However, the two active ingredients in the present invention may also be contained independently in different pharmaceutical preparations, sequentially and in combination. It should be noted that pharmaceutical preparations containing other agents (third and fourth medicinal ingredients, etc.) such as other antitumor agents are of course also within the scope of the present invention as long as these pharmaceutical preparations contain the active ingredients used in the present invention. In addition, the antitumor agent of the present invention may contain a carrier, a diluent and other substances which are pharmaceutically acceptable for any of the pharmaceutical preparations of the present invention (a single pharmaceutical preparation of the present invention containing two components, and separate pharmaceutical preparations for combined use containing either of the two components separately).

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments thereof. It should be noted that they are given by way of example only and are not intended to limit the present invention.

A pharmaceutical preparation for infusion was prepared using combretastatin Z and a-4, which are compounds represented by the following chemical formulae (1) and (2), respectively, according to the following composition:

compound (I) (in the form of phosphate) 10mg

Tween 800.5 ml and

physiological saline 9.5ml

Compound (IIa) (in the form of the hydrochloride) 5mg

Tween 800.5 ml and

physiological saline 9.5ml

The preparation of paclitaxel, taxotere and derivatives thereof is for example the subject of european patents EP0,253,738 and EP0,253,739 and international application PCT WO 92/09,589 and is incorporated herein by reference.

The dose of taxane used, depending on the distinguishing factors of the patient to be treated, is generally 1-10mg/kg administered intraperitoneally or 1-3mg/kg administered intravenously.

Antitumor Effect and safety test

The effectiveness of the combination drug against solid tumors can be experimentally determined in the following manner:

animals, usually mice, were tested by subcutaneously implanting 30-60mg of tumor fragments on both sides on day 0. Animals with tumors were pooled and then subjected to various treatment treatments and controls. When treating deep tumors, tumors were allowed to develop to the desired size and underdeveloped animals were excluded. Selected animals were randomized, treated and control treated. Animals that do not have a tumor are also treated the same as animals that do have a tumor, so that toxic effects can be distinguished from specific effects on the tumor. Chemotherapy usually starts 3-22 days after transplantation, depending on the type of tumor, and animals are observed daily. Animals of different groups were weighed 3 or 4 times a week until the maximum weight loss was reached, and then animals of these groups were weighed at least once a week until the end of the test.

Tumors were assayed 2 or 3 times per week until tumors reached approximately 2g, or until the animal died (if death occurred before tumors reached 2 g). Dead animals were dissected.

The antitumor activity was determined according to various parameters recorded, such as dose (mg/kg), mode of administration, time of administration, cytotoxicity, toxicity and log cell kill rate.

To study the effect of the combination on leukemia, animals were transplanted with a specific number of cells and the antitumor activity was measured by measuring the increased survival time of the treated mice relative to the control mice. For P388 leukemia, the product is considered active if the increased survival time is greater than 27%, and very active if greater than 75%.

The results obtained with combretastatin in combination with various chemotherapeutic agents, such as taxotere (taxane), doxorubicin (antibiotic) and vincristine (vinca alkaloid), which are used in their optimal doses, are reported below.

In vivo evaluation of Compound (IIA) as the hydrochloride salt and cisplatin combination drug

Medicament	Tumor(s)	Number of days of time course	HNTD dose mg/kg	Days T-C	LcK	RR
									PR	CR	TFS
						Individual agents: compound (IIA) (as hydrochloride salt) CDDP	C51	12，1612，16				1166.2	1016.5	1.21.9	6/65/6	0/60/6	0/60/6
Compound medicine: while Compound (IIA) (in the form of the hydrochloride salt) is first CDDP		12，1612，16	11610	NA	NA				6/6	6/6	6/6
						The sequential compound (IIA) (in the form of the hydrochloride salt) CDDP		1415，19				5810	51	5.9	5/5	5/5	0/5

BCM-1209(09.20.00-01.29.01)

The abbreviations used:

HNTD is the highest non-toxic dose; T-C ═ tumor growth delay; LcK ═ log cell kill rate; RR-reaction ratio; PR ═ partial reaction; CR is complete reaction; TFS is a tumor-free survivor.

And (4) conclusion: the compound (IIA) in the form of hydrochloride and cisplatin compound has synergistic effect.

In vivo evaluation of Compound (IIA) (as hydrochloride salt) and Venolibin combination drug

Medicament	Tumor(s)	Number of days of time course	HNTD dose mg/kg	Days T-C	LcK	RR
									PR	CR	TFS
						Individual agents: compound (IIA) (in the form of the hydrochloride) vinorelbine	MA13/C	15，2515，25				15019.8	545.5	0.54.6	0/55/5	0/55/5	0/50/5
Compound medicine: sequential Compound (IIA) (in the form of the hydrochloride salt) firstly Winonibin secondly		1415，25	7532	84.7	8.5*				5/5	5/5	2/5

BCM-1234(11.23.00-05.10.01)

Log cell kill rates evaluated on a limited number of tumor-developing mice, all other mice in the group were tumor-free survivors.

The abbreviations used:

HNTD is the highest non-toxic dose; T-C ═ tumor growth delay; LcK ═ log cell kill rate; RR-reaction ratio; PR ═ partial reaction; CR is complete reaction; TFS is a tumor-free survivor.

And (4) conclusion: the compound (IIA) in the form of hydrochloride and vinorelbine (vinorelbine) have synergistic effect.

In vivo evaluation of Compound (IIA) as the hydrochloride salt and docetaxel combination

Medicament	Tumor(s)	Number of days of time course	HNTD dose mg/kg	Days T-C	LcK	RR
									PR	CR	TFS
						Individual agents: docetaxel compound (IIA) (in the form of hydrochloride)	MA13/C	17，2417，24(2x/d)				68242	26.710.8	3.2*1.3	6/61/6	4/61/6	3/60/6
Compound medicine: sequential compound (IIA) (in the form of hydrochloride) docetaxel		16，23(2x/d)17，24	150109.6	74.8	6.0*				6/6	6/6	4/6

BCM-1269(09.04.01-03.08.02)

Log cell kill rates evaluated on a limited number of tumor-developing mice, all other mice in the group were tumor-free survivors.

The abbreviations used:

HNTD is the highest non-toxic dose; T-C ═ tumor growth delay; LcK ═ log cell kill rate; RR-reaction ratio; PR ═ partial reaction; CR is complete reaction; TFS is a tumor-free survivor.

And (4) conclusion: the combination of compound (IIA) (in the form of the hydrochloride salt) and Docetaxel (Docetaxel) has a synergistic effect.

In vivo evaluation of Compound (IIA) as hydrochloride salt and Adriamycin combination

Medicament	Tumor(s)	Number of days of time course	HNTD dose mg/kg	Days T-C	LcK	RR
									PR	CR	TFS
						Individual agents: adriamycin Compound (IIA) (in the form of a hydrochloride salt)	MA13/C	15，2215，22				17.4186.0	53.530.2	4.51.3	4/60/6	4/60/6	0/60/6
Compound medicine: the sequential compound (IIA) doxorubicin in the form of the hydrochloride		15，2116，22	139.617.4	80.6	11*				7/7	7/7	2/7

BCM-1262(07.23.01-02.14.02)

Log cell kill rates evaluated on a limited number of tumor-developing mice, all other mice in the group were tumor-free survivors.

The abbreviations used:

HNTD is the highest non-toxic dose; T-C-the extent of tumor growth delay; LcK ═ log cell kill rate; RR-reaction ratio; PR ═ partial reaction; CR is complete reaction; TFS is a tumor-free survivor.

And (4) conclusion: the compound (IIA) in the form of hydrochloride and adriamycin have synergistic effect.

In vivo evaluation of Compound (IIA) (as the hydrochloride salt) and CPT-11 combination drug

Medicament	Tumor(s)	Number of days of time course	HNTD dose mg/kg	Days T-C	LcK	RR
									PR	CR	TFS
						Individual agents: compound (IIA) (in the form of the hydrochloride salt) CPT-11 (oral)	C51	13-17(2x/d)14-17				116.5400.0	10.38.7	1.31.1	5/50/5	0/50/5	0/50/5
Compound medicine: sequence CPT-11 (oral) Compound (IIA) (in the form of the hydrochloride salt)		13-1617	40036	15.1	1.9				5/5	3/5	0/5

BCM-1184(06.06.00-07.24.00)

The abbreviations used:

HNTD is the highest non-toxic dose; T-C-the extent of tumor growth delay; LcK ═ log cell kill rate; RR-reaction ratio; PR ═ partial reaction; CR is complete reaction; TFS is a tumor-free survivor.

And (4) conclusion: combination of compound (IIA) (as the hydrochloride salt) and CPT-11 resulted in an increase in the number of complete responses and an increase in log cell kill rate.

The antitumor agent according to the present invention, which comprises a 1, 2-stilbene derivative and an auxiliary anticancer compound such as taxane, alkylating agent, antimetabolite, vinca alkaloid, epipodophyllotoxin and antibiotic, in the form of a combination drug or in the form of a mixture, can be used as a cancer chemotherapeutic drug, and is highly effective in treating, inhibiting and preventing cancer, particularly solid cancer, since the combination drug of 1, 2-stilbene such as combretastatin Z and another anticancer agent as described above has therapeutic and sometimes synergistic effects.

Claims (2)

1. A combination medicament for treating a solid tumor, comprising an effective amount of doxorubicin and an effective amount of combretastatin, wherein said combretastatin has the formula:

2. the combination as recited in claim 1, wherein said combretastatin is in the form of a hydrochloride salt.