RU2268729C2 - Combined therapies using of angiogenesis damaging activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed are combine product and kits useful in treatment for solid tumor by application of ZD6126 compound having formula

in combination with platinum antitumor drug (e.g. cysplatine) and/or taxane. Treatment methods may include ionizing radiation. In was discovered that certain doses of abovementioned combined substances according to method of present invention have synergic action on solid tumors (as well as on angiogenesis neoplasm).

EFFECT: new method for solid tumor treatment.

12 cl, 5 tbl, 9 dwg

Description

The present invention relates to a method for producing a vascular damage effect in a warm-blooded animal, such as a human, in particular to a method for treating cancer, including a solid tumor, which comprises administering ZD6126 in combination with one of a platinum antitumor agent, taxane, or ionizing radiation; a pharmaceutical composition comprising ZD6126 and one of a platinum antitumor agent and taxane; a combination product comprising ZD6126 and one of a platinum antitumor agent and taxane for use in a therapeutic method for treating a human or animal body; a kit comprising ZD6126 and one of a platinum antitumor agent and taxane; the use of ZD6126 and one of: a platinum antitumor agent and taxane in the manufacture of a medicament for use in obtaining the effect of vascular damage in a warm-blooded animal, such as a human being, which is optionally subjected to concomitant treatment with ionizing radiation; and to the use of ZD6126 in the manufacture of a medicament for use in obtaining the effect of vascular damage in a warm-blooded animal, such as a person who undergoes concomitant treatment with ionizing radiation.

Further, the present invention relates to a method for producing a vascular damage effect in a warm-blooded animal, such as a human, in particular to a method for treating cancer, including a solid tumor, which comprises administering ZD6126 in divided doses in combination with one of a platinum antitumor agent, taxane or ionizing radiation ; to a combination product comprising two or more doses of ZD6126 for administration in divided doses and one of a platinum antitumor agent and taxane for use in a therapeutic method for treating a human or animal body; to a kit comprising two or more doses of ZD6126 for administration in divided doses and one of a platinum antitumor agent and taxane; to the use of ZD6126 in the manufacture of a medicament for use in divided doses to obtain the effect of vascular damage in a warm-blooded animal, such as a person who undergoes concomitant treatment with one of the platinum antitumor agent and taxane; and to the use of ZD6126 in the manufacture of a medicament for use in divided doses to obtain the effect of vascular damage in a warm-blooded animal, such as a human being, that is undergoing concomitant treatment with ionizing radiation.

Normal angiogenesis plays an important role in a number of processes, including embryonic development, wound healing and some components of female reproductive function. Undesirable or pathological angiogenesis is associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaloshi 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 as a result of angiogenesis is the main pathological sign of certain diseases (J. Folkman, New England Journal of Medicine 333, 1757-1763 (1995)). For example, for the growth of a solid tumor, the development of its own blood supply system is necessary, which is a critical factor for growth, as it provides oxygen and nutrients; if this blood supply system is mechanically shut off, necrotic tumor death occurs. Revascularization is also a clinical sign of skin lesions in psoriasis, invasive pannus in the joints of patients with rheumatoid arthritis and atherosclerotic plaques. Retinal revascularization is a pathological process observed in retinal degeneration and in diabetic retinopathy.

It is believed that woodoscularization as a result of damage to the newly formed vascular endothelium should have a beneficial therapeutic effect. International patent application No. PCT / GB98 / 01977 (publication No. WO 99/02166) describes tricyclic compounds that have the characteristic effect of selectively damaging a newly formed vasculature compared to a normal, steady state vascular endothelium of the host. This is a criterion of value in the treatment of disease conditions associated with angiogenesis, such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi’s sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scarring and adhesion , endometriosis, dysfunctional uterine bleeding and eye diseases with proliferation of retinal vessels.

Compounds that damage the newly formed vasculature are vascular damaging agents (VDAs) and are also known as vascular agents (VTAs).

One compound described in International Patent Application No. 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 of International Patent Application No. PCT / GB98 / 01977 (Publication No. WO 99/02166) referred to in this specification like the ZD6126.

It is believed, although this does not limit the invention, that ZD6126 destroys a newly formed vasculature, such as the vasculature of tumors, thereby effectively terminating the process of angiogenesis. This effect can be compared with the action of other known anti-angiogenic agents, which tend to be less effective in the case of an already formed vasculature.

International Patent Application No. PCT / GB98 / 01977 (Publication No. WO 99/02166) states that:

"the compounds of this invention can be introduced as monotherapy or in combination with other methods of treatment. For the treatment of solid tumors, the compounds of this invention can be introduced in combination with radiotherapy or in combination with other antitumor substances, for example substances selected from mitosis inhibitors, for example vinblastine paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin and cyclophosphamide, antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxy urine faults; intercalating agents, e.g. adriamycin and bleomycin; enzymes, e.g. asparaginase; topoisomerase inhibitors, e.g. etoposide, topotecan and irinotecan; thymidylate synthase inhibitors, e.g. raltitrexed; biological modifiers, e.g. interferon; treatment may include the simultaneous or sequential use of individual treatment components. "

International patent application No. PCT / GB98 / 01977 (publication No. WO 99/02166) does not state anywhere that the use of any compound of the invention claimed therein with other treatment methods results in extremely beneficial effects.

To date, the inventors of the present invention have unexpectedly discovered that a particular compound ZD6126 used in combination with a specific selection of combination therapies presented in international patent application No. PCT / GB98 / 01977 (publication No. WO 99/02166), namely, one of a platinum antitumor agent, taxane and ionizing radiation, has a significantly better effect on solid tumors than any of ZD6126, a platinum antitumor agent, taxan and ionizing radiation, when used separately.

The antitumor effects of the treatment method of the present invention include, but are not limited to, inhibiting tumor growth, delaying tumor growth, regressing the tumor, reducing the tumor, increasing the time required for the tumor to re-grow when treatment is stopped, and slowing the progression of the disease. It is believed that if the method of treatment of the present invention is applied to a warm-blooded animal, such as a person in need of cancer treatment, including a solid tumor, then this method of treatment has an effect, measured, for example, by one or more factors from: the magnitude of the antitumor effect, the speed of response, the time of the development of the disease and the degree of survival.

In accordance with another aspect of the present invention, it is believed that the effect of the treatment method of the present invention is at least equivalent to the sum of the effects of each of the components of the specified treatment, used separately, that is, of each of ZD6126 and one of: a platinum antitumor agent, taxane and ionizing radiation used separately.

In accordance with another aspect of the present invention, it is believed that the effect of the treatment method of the present invention exceeds the sum of the effects of each of the components of the specified treatment, used separately, that is, from each of ZD6126 and one of: platinum antitumor agent, taxane and ionizing radiation, used separately .

Particularly unexpected is that, without regard to theoretical analysis, ZD6126 in combination with taxane has a significantly better effect on solid tumors than ZD6126 or taxane, used alone. This fact is particularly surprising, since taxanes stimulate microtubule assembly and inhibit their depolymerization to form free tubulin (The Merck Index 1996, 12 ^th Edition entry nos. 7117 and 3458, for paclitaxel and docetaxel, respectively), this effect is believed to be antagonistic to the damaging effects of ZD6126 on the newly formed vasculature, instead, when using ZD6126 in combination with taxane, unexpectedly an increased antitumor effect is obtained.

Surprisingly, the inventors have found that when used in divided doses (also known as fractional doses), ZD6126 produces a higher antitumor effect than when using ZD6126 as a single dose.

In accordance with the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126:

or its pharmaceutically acceptable salt, before, after, or simultaneously with the introduction of an effective amount of one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxon.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of ionizing radiation.

According to a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of a platinum antitumor agent.

According to a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of taxane.

In accordance with a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxon.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of ionizing radiation.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with the administration of an effective amount of platinum antitumor agent.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of taxane .

In accordance with another aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of one of the following therapies :

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of ZD6126, a platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with another aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of ionizing radiation, where ZD6126 may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of a platinum antitumor agent, wherein each of ZD6126 and a platinum antitumor agent may optionally be administered together with a pharmaceutically acceptable excipient or carrier telly.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of taxane, where each of ZD6126 and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of ZD6126, a platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of ionizing radiation, where ZD6126 may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with the administration of an effective amount of platinum an antitumor agent, where each of ZD6126 and a platinum antitumor agent may optionally be administered together with a pharmaceutically acceptable excipient or nose Thelema.

According to a further aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of taxane wherein each of ZD6126 and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a pharmaceutical composition which comprises ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a pharmaceutical composition which comprises ZD6126, or a pharmaceutically acceptable salt thereof, and taxane together with a pharmaceutically acceptable excipient or carrier.

According to a further aspect of the present invention, there is provided a combination product comprising ZD6126, or a pharmaceutically acceptable salt thereof, and one of a platinum antitumor agent and taxane for therapeutic use in a method of treating a human or animal body.

According to a further aspect of the present invention, there is provided a combination product comprising ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent for therapeutic use in a method of treating a human or animal body.

In accordance with another aspect of the present invention, there is provided a combination product comprising ZD6126, or a pharmaceutically acceptable salt thereof, and a taxane for therapeutic use in a method of treating a human or animal body.

In accordance with another aspect of the present invention, there is provided a kit comprising ZD6126, or a pharmaceutically acceptable salt thereof, and one of a platinum antitumor agent and taxane.

In accordance with another aspect of the present invention, there is provided a kit comprising ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent.

In accordance with a further aspect of the present invention, there is provided a kit comprising ZD6126, or a pharmaceutically acceptable salt thereof, and taxane.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, in a first dosage form;

b) one of: a platinum antitumor agent and taxane in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, in a first dosage form;

b) a platinum antitumor agent in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, in a first dosage form;

b) taxane in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first dosage form;

b) one of: a platinum antitumor agent and taxane, together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first dosage form;

b) a platinum antitumor agent together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) ZD6126, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first dosage form;

b) taxane, together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

In accordance with another aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and one of: a platinum antitumor agent and taxane, in the manufacture of a medicament for use in the preparation of a vascular damage effect in a warm-blooded animal such as a human.

In accordance with another aspect of the present invention, the use of ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent in the manufacture of a medicament for use in the preparation of a vascular damage effect in a warm-blooded animal, such as a human, is provided.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and taxane in the manufacture of a medicament for use in obtaining the effect of vascular damage 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, and one of: a platinum antitumor agent and taxane, in the manufacture of a medicament for use in obtaining an anticancer effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent in the manufacture of a medicament for use in obtaining an anticancer effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and taxane in the manufacture of a medicament for use in obtaining an anti-cancer effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and one of: a platinum antitumor agent and taxane, in the manufacture of a medicament for use in obtaining an antitumor effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and a platinum antitumor agent in the manufacture of a medicament for use in obtaining an antitumor effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, and taxane in the manufacture of a medicament for use in obtaining an antitumor effect in a warm-blooded animal such as a human.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the preparation of a vascular damage effect in a warm-blooded animal, such as a human being, who is being treated with ionizing radiation.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in obtaining the anticancer effect of a warm-blooded animal, such as a person who is being treated with ionizing radiation.

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 medicament for use in obtaining an antitumor effect in a warm-blooded animal, such as a human being, who is being treated with ionizing radiation.

A warm-blooded animal, such as a person who is being treated with ionizing radiation, means a warm-blooded animal, such as a person who is being treated with ionizing radiation before, after, or during the administration of a drug, including ZD6126. For example, said warm-blooded animal, such as a human, can receive said ionizing radiation for a period ranging from a week before to a week after administration of a drug including ZD6126.

In accordance with another aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of one of:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of the platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier;

a warm-blooded animal, such as a person in need of such therapeutic treatment. Such therapeutic treatment includes the effect of vascular damage, anticancer effect, and antitumor effect.

According to a further aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of ionizing radiation to a warm-blooded animal such as a human being in need of such therapeutic treatment.

In accordance with another aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of a platinum antitumor agent, where the platinum antitumor agent can optionally be introduced with a pharmaceutically acceptable excipient or carrier smooth animal, such as man in need of such therapeutic treatment.

According to a further aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of taxane, where the taxan may optionally be administered together with a pharmaceutically acceptable excipient or carrier for a warm-blooded animal, such as a person in need of such remedial treatment.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxon.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount ionizing radiation.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount platinum antitumor agent.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of 2D6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount taxana.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxon.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of ionizing radiation.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of a platinum antitumor agent.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of taxane.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of ZD6126, a platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount ionizing radiation, where ZD6126 may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount a platinum antitumor agent, wherein each of ZD6126 and a platinum antitumor agent may optionally be administered together with a pharmaceutically acceptable e host or carrier.

In accordance with a further aspect of the present invention, there is provided a method for producing a vascular damage effect in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with administering an effective amount a taxane, where each of ZD6126 and a taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of one of the following therapies:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of ZD6126, a platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier.

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

In accordance with another aspect of the present invention, there is provided a method of treating cancer, including a solid tumor, in a warm-blooded animal, such as a human, which comprises administering to said animal an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, in divided doses, before, after, or simultaneously with the introduction of an effective amount of a platinum antitumor agent, where each of ZD6126 and a platinum antitumor agent may optionally be administered together with a pharmaceutically acceptable kstsipientom or carrier.

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

In accordance with another aspect of the present invention, there is provided a combination product comprising two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together comprise a total daily dose for administration in divided doses, and one of: a platinum antitumor agent and taxane, for use in a therapeutic method for treating a human or animal organism.

In accordance with another aspect of the present invention, there is provided a combination product comprising two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, for administration in divided doses, and a platinum antitumor agent for use in a therapeutic therapeutic method of the body human or animal.

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

In accordance with another aspect of the present invention, there is provided a kit comprising two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, for administration in divided doses, and one of: a platinum antitumor agent and taxane.

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 comprise a total daily dose for administration in divided doses, and a platinum antitumor agent.

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

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, in first dosage forms, for administration in divided doses;

b) one of: a platinum antitumor agent and taxane in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, in first dosage forms, for administration in divided doses;

b) a platinum antitumor agent in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, in first dosage forms, for administration in divided doses;

b) taxane in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, together with a pharmaceutically acceptable excipient or carrier, in the first dosage forms, for administration in divided doses;

b) one of: a platinum antitumor agent and taxane, together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, together with a pharmaceutically acceptable excipient or carrier, in the first dosage forms, for administration in divided doses;

b) a platinum antitumor agent together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

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

a) two or more parts of doses of ZD6126, or a pharmaceutically acceptable salt thereof, which together make up the total daily dose, together with a pharmaceutically acceptable excipient or carrier, in the first dosage forms, for administration in divided doses;

b) taxane, together with a pharmaceutically acceptable excipient or carrier, in a second dosage form; and

c) containers for storing said first and second dosage forms.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use when administered in divided doses, in obtaining the effect of vascular damage in a warm-blooded animal, such as a human being, who is being treated with an ionizing radiation.

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament intended for use, when administered in divided doses, in producing an anti-cancer effect in a warm-blooded animal, such as a human being, who is being treated with ionizing radiation .

According to a further aspect of the present invention, there is provided the use of ZD6126, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament intended for use, when administered in divided doses, in obtaining an antitumor effect in a warm-blooded animal, such as a human being, who is being treated with ionizing radiation .

In accordance with another aspect of the present invention, there is provided a combination treatment comprising administering in divided doses an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of one of:

i) ionizing radiation;

ii) a platinum antitumor agent; and

iii) taxane

where each of the platinum antitumor agent and taxane may optionally be administered together with a pharmaceutically acceptable excipient or carrier;

a warm-blooded animal, such as a person in need of such therapeutic treatment. Such therapeutic treatment includes the effect of vascular damage, anticancer effect, and antitumor effect.

According to a further aspect of the present invention, there is provided a combination treatment comprising administering in divided doses an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of ionizing radiation to a warm-blooded animal, such as a person in need of such a therapeutic treatment.

In accordance with another aspect of the present invention, there is provided a combination treatment comprising administering in divided doses an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient or carrier, and simultaneously, sequentially or separately administering an effective amount of a platinum antitumor agent, wherein a platinum antitumor agent may optionally be administered together with a pharmaceutically acceptable exc pientom or carrier to a warm blooded animal such as man in need of such therapeutic treatment.

In accordance with another aspect of the present invention, there is provided a combination treatment comprising administering in divided doses an effective amount of ZD6126, or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient or carrier, and simultaneous, sequential or separate administration of an effective amount of taxane, where the taxane may optionally administered with a pharmaceutically acceptable excipient or carrier to a warm-blooded animal such as Lovek in need of such therapeutic treatment.

As indicated above, the combination treatment methods of the present invention, as defined herein, are of interest due to their vascular damage effects. It is believed that such combination treatment methods of the present invention can be used to prevent and treat a wide range of disease conditions in which unwanted angiogenesis occurs, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi’s sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, endometriosis, dysfunctional uterine bleeding and ocular diseases with proliferation of retinal vessels. In particular, it is believed that such combination treatment methods of the present invention will advantageously slow down the growth of primary and recurrent solid tumors, for example, colon, breast, prostate, lung, and skin.

The combined treatment of the present invention, as defined herein, can be carried out by simultaneous, sequential or separate administration of the individual components of the specified treatment. The combination treatment defined herein may be used as monotherapy, or may include surgery in addition to the combination treatment of the present invention. Surgical intervention may include the stage of partial or complete resection of the tumor before, during or after the introduction of the combined treatment using ZD6126 described in this document.

The compositions described herein may be in a form suitable for oral administration, for example, in the form of a tablet or capsule, for nasal administration, or administration by inhalation, for example, in the form of 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 ulation a direct injection into the tumor, or regional or local delivery. In other embodiments of the present invention, in combination treatment, ZD6126 can be delivered endoscopically intratracheally, to the site of injury, through the skin, intravenously, subcutaneously, intraperitoneally or into the tumor. In general, the compositions described herein can be prepared in a conventional manner using conventional excipients. The compositions of the present invention are preferably presented in unit dosage form.

ZD6126 is usually administered to a warm-blooded animal 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 for humans. A single dose is provided in the range of, for example, 0.3-15 mg / kg, preferably 0.5-5 mg / kg, which is usually a therapeutically effective dose. A dosage form, 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 0.5-5 mg / kg is used.

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

Time intervals between doses, for example, can be selected from:

About one hours about 1,5 hours About 2 hours about 2,5 hours About 3 hours about 3,5 hours About four hours about 4,5 hours About 5 hours about 5.5 hours and About 6 hours.

The time intervals between doses can be any number (including non-integer values) minutes, 0-600 minutes, preferably 45-375 minutes inclusive. If more than two doses are administered, the time intervals between each pair of doses may be approximately equal or unequal.

Preferably, two doses are obtained with a time interval between them that is greater than or equal to 1 hour and less than 6 hours.

More preferably, two doses are obtained with a time interval between them that is greater than or equal to two hours and less than 5 hours.

Even more preferably, two doses are obtained with a time interval between them that is greater than or equal to two hours and less than or equal to 4 hours.

In particular, the total dose is divided into two parts, which may be approximately equal or unequal, with a time interval between doses greater than or equal to approximately two hours and less than or equal to approximately 4 hours.

More specifically, the total dose is divided into two parts, which can be approximately equal, with a time interval between doses greater than or equal to approximately two hours and less than or equal to approximately 4 hours.

For the avoidance of doubt, the term “approximately” in the description of time intervals means the given time, plus or minus 15 minutes, thus, for example, approximately 1 hour means 45 to 75 minutes, approximately 1.5 hours means 75 to 105 minutes. In other places, the term “approximately” has its usual vocabulary meaning.

Platinum antitumor agents include cisplatin, carboplatin, oxaliplatin and (SP-4-3) - (cis-aminodichloro [2-methylpyridine] platinum (II), also known as ZD0473.

Taxanes include paclitaxel and docetaxel.

Platinum antitumor agents and taxanes can be dosed in accordance with known methods of administration and dosages.

For example, cisplatin can be administered as a single intravenous infusion over a period of 6-8 hours, at a dose of 40-120 mg / m ² , every 3-4 weeks. Alternatively, for example, cisplatin can be administered as a single intravenous infusion over a period of 6-8 hours, at a dose of 15-20 mg / m ² , daily, up to 5 days, every 3-4 weeks.

For example, carboplatin can be administered as a single short-term intravenous infusion over a period of 15-60 minutes, at a dose of 250-400 mg / m ² , every 4 weeks.

For example, oxaliplatin can be administered by intravenous infusion over a period of 2-6 hours, at a dose of approximately 85 mg / m ² , every 2 weeks.

For example, paclitaxel can be administered as an infusion over a period of approximately 24 hours, at a dose of 135-200 mg / m ² , every 3 weeks. Alternatively, for example, paclitaxel can be administered as an infusion over a period of approximately 3 hours, at a dose of 135-225 mg / m ² , every 3 weeks. Alternatively, for example, paclitaxel can be administered as an infusion over a period of approximately 1 hour, at a dose of 80-100 mg / m ² , every week, for several weeks. Alternatively, for example, paclitaxel can be administered as an infusion over a period of approximately 96 hours, at a dose of 120-140 mg / m ² , every 3 weeks.

Docetaxel may be dosed in accordance with known methods of administration and dosages. For example, docetaxel can be administered as an infusion over a period of 1 hour, at a dose of 55-100 mg / m ² , every 3 weeks.

In certain embodiments of the present invention, the ionizing radiation used may be x-rays, γ-rays or β-radiation.

Use doses of ionizing radiation known for use in clinical radiotherapy. Used radiation therapy includes, for example, the use of γ-rays, x-rays and / or targeted delivery of radiation from radioactive isotopes. Other forms of DNA damaging factors, such as microwaves and UV radiation, are also included in the present invention. Most likely, all of these factors cause a wide range of DNA damage, DNA precursors, during DNA replication and repair, and during the assembly and maintenance of chromosomes. For example, X-ray doses may be 1.8-2.0 Gy daily 5 days a week for 5-6 weeks. Typically, the total fractionated dose is in the range of 45-60 Gy. Single increased doses, for example 5-10 Gy, may be administered as part of a course of radiotherapy. Single doses may be administered during surgery. Hyperfractionated radiotherapy can be used, in which small doses of x-rays are administered regularly over a period of time, for example 0.1 Gy per hour for several days. Dosage intervals for radioisotopes vary widely and depend on the half-life of the isotope, the strength and type of radiation emitted, as well as on its absorption by cells.

As stated above, the dose of each therapy, which is necessary for therapeutic or prophylactic treatment of a particular disease state, inevitably varies depending on the host being treated, the method of administration and the severity of the disease to be treated. Accordingly, the optimal dosage regimen can be determined by a medical practitioner who treats a particular patient. For example, in order to reduce toxicity, it may be necessary or desirable to reduce the aforementioned doses of the components of the combination treatment.

The present invention relates to combinations of ionizing radiation, cisplatin, or paclitaxel, or docetaxel, with ZD6126, or with a salt of ZD6126. The salts used in the pharmaceutical compositions are pharmaceutically acceptable salts, but other salts may be used in the preparation of ZD6126 and its pharmaceutically acceptable salts. Such salts can be formed with an inorganic or organic base, which gives a pharmaceutically acceptable cation. Such salts of 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 methylamine, dimethylamine, trimethylamine, piperidine, morpholine salt, or tris- (2-hydroxyethyl) amine.

ZD6126 can be obtained in accordance with the following method.

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 approximately 20 ° C until the formation of the intermediate phosphite ester was completed. Cumene hydroperoxide (24.4 g, 159.2 mmol) was added at approximately 10 ° C and the reaction mixture was stirred until oxidation was complete. Butyl acetate (50 ml) and sodium hydroxide solution (250 ml of a 1M solution) are added, the reaction mixture is stirred and the aqueous phase is discarded. The organic solution was washed with sodium hydroxide solution (2 × 250 ml of a 1M solution) and saturated sodium chloride solution. Trifluoroacetic acid (95.3 g, 836 mmol) is added at approximately 15 ° C. The reaction mixture was distilled at atmospheric pressure, ZD6126 crystallized and isolated at ambient temperature.

The following tests are used to demonstrate the activity of ZD6126 in combination with cisplatin, paclitaxel, or ionizing radiation.

ZD6126 in combination with cisplatin

a) Tumor model CaNT

In a tumor model of mouse CaNT adenocarcinoma grown in CBA female mice (Hill, SA et al., Int. - J. Cancer 63, 119-123, 1995), the combination of ZD6126 and cisplatin significantly improved growth retardation compared to each agent separately.

(i) First study

Doses of one ZD6126 are administered on days 0, 2 and 4 using a fractional dosage regimen including 100 mg / kg ZD6126, then a 2-hour interval and another 100 mg / kg ZD6126; doses are administered intraperitoneally (ip).

Only cisplatin (David Bull Laboratories) is administered on day 0 at a dose of 5 mg / kg i.p.

Combined treatment consists of:

0 Day: 100 mg / kg ZD6126 ip, then a 2-hour interval and another 100 mg / kg ZD6126 ip; and 5 mg / kg cisplatin is given 10 minutes before the first dose of ZD6126.

Day 2 and 4: 100 mg / kg ZD6126 I.P., then a 2-hour interval and another 100 mg / kg ZD6126 I.P.

Calculate the time of increasing the geometric mean value of the diameter of the tumor, measured in three directions, by 3 mm, the results are shown in table 1 and figure 1.

Table 1
Antitumor activity of ZD6126 and cisplatin on CaNT tumors - study 1 Treatment 3 mm average diameter increase time (days) The average value of growth inhibition (compared with control) - days The control 8.4, 8.2, 4.7, 7.2, 5.9 Cisplatin only 10.0, 6.9, 9.2, 9.8 2.1 ZD6126 only 16.4, 11.8, 11.6, 13.8 6.5 Cisplatin Plus ZD6126 17.8, 16.1, 20.1, 19.3, 19.3 11.6

Tumor growth retardation caused by the combination of ZD6126 and cisplatin significantly (Mann-Whitney U-test) exceeds the delay caused by cisplatin alone (P <0.01) or only ZD6126 (P <0.01) . The growth retardation caused by the combination exceeds the sum of the growth retardation caused by the individual components.

(ii) The second study

Doses of ZD6126 alone are administered on days 0, 4, 7 and 11 using a fractional dosage regimen including 100 mg / kg ZD6126 i.p., then a 2-hour interval and another 100 mg / kg ZD6126 i.p.

Only cisplatin is administered on days 0 and 7 at a dose of 5 mg / kg, etc.

Combined treatment consists of:

0 and 7 Days: 100 mg / kg ZD6126 i.p., then a 2-hour interval and another 100 mg / kg ZD6126 i.p .; cisplatin is given 10 minutes before the first dose of ZD6126.

3, 7 and 10 Days: 100 mg / kg ZD6126 I.P., then a 2-hour interval and another 100 mg / kg ZD6126 I.P.

Calculate the time of increase in the geometric mean value of the diameter of the tumor, measured in three directions, by 3 mm, the results are shown in table 2 and figure 2.

table 2
Antitumor Activity of ZD6126 and Cisplatin on CaNT Tumors - Study 2 Treatment 3 mm average diameter increase time (days) The average value of growth inhibition (compared with control) - days The control 8.4, 8.2, 4.7, 7.2, 5.9 Cisplatin only 15.7, 13.4, 12.5, 16.9 7.7 ZD6126 only 16.4, 15.4, 17.8, 18.0, 16.5 9.9 Cisplatin Plus ZD6126 27.4, 24.3, 30.6, 26.7, 29.9 20.9

Tumor growth retardation caused by the combination of ZD6126 and cisplatin significantly exceeds the delay caused by cisplatin alone (P <0.01) or only ZD6126 (P <0.01). The growth retardation caused by the combination exceeds the sum of the growth retardation caused by the individual components of the treatment.

b) Tumor model Calu 6

The second tumor model, Calu 6, confirms the advantage of the combination of ZD6126 and cisplatin (cisplatin (II) diamine dichloride - Sigma P-4394). Nude mice lacking a thymus are implanted subcutaneously with 1 × 10 ⁶ human Calu 6 tumor cells (obtained from the American Type Culture Collection, 10801 University Boulevard, Manassas, VA 20110-2209, NTV-56 catalog) and tumors let grow until they reach approximately 9 mm in diameter.

Then groups of 10 mice bearing tumors are treated as follows:

Only ZD6126 introduce ip at a dose of 100 mg / kg for 0, 1, 2, 3, 4 days.

Only cisplatin is administered ip at a dose of 4 mg / kg on day 0.

In the case of combination, cisplatin is administered ip at a dose of 4 mg / kg on day 0, and ZD6126 is administered ip at a dose of 100 mg / kg for 1, 2, 3, 4 and 5 days. The results are shown in FIG.

The combination of cisplatin and ZD6126 gives a growth retardation (time to achieve a twofold increase in the initial volume) of 20.5 days compared to control tumors. This delay significantly (p <0.05 - the Man-Whitney U-test) exceeds the delay caused only by ZD6126 (10.1 days) or only cisplatin (6.0 days). The growth retardation caused by the combination exceeds the sum of the growth retardation caused by the individual components of the treatment.

c) Tumor model of CST sarcoma

In a model of murine sarcoma of CST (Lingyun Li, BS et al, Int. J. Radiation Oncology Biol. Phys 42, 899-903, 1998), tumors are treated either with cisplatin alone 10 mg / kg ip or 10 mg / kg cisplatin plus ZD6126 (10-100 mg / kg ip), cisplatin is given 1 hour before ZD6126. The effect of treatment on the survival of tumor cells is evaluated after 24 hours by excising the tumor, separating the cells and determining the number of colonies formed after 10-14 days. Then determine the surviving fraction compared with untreated cells. The results are shown in FIG.

Only cisplatin leads to the death of approximately 98% of the cells (shaded area in FIG. 4), and this effect is enhanced in a dose-dependent manner in the presence of ZD6126.

The average percentage of cell survival at 20, 50 and 100 mg / kg is 0.4, 0.011 and 0.0012%, respectively, and, therefore, these doses increase cell death compared to cisplatin alone by 5, 182 and 1667 times, respectively.

ZD6126 in combination with ionizing radiation

a) Tumor model CaNT

The activity of the combination of ZD6126 and radiation is also investigated in the CaNT tumor model. Tumors are either treated only with radiation (15 Gy on days 0 and 7), only ZD6126 (single dose of ZD6126 125 mg / kg ip on 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11 days ), or a combination of both (15 Gy on days 0 and 7, ZD6126 125 mg / kg, ip on days 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11). On days when radiation and ZD6126 are administered together, radiation treatment is carried out 3 hours after administration of ZD6126. Radiation is introduced by placing mice in lead boxes so that only the back of the back carrying the tumor is exposed to a horizontal x-ray beam (Sheldon and Hill, BJC, 35, 795-808, 1997). Mice are irradiated with 240 kV X-rays at a dose rate of 3.6 Gy / min.

Calculate the time to increase the geometric mean value of the diameter of the tumor, measured in three directions, by 3 mm, the results are shown in table 3 and figure 5.

Table 3
Antitumor effects of ZD6126 and radiation on CaNT tumors Treatment 3 mm average diameter increase time (days) The average value of growth inhibition (compared with control) - days The control 6.0, 8.0, 6.7, 5.1, 6.3, 6.6, 5.1, 6.4 Radiation only 47.3, 53.0, 31.5, 54.3, 37.0 38.3 ZD6126 only 15.6, 17.7, 14.1, 14.6, 14.7 9.1 Radiation and ZD6126 49.0, 58.0, 57.5, 63.5, 55.6 50,4

Tumor growth retardation caused by a combination of ZD6126 and radiation significantly exceeds the delay caused by radiation alone (P <0.05) or only ZD6126 (P <0.01). The growth retardation caused by the combination exceeds the sum of the growth retardation caused by the individual components.

b) Tumor model of CST sarcoma

CST mouse sarcoma grown in C3H mice are also used to confirm the benefits of combining ZD6126 and radiation. Tumors are treated either with radiation alone (a single dose of 0, 5, 10, 15 or 20 Gy), ZD6126 100 mg / kg ip, or radiation an hour after ZD6126 100 mg / kg ip The effect of either radiation alone, only ZD6126, or a combination thereof, on the survival of tumor cells is evaluated after 24 hours by excising the tumor, separating the cells and determining the number of colonies formed after 10-14 days. Then determine the surviving fraction compared with untreated cells. The results are shown in Fig.6.

Only ZD6126 (100 mg / kg) results in the death of approximately 97-98% of the tumor cells and increases the level of tumor death for all 3 radiation doses tested. The combination of ZD6126 with radiation doses of 5, 10 or 15 Gy leads to a 100-200-fold increase in cell death (one ZD6126 in the absence of radiation increases cell death by 40 times compared to the control) - Table 4.

Table 4
Antitumor effects of ZD6126 and radiation on CST sarcoma Radiation Dose (Gy) % cell survival Plus ZD6126% cell survival ZD6126 Magnification 0 one hundred 2,5 40 5 twenty 0.16 125 10 1,5 0.015 one hundred fifteen 0.35 0.0016 219 twenty 0.05 Nd ND = not defined

ZD6126 in combination with paclitaxel

a) Tumor model FaDu

For the third tumor model, 5 × 10 ⁵ FaDu cells (squamous cells of human pharynx carcinoma) are implanted in the back of female SCID mice 12-16 weeks old. When tumors develop, they are removed and cut into small fragments of approximately 1 mm ³ . These fragments are implanted subcutaneously with other SCID mice. When these tumors develop (approximately 6 mm in diameter), the mice are treated with either a single dose of only ZD6126 (125 mg / kg ip), a single dose of one paclitaxel (Taxol-BMS) (15 or 30 mg / kg ip ), or a combination of a single dose of paclitaxel (15 mg / kg ip) and ZD6126 (125 mg / kg ip), with paclitaxel being given 15 minutes before ZD6126.

Calculate the time of increasing the geometric mean value of the diameter of the tumor, measured in three directions, by 3 mm, the results are shown in table 5 and Fig.7.

Table 5
Antitumor Effects of ZD6126 and Paclitaxel on FaDu Tumors Treatment 3 mm average diameter increase time (days) The average value of growth inhibition (compared with control) - days The control 6.0, 5.0, 5.0, 5.4, 5.8, 7.0, 6.8, 5.2, 6.8 Paclitaxel only (15 mg / kg) 11.2, 10.8 5.1 ZD6126 only 8.9, 12.5, 12.0, 7.3 4.3 Paclitaxel and ZD6126 22.4, 19.6, 18.1 14.1

Tumor growth retardation caused by a combination of ZD6126 and paclitaxel significantly exceeds the delay caused by ZD6126 alone (P <0.05). The growth retardation caused by the combination exceeds the sum of the growth retardation caused by the individual components of the treatment.

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 by exclusion analysis (D.J. Chaplin et al., Anticancer Research 19: 189-196 (1999)).

For each of the analyzes a) and b) below, the surviving fraction of tumor cells is determined as follows:

Tumors are removed approximately 18 hours after treatment, weighed and disaggregated for 1 hour at 37 ° C in an enzyme mixture containing 1 mg / ml pronase, 0.5 mg / ml DNase and 0.5 mg / ml collagenase. Using a hemocytometer, trypan blue-excluded cells are counted and viable cells are seeded at appropriate concentrations to give approximately 50 colonies / plate after in vitro incubation. To ensure the growth of surviving CaNT cells, highly irradiated feeding cells (V79 cells) are used at a concentration of 25,000 / ml. Data are calculated as the surviving fraction per gram of tumor.

a) Tumor model of CaNT: effect of the dosage interval

In a tumor model of mouse CaNT adenocarcinoma grown in CBA female mice (Hill, SA et al., Int. J. Cancer 63, 119-123, 1995), administration of ZD6126 in divided doses leads to an improved antitumor effect, which is measured by the surviving fraction tumor cells compared to a single dose of ZD6126. See Fig. 8.

Methodology

Single dose

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

Divided doses

ZD6126 is administered using a fractional dosage regimen comprising 100 mg / kg ZD6126, then a time interval and another 100 mg / kg ZD6126; doses are administered intraperitoneally (i.p.) in physiological saline containing a small amount of 1% sodium carbonate, added to facilitate the dissolution of ZD6126.

The time intervals used are 1, 2, 3, 4 and 6 hours.

The surviving fraction per gram of tumor is determined as described above and plotted as shown in FIG.

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

b) Tumor model of CaNT: effect of the dosage interval and fractional dose ratios

In a tumor model of mouse CaNT adenocarcinomas grown in CBA female mice (Hill, SA et al., Int. J. Cancer 63, 119-123, 1995), the administration of ZD6126 in divided doses with an interval of 2 hours leads to an improved antitumor effect, which is measured by the surviving fraction of tumor cells, compared with ZD6126 administered in a single dose. This effect varies depending on the ratio of the first and second doses that make up the total dose. See FIG. 9.

Methodology

Single dose

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

Divided doses

ZD6126 is administered using fractional dosage modes, including:

i) 25 mg / kg ZD6126, then a 2-hour interval and an additional 175 mg / kg ZD6126;

ii) 50 mg / kg ZD6126, then a 2-hour interval and an additional 150 mg / kg ZD6126;

iii) 100 mg / kg ZD6126, then a 2-hour interval and an additional 100 mg / kg ZD6126;

iv) 150 mg / kg ZD6126, then a 2-hour interval and an additional 50 mg / kg ZD6126;

v) 175 mg / kg ZD6126, then a 2-hour interval and an additional 25 mg / kg ZD6126.

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

The antitumor effect, which is measured by the surviving fraction of tumor cells obtained by administering ZD6126 in divided doses, exceeds the effect of a single dose of ZD6126 of 200 mg / kg. This excess effect is significant if the divided doses of ZD6126 are administered in accordance with i), iii) or iv) above. The best effect is observed with equal divided doses, i.e. in accordance with paragraph iii) above.

Claims (12)

1. The combined product for the treatment of a solid tumor in the human or animal body, including ZD6126:

or a pharmaceutically acceptable salt thereof in an amount of 10-500 mg / m ² body area, and a platinum antitumor agent in an amount of 15-400 mg / m ² body area. 2. A combined product for the treatment of a solid tumor in the human or animal body, including ZD6126 or a pharmaceutically acceptable salt thereof in an amount of 10-500 mg / m ² body area, and taxane in an amount of 55-225 mg / m ² body area. 3. A combined product for the treatment of a solid tumor in a human or animal body, comprising two or more parts of doses of ZD6126 or a pharmaceutically acceptable salt thereof, which together comprise a total daily dose of 10-500 mg / m ² body area, for administration in divided doses, and one of the platinum antitumor agent in an amount of 15-400 mg / m ² body area and taxane in an amount of 55-225 mg / m ² body area. 4. A kit for treating a solid tumor in a human or animal body, comprising ZD6126 or a pharmaceutically acceptable salt thereof in an amount of 10-500 mg / m ² body area, and one of the platinum antitumor agent in an amount of 15-400 mg / m ² body area, and taxane in an amount of 55-225 mg / m ² body area. 5. A kit for treating a solid tumor in a human or animal body, comprising two or more parts of doses of ZD6126 or a pharmaceutically acceptable salt thereof, which together comprise a total daily dose of 10-500 mg / m ² body area, for administration in divided doses, and one from a platinum antitumor agent in an amount of 15-400 mg / m ² body area, and taxane in an amount of 55-225 mg / m ² body area. 6. A method of treating a solid tumor in a warm-blooded animal, such as a human, comprising administering to said animal an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof, before, after, or simultaneously with administering an effective amount of one of the following therapies: i) ionizing radiation; ii) a platinum antitumor agent; ill) taxon. 7. A method of treating a solid tumor in a warm-blooded animal, such as a human, comprising administering to said animal an effective amount of ZD6126 or a pharmaceutically acceptable salt thereof in divided doses before, after, or simultaneously with administering an effective amount of one of the following therapies: i) ionizing radiation; Ii) a platinum antitumor agent; iii) taxon. 8. The method according to claim 1, where the total dose of ZD6126, which must be administered to a warm-blooded animal during any one-day period, is divided into two or more parts that are approximately equal or unequal, and where these parts are administered to the specified warm-blooded animal with an interval of time between each part making up more than about 0 hours to about 6 hours. 9. The method of claim 8, where the time interval between each part is from about 2 hours to about 4 hours. 10. The method according to claim 8 or 9, where the total dose of ZD6126, which must be administered to a warm-blooded animal during any one-day period, is divided into two parts that are approximately equal or unequal, and where these parts are administered to the specified warm-blooded animal with an interval of time between each part that is approximately greater than or equal to 2 hours and less than 5 hours. 11. The method according to any one of claims 6, 7, 8 or 9, intended for the treatment of cancer, including a solid tumor. 12. The method according to any one of claims 6, 7, 8 or 9, where the platinum antitumor agent is selected from cisplatin, oxaliplatin and ZD0473 and the taxane is selected from paclitaxel and docetaxel.

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