RU2279277C2 - Therapy with divided dosages of agents of vasculodestroying activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying a vasculodestroying agent or its pharmaceutically acceptable salt to be introduced for a warm-blooded animal as divided dosages to obtain anti-tumor effect. In particular, a vasculodestroying agent is being ZD6126, AC-7700, combrestatin A4 phosphate or their pharmaceutically acceptable salts. Moreover, total daily dosage of vasculodestroying agent is divided into two or more equal or unequal parts, and interval of time between introduction of every part corresponds to above 0 to about 6 h. The innovation enables to obtain greater anti-tumor effect against the one obtained at introducing the same total dosage of vasculodestroying agent as a single dosage.

EFFECT: higher efficiency of therapy.

18 cl, 2 dwg

Description

The present invention relates to a method for achieving a vasodilating effect in warm-blooded animals such as humans, in particular to a method for treating cancer, including a solid tumor, which comprises administering a vasodilating agent in divided doses. In particular, the present invention relates to such a method where the vasodilating agent is ZD6126.

Normal angiogenesis plays an important role in various processes, including embryonic development, wound healing and some of the components of women's reproductive function. Undesirable or pathological angiogenesis is associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi’s sarcoma, and hemangioma (Fan et al., 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). The formation of a new vasculature through angiogenesis underlies the development of the pathological picture of various diseases (J. Folkman, New England Journal of Medicine 333, 1757-1763 (1995)). For example, for the growth of a solid tumor, its own blood supply system must develop, on which its supply of oxygen and nutrients critically depends; if this blood supply system is mechanically destroyed, the tumor will undergo necrotic death. Neovascularization is also a clinical feature of skin damage in psoriasis, an invasive pannus in the joints of patients with rheumatoid arthritis and in atherosclerotic plaques. Pathological is retinal neovascularization in macular degeneration and in diabetic retinopathy.

It can be expected that the reverse development during the destruction of the endothelium of the newly formed vessels will have a useful therapeutic effect. A number of vasodilating agents (also known as vascular targeting agents) have been identified, for example combretastatin A4 phosphate and the Ajimonoto AC-7700 compound (Nihei Y. Et al., Japanese Journal of Cancer Research, 1999, 90, 1016-1025).

Connections found:

International Patent Application No. PCT / GB98 / 01977 (Publication No. WO 99/02166) and International Patent Application No. PCT / GB99 / 04436 (Publication No. WO 00/40529) which describe tricyclic compounds; and

International Patent Application No. PCT / GB / 00099 (Publication No. WO 00/41669), which describes heteroaromatic compounds;

possess a selective destructive effect on the newly formed vasculature, in contrast to various types of normal, existing vascular endothelium of the host. This property is essential in the treatment of diseases associated with angiogenesis, such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi’s sarcoma, hemangioma, acute and chronic nephropathies, atheroma, restenosis of the arteries, autoimmune diseases, acute inflammation, excessive scar formation and formation adhesions, endometriosis, dysfunctional bleeding from the bladder and eye diseases with proliferation of retinal vessels.

One compound described in PCT / GB98 / 01977 (Publication No. WO 99/02166) is N-acetylcolquinol-O-phosphate (also known as (5S) -5- (acetylamino) -9,10,11-trimethoxy-6 , 7-dihydro-5H-dibenzo [a, c] cyclohepten-3-yl-dihydrogen phosphate; Example 1 in WO 99/02166), which is defined as ZD6126.

It is believed, without limiting this invention, that ZD6126 destroys a newly formed vasculature, for example a vasculature of tumors, thereby effectively reversing the process of angiogenesis. This can be compared with other known antiangiogenic agents, which tend to be less effective when the vasculature is already formed.

Surprisingly, the authors of the application unexpectedly found that vasodilating agents, such as ZD6126, when dosed in divided doses (also known as fractional doses) produce a greater antitumor effect than when administered as a single dose of the agent.

The antitumor effects of the treatment method of the present invention include, but are not limited to, suppressing tumor growth, slowing down tumor growth, regressing the tumor, reducing the size of the tumor, increasing the time for tumor re-growth upon cessation of treatment, and slowing the progression of the disease. It is expected that when the treatment method of the present invention is prescribed to a warm-blooded animal, such as a person in need of cancer treatment, including a solid tumor, this treatment method will produce an effect determined, for example, by one or more of the following indicators: degree of antitumor effect, speed response, disease progression time and survival rate.

The present invention provides a method for producing a vasoconstrictor effect in warm-blooded animals, such as humans, which comprises administering to said animal in divided doses an effective amount of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in warm-blooded animals, such as humans, which comprises administering to said animal in divided doses an effective amount of a vaso-destructive agent or a pharmaceutically acceptable salt thereof.

In accordance with another aspect of the invention, there is also provided a method for producing a vasoconstrictor effect in warm-blooded animals, such as humans, which comprises administering to said animal in divided doses an effective amount of ZD6126:

or a pharmaceutically acceptable salt thereof.

In accordance with another aspect of the invention, there is provided a method of treating cancer, including a solid tumor, in warm-blooded animals, such as humans, which comprises administering to said animal in divided doses an effective amount of ZD6216 or a pharmaceutically acceptable salt thereof.

The present invention provides a method for obtaining a vasodilating effect in warm-blooded animals, such as humans, which comprises administering to said animal in divided doses an effective amount of a vasodilating agent or a pharmaceutically acceptable salt thereof, wherein the vasodilating agent or a pharmaceutically acceptable salt thereof may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with yet another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in warm-blooded animals, such as a human, which comprises administering to said animal in divided doses an effective amount of a vasodilating agent or a pharmaceutically acceptable salt thereof, wherein the vasodilating agent or its pharmaceutically an acceptable salt may optionally be administered with a pharmaceutically acceptable excipient or carrier.

In accordance with another aspect of the present invention, there is provided a method for producing a vasoconstrictor effect in warm-blooded animals, such as humans, which comprises administering to the animal in divided doses an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, where ZD6126 or a pharmaceutically acceptable salt thereof may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with yet another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in warm-blooded animals, such as a human, which comprises administering to the animal in divided doses an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, where ZD6126 or a pharmaceutically acceptable salt thereof may optionally be administered with a pharmaceutically acceptable excipient or carrier.

In accordance with yet another aspect of the present invention, it is expected that the effect of the treatment method of the present invention using divided doses of a vasoconstrictor agent such as ZD6126 will be significantly greater than the effect of the treatment method using a single dose of a vasoconstrictor agent such as ZD6126.

In accordance with another aspect of the present invention, there is provided a medicament comprising two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together comprise a total daily dose, for administration in divided doses for use in a therapeutic method for treating a human or animal .

In accordance with another aspect of the present invention, there is provided a kit comprising two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose for administration in divided doses.

In accordance with another aspect of the invention, a kit is provided comprising:

a) two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose for administration in divided doses;

b) a container for containing said dosage forms.

In accordance with another aspect of the present invention, there is provided a kit comprising:

a) two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose together with a pharmaceutically acceptable excipient or carrier, in unit dosage forms; and

b) a container for containing said dosage forms.

In accordance with yet another aspect of the present invention, there is provided the use of a vasodilating agent or a pharmaceutically acceptable salt thereof in the manufacture of a divided dose administration drug for use in obtaining a vasodilating effect in warm-blooded animals such as humans.

In accordance with yet another aspect of the present invention, there is provided the use of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof in the manufacture of a divided-dose drug for use in obtaining the anti-cancer effect in warm-blooded animals such as humans.

In accordance with yet another aspect of the present invention, there is provided the use of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof in the manufacture of a divided-dose drug for use in obtaining an antitumor effect in warm-blooded animals such as humans.

In accordance with another aspect of the present invention, there is provided a medicament comprising two or more parts of doses of ZD6126 or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose for administration in divided doses for use in a therapeutic method for treating a human or animal.

In accordance with another aspect of the present invention, there is provided a kit comprising two or more parts of a dose of ZD6126 or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose for administration in divided doses.

In accordance with another aspect of the present invention, there is provided a kit comprising:

a) two or more parts of ZD6126 or its pharmaceutical salt, which together make up the total daily dose, in unit dosage forms for administration in divided doses;

b) a container for containing said dosage forms.

In accordance with another aspect of the present invention, there is provided a kit comprising:

a) two or more parts of doses of SD6126 or its pharmaceutical salt, which together make up the total daily dose together with a pharmaceutically acceptable excipient or carrier in unit dosage forms;

b) a container for containing said dosage forms.

In accordance with another aspect of the present invention, the use of ZD6126 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration in divided doses for use in obtaining a vasoconstrictive effect in warm-blooded animals such as humans is provided.

In accordance with yet another aspect of the present invention, there is provided the use of ZD6126 or a pharmaceutically acceptable salt thereof in the manufacture of a divided dose administration drug for use in obtaining the anti-cancer effect in a warm-blooded animal such as a human.

In accordance with another aspect of the present invention, there is provided the use of ZD6126 or a pharmaceutically acceptable salt thereof in the manufacture of a divided-dose drug for use in obtaining an anti-tumor effect in a warm-blooded animal such as a human.

Vascular Destructing Agents (VDAs) are agents that destroy the vasculature, especially a newly formed vasculature, such as the vasculature of a tumor.

Preferred (VDAs) are those described in international patent application No. PCT / GB98 / 01977 (publication WO 99/02166), the entire disclosure of which is incorporated herein by reference.

Other preferred (VDAs) are those described in International Patent Application No. PCT / GB99 / 04436 (Publication No. WO 00/40529), the entire disclosure of which is incorporated herein by reference.

Other preferred (VDAs) are those described in international patent application No. PCT / GB99 / 00099 (publication No. WO 00/41669), the entire disclosure of which is incorporated by reference.

Another VDA is combretastatin A4 phosphate.

Another VDA is an Ajinomoto AC-7700 compound (Nihei Y et al., Japanese Journal of Cancer Research, 1999, 90, 1016-1025).

The most preferred VDA is ZD6126.

The vasoconstrictor agent may be presented in a form suitable for oral administration, for example, as a tablet or capsule, for nasal administration or administration by inhalation, for example, as a powder or solution, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example, as a sterile solution, suspension or emulsion, for topical administration, for example, as an ointment or cream, for rectal administration, for example, as a suppository, or the route of administration may be presented as eposredstvennoy injection into the tumor, or regional delivery or topical delivery. In other embodiments of the present invention, the VDA of the treatment method can be delivered endoscopically, intratracheally, intracranially, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumorally. The VDA may be in the form of a pharmaceutical composition, wherein the VDA or a pharmaceutically acceptable salt thereof is together with a pharmaceutically acceptable excipient or carrier. In general, the compositions described herein can be prepared in a conventional manner using conventional excipients. The compositions of the present invention are conveniently formulated in unit dosage forms.

Separated doses, also called fractional doses, mean that the total dose to be administered to a warm-blooded animal, such as a human being, is divided into two or more parts of the total dose at any daily period (for example, within 24 hours from midnight to midnight), and these parts are introduced after a time period between each part of from about more than 0 hours to about 10 hours, preferably from about 1 hour to about 6 hours, more preferably from about 2 hours to about 4 hours. Parts of the total dose may be equal or unequal. Preferably, the total dose is divided into two parts, which may be approximately equal or unequal. The time intervals between doses may, for example, be selected from the following:

about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours and about 6 hours.

The time intervals between doses may have any number (including non-integer) minutes, from more than 0 minutes to 600 minutes, preferably from 45 to 375 minutes inclusive. If more than 2 doses are administered, the time intervals between each dose may be equal or unequal.

Preferably, two doses are administered with a time interval between them of more than or equal to 1 hour and less than 6 hours.

More preferably, two doses are given at intervals between them of more than or equal to two hours to less than 5 hours.

Even more preferably, two doses are given with a time interval between them from more than or equal to two hours to less than or equal to 4 hours.

Specifically, the total dose is divided into two parts, which can be equal or unequal with a time interval between doses from more than or equal to two hours to less than or equal to about 4 hours.

More specifically, the total dose is divided into two parts, which can be approximately equal with an interval of time from more than or equal to two hours to less than or equal to about 4 hours.

To avoid doubt about the term “about”, in the description of time periods it means a given time plus or minus 15 minutes, for example, about one hour means from 45 to 75 minutes, about 1.5 hours means from 75 to 105 minutes. Elsewhere in the description, the term “about” has its usual vocabulary meaning.

ZD6126 is usually administered to warm-blooded animals in a single dose in the range of 10-500 mg per square meter of animal body area, for example, about 0.3-15 mg / kg in humans. A dosage unit in the range of, for example, 0.3-15 mg / kg, preferably 0.5-5 mg / kg, which is a normal effective therapeutic dose, is contemplated. A dosage unit, such as a tablet or capsule, usually contains, for example, 25-250 mg of the active ingredient. Preferably, a daily dose in the range of 0.5 to 5 mg / kg is used.

As for the size of the total daily dose required for therapeutic or prophylactic treatment of a particular disease state, it varies depending on the host being treated, the route of administration and the severity of the disease to be treated. Accordingly, the optimal dosage will be determined by the attending physician who treats any particular patient. For example, it may be necessary or desirable to reduce the above doses of treatment in order to reduce toxicity.

The methods of treatment of the present invention, as defined in the description, can be used as the only treatment, or may include, in addition to the vaso-destructive agent, administered in divided doses, one or more other substances and / or treatments. Such combined treatment can be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each cancer patient. In medical oncology, another component (s) of such a combination treatment, in addition to a divided dose VDA, may be surgery, radiotherapy or chemotherapy. So chemotherapy may include the following categories of therapeutic agents:

(i) anti-angiogenic agents (for example, linomide, integrin inhibitors of αvβ3 function, angiostatin, endostatin, rasoxin, thalidomide) and including vascular endothelial growth factor (VEGF) tyrosine kinase receptor inhibitors (RTKIs) (for example, described in international patent publications No. WO 97 / 22596, WO 97/30035, WO 97/32856 and WO 98/13354, the full disclosure of which is incorporated by reference, also, for example, described in published international patent application No. WO 00/47212, the full description of which is incorporated by reference);

(ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), gestagens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrazole, brazole, exemestane), anti-gestagens (e.g. antiandrogen , flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), testosterone inhibitors 5α-dihydroreductases (e.g. finasteride), anti-invasive agents (e.g. metal inhibitors, such as inhibitors at and inhibitors of plasminogen urokinase receptor function activator inhibitors) and growth factor function inhibitors (the growth factor including, for example, epidermal growth factor (EGF), platelet growth factor and hepatocyte growth factor, and such inhibitors include antibodies to growth factor, antibodies to factor receptor growth, tyrosine kinase inhibitor and serine / threonine kinase inhibitors);

(iii) biological response modifiers (e.g., interferon);

(iv) antibodies (e.g. edrecolomab);

(v) antiproliferative / antineoplastic drugs and their combinations used in medical oncology, such as antimetabolites (e.g. antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogs, cytosine arabinoside); antitumor antibiotics (e.g., anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin), platinum derivatives (e.g. cisplatin, carboplatin); alkylating agents (e.g., nitrogen mustard, melphalan, chlorambicil, busulfan, cyclophosphamide, ifosfamide, nitrosourea, thiotepa); antimitotic agents (for example, vinca alkaloids, such as vincristine, and taxoids, such as taxol, taxotere); enzymes (e.g. asparaginase); thymidylate synthase inhibitors (e.g. raltitrexed); topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amzacrine, topotecan, irinotecan).

If the VDA is ZD6126, salts for use in the pharmaceutical composition will be pharmaceutically acceptable salts, but other salts may be suitable in the manufacture of ZD6126 and its pharmaceutically acceptable salts. Such salts may be formed with an inorganic or organic base that provides a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include, for example, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, an ammonium salt or, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethylamine).

ZD6126 can be obtained in accordance with the following process.

N-acetylcolquinol (30.0 g, 83.9 mmol) was dissolved in acetonitrile in an inert atmosphere, and 1,2,3-triazole (14.67 g, 212.4 mmol) was added via syringe. Di-tert-butyl-diethylphosphoramidite (37.7 g, 151.4 mmol) was added and the reaction mixture was stirred at about 20 ° C to complete the formation of an intermediate phosphite ester. Hydroperoxide (24.4 g, 159.2 mmol) was added at 10 ° C and the reaction mixture was stirred until oxidation was complete. Butyl acetate (50 ml) and sodium hydroxide solution (250 ml 1 M) were added, the reaction mixture was stirred and the aqueous phase was discarded. The organic solution was washed with sodium hydroxide solution (2 × 250 ml 1M) and saturated sodium chloride solution. Trifluoroacetic acid (95.3 g, 836 mmol) was added at 15 ° C. The reaction mixture was distilled at atmospheric pressure, ZD6126 crystallized and isolated at room temperature.

Cell survival analysis

The activity of ZD6126 administered in fractional doses can be demonstrated using the following cell survival assay.

In vivo cell survival is measured using excision analysis (D.J. Chaplin et al., Anticancer Reseach 19: 1890196 (1999)).

For each analysis a) and b) below, the surviving tumor cell fraction is determined as follows:

The tumor is excised approximately 18 hours after treatment, weighed and disaggregated for 1 hour at 37 degrees Celsius in an enzyme shake containing 1 mg / ml pronase, 0.5 mg / ml DNase and 0.5 mg / ml collagenase. Hemocytometric measurements of cells not stained with trypan blue are carried out, and visible cells are seeded at appropriate concentrations, obtaining 50 colonies per plate after incubation in vitro. High-dose irradiated feeder cells (V79 cells) are used at a concentration of 25,000 / ml to support the growth of surviving CaNT cells. Data are calculated as surviving fractions per gram of tumor.

A) CaNT Tumor Model: Dose Interval Effect

In a CaNT mouse adenocarcinoma tumor model grown on female CBA mice (Hill, SA et al., Int. J. Cancer 63, 119-123, 1995), ZD6126 was administered in divided doses, resulting in an improved antitumor effect compared to ZD6126 administered in a single dose when measuring the surviving fraction of tumor cells. See Figure 1.

Methodology

Single dose

ZD6126 is administered in a single dose of 200 mg intraperitoneally (i.p.) in saline with a small amount of 1% sodium carbonate added to facilitate the dissolution of ZD6126.

Divided doses

ZD6126 is dosed using a fractional schedule of administration as 100 mg / kg ZD6126 followed by another 100 mg / kg ZD6126; doses are administered intraperitoneally (i.p.) in saline with a small amount of 1% sodium carbonate added to facilitate the dissolution of ZD6126. The time intervals used were 1,2,3,4 and 6 hours.

The surviving fractions per gram of tumor were determined as described above and plotted as shown in Figure 1.

Two doses of 100 mg / kg, divided by 2, 3 or 4 hours, are significantly more effective on this model than a single dose of 200 mg / kg.

b) Tumor CaNT Modem: Effect of interval between doses and fractional dose proportions

In a model of CaNT mouse adenocarcinoma tumor grown on female CBA mice (Hill, SA et al., Int. J. Cancer 63, 119-123, 1995), ZD6126 was administered in divided doses, resulting in an improved antitumor effect, as measured by fractions of surviving tumor cells compared to a single dose of ZD6126. This improved effect varied in proportion to the total dose administered in the first and second doses. See figure 2.

Methodology

Single dose

ZD6126 is administered as a single dose in 200 mg intraperitoneally (i.p.) in physiological saline with a small amount of 1% sodium carbonate added to facilitate the dissolution of ZD6126.

Divided doses

ZD6126 is dosed using fractional doses:

i) 25 mg / kg ZD6126, then an interval of 2 hours, followed by another 175 mg / kg ZD6126;

ii) 50 mg / kg ZD6126, then an interval of 2 hours, followed by another 150 mg / kg ZD6126;

iii) 100 mg / kg ZD6126, then an interval of 2 hours, followed by the introduction of another 100 mg / kg ZD6126;

iv) 150 mg / kg ZD6126, then an interval of 2 hours, followed by a further 50 mg / kg ZD6126;

v) 175 mg / kg ZD6126, then an interval of 2 hours, followed by a further 25 mg / kg ZD6126;

All doses are given intraperitoneally (i.p.) in saline with a small amount of 1% sodium carbonate added to facilitate the dissolution of ZD6126.

The antitumor effect, measured by the surviving fraction of the tumor cells, was greater with divided doses of ZD6126 than with a single dose of ZD6126. A similar enhanced effect was important when divided doses of ZD6126 were administered in accordance with i), iii), or iv described above. The best effect was observed with equal fractional doses, that is, in accordance with the above iii).

Claims (18)

1. A method of obtaining an antitumor effect in a warm-blooded animal, such as a human, comprising administering to said animal in divided doses an effective amount of a vasodilating agent or a pharmaceutically acceptable salt thereof, wherein the total dose of vasodilating agent administered over one day is divided into two or more parts that are equal or unequal and the time interval between the introduction of each part is from more than 0 h to about 6 h, and the antitumor effect obtained when introduced and a total daily dose of the agent sosudorazrushayuschego said separated portions is greater than the effect obtained on administration of the same total dose sosudorazrushayuschego agent in a single dose. 2. The method according to claim 1, in which the time interval between the introduction of each part of the vasoconstrictor agent is more than or equal to 1 hour or less than about 6 hours 3. The method according to claim 1, in which the time interval between the introduction of each part of the vasoconstrictor agent is more than or equal to 2 hours and less than 5 hours 4. The method according to any one of the preceding paragraphs, in which the total dose of a vasoconstrictor agent administered over one day is divided into two parts that are equal or unequal. 5. The method according to any one of the preceding paragraphs, in which the total dose of a vasoconstrictor agent administered in any one-day period is divided into two parts, which are equal. 6. The method according to claim 1, in which the total dose of the vasoconstrictor agent is divided into two parts that are equal or not equal, with a time interval between the introduction of each part more than or equal to about 2 hours or less, or equal to about 4 hours 7. The method according to any one of the preceding claims, wherein the tumor targeting agent is ZD6126

or a pharmaceutically acceptable salt thereof. 8. The method according to any one of claims 1 to 6, in which the vasodilating agent is AC-7700 or its pharmaceutically acceptable salt. 9. The method according to any one of claims 1 to 6, in which the vasodilating agent is combrestatin A4 phosphate or a pharmaceutically acceptable salt thereof. 10. A method of obtaining an antitumor effect in a warm-blooded animal, such as a human, comprising administering to said animal in divided doses an effective amount of ZD6126

or a pharmaceutically acceptable salt thereof, wherein the total dose of ZD6126 administered over one day is divided into two or more parts that are equal or unequal, and the time interval between the administration of each part is more than or equal to about 2 hours or less, or equal to about 4 h, and the antitumor effect obtained with the introduction of the total daily dose of ZD 6126 in these divided parts is greater than the effect obtained with the introduction of the same total dose of ZD 6126 in the form of a single dose. 11. The method according to claim 10, in which the total dose of ZD6126 administered in any one-day period is divided into parts that are equal or unequal. 12. The method according to any one of the preceding paragraphs, wherein said antitumor effect provides a treatment for cancer, including solid tumors in said warm-blooded animals. 13. A medicament for use in obtaining an antitumor effect in a warm-blooded animal, including humans, comprising two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, for administration in divided doses intended for use in treatment the human or animal body in a therapeutic manner. 14. The drug according to item 13, in which the vasoconstrictor agent is ZD6126 or its pharmaceutically acceptable salt. 15. A kit for use in obtaining an antitumor effect in a warm-blooded animal, including humans, comprising two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose for administration in divided doses. 16. The kit of claim 15, wherein the vasoconstrictor is ZD6126 or a pharmaceutically acceptable salt thereof. 17. A kit comprising a) two or more parts of a dose of a vasoconstrictor agent or a pharmaceutically acceptable salt thereof, which together constitute a total daily dose in unit dosage forms for administration in divided doses, and b) a container for containing said dosage forms. 18. The kit of claim 17, wherein the vasoconstrictor agent is ZD6126 or a pharmaceutically acceptable salt thereof.

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