Anticancer compositions containing agent inhibiting vegf and 5fu or one of its derivatives

FIELD: medicine.

SUBSTANCE: invention represents a combination containing VEGF Trap and 5-fluorouracil to be applied in treatment of neoplasms.

EFFECT: higher effectiveness of the combination ensured by therapeutic synergism of its components, and reduced toxicity.

4 cl, 1 ex, 1 tbl

 

DESCRIPTION

The present invention relates to combinations of an inhibitor of VEGF and hemotoxins agent class of 5-fluorouracil or 5-peroperative suitable for treatment of tumors.

Inhibitors of VEGF, which are inhibitors of growth factor vascular endothelium, in most cases, are biological products selected from soluble receptors, antisense sequences, RNA aptamers and antibodies. Derivatives of 5-peroperative selected from 5-fluorouracil, involving capecitabine or gemcitabine, which possess remarkable anti-tumor and antilysozyme properties, they are particularly suitable for the treatment of ovarian cancer, breast, lung and colon. The proposed combination is more specifically intended for the treatment of cancer of the colon and stomach.

Description and receiving VEGF inhibitor, preferably used according to the invention, which is a chimeric protein VEGF-Trap, as described in the application WO 00/75319. There are various forms of obtaining chimeric protein. The receipt form, the corresponding VEGF-Trap, described in figure 24 (sequence). VEGF-Trap, used according to the invention is a fusion protein containing the signal sequence of VEGFR1, merged with the domain IgD2 receptor VEGFR1, which merged with the domain IgD3 receptor VEGFR2, merged, in turn, to the Yong Fc IgG1, also called VEGR1R2-FcΔC1 or Flt1D2.Flk1D3.FcΔC1.

Commonly used doses that depend on factors related to the patient, range from 20 to 800 micrograms per kg, if the introduction is carried out subcutaneously, and from 2 to 20 micrograms per kg, if the introduction is carried out intravenously, or may enter through the nose in a smaller dose of the order of from 0.01 PG to 1 mg per kg

5-fluorouracil is usually administered intravenously in doses of 500 mg/m2up to 5000 mg/m2in the week that relates to derivatives of 5-torpedinidae, such as capecitabine, it is administered orally at a dose of from 500 to 3000 mg/m2usually 2 times a day. Gemicitabine is usually administered intravenously in a dose of from 500 to 2000 mg/m2a week.

In article H.Hurwitz, L.Fehrenbacher, W.Novotny, T.Cartwright, J.Nainswort, W.Heim, J.Berlin, A.Baron, S.Griffing, E.Holmgren, N.Ferrara, G.Fyfe, B.Rogers, R.Ross, F.Kabbinavar published in The New England Journal of Medicine described a clinical experiment, proving a higher survival rate when using a combination bevacizumab with irinotecan, 5FU and leucovorin compared with the same combination that does not contain bevacizumab. This clinical experiment does not prove that increasing the degree of survival caused by the combination of 5FU and bevacizumab, it may also be associated with the combination of irinotecan or leucovorin with bevacizumab or four component combinations. So since we know that each is th of anticancer agents along with a therapeutic effect has also toxic side effect, it is advisable to limit their presence, especially if the same therapeutic effect can be obtained in the absence of at least one of them. In this case, it is known that irinotecan causes diarrhea, and therefore the treatment is sometimes necessary to stop. On the other hand, this article does not prove the existence of synergies in the sense of Corbett, i.e. an effect that cannot be obtained by applying each of the elements separately in combination the maximum tolerated dose.

At the present time it was discovered, and it is an object of the present invention that the efficiency of VEGF inhibitors can be significantly increased when administered in combination with at least one substance suitable for the treatment of cancer, mechanism of action which is distinct from the mechanism of action of VEGF inhibitors.

Moreover, since the activity of the products depends on the used doses, you can use higher doses and to increase the activity, while reducing toxicity or slowing their appearance by the Association of VEGF inhibitors or their analogues with other therapeutically active substances of hematopoietic growth factors type, such as G-CSF or GM-CSF or some interleukins.

More specifically the invention relates to the associations of VEGF Trap with 5-fluorouracil or it is derived, such as capecitabine or gemcitabine. It also relates to combinations, optionally containing polynovo acid, mainly in combination with 5FU.

Improving the efficiency of the combinations according to the invention can be identified by determining therapeutic synergism.

The combination has therapeutic synergy if its therapeutic effect greater than the effect of one or other of the components used in their optimal dose [T.H.CORBETT et coll, Cancer Treatment Reports, 66, 1187(1982)].

To identify the effectiveness of the combination it is necessary to compare the maximum tolerated dose of the combination with the maximum tolerated dose of each of the compounds isolated in this study. This efficiency can be quantitatively determined, for example, using log10destroyed cells, which is determined by the following formula:

log10destroyed cells=T-C(days)/3,32 × Td,

in which T-C represents the period of cell growth, which represents the average period of time, expressed in days, required for tumor groups, treatment (T), and tumors of the control group (C) has reached a predetermined size (for example, 1 g), and Tdrepresents a period of time, expressed in days, required to double the volume of tumors in the control belly is s [T.H.CORBETT et coll, Cancer, 40, 2660.2680(1977) and F.M.SCHABEL et coll., Cancer drug Development, Part B, Methods in Cancer Research, a 17.3-51, New York,Academic Press Inc.(1979)]. The product is active when you log10destroyed cells is greater than or equal to 0.7. The product is considered to be very active, if log10destroyed cells more 2,8.

The combination used in the maximum tolerated dose of the actual active substance, in which each component is present in a dose, usually less than or equal to its maximum tolerated dose, has therapeutic synergy if log10destroyed cells greater than log10destroyed cells best component if it is a separate application.

The effectiveness of combinations against solid tumors can be determined experimentally in the following way:

the animals involved in the experiment, usually mice, grafted bilaterally subcutaneously 30 to 60 mg of tumor tissue of breast cancer MS 13/S on day 0. Before you expose animals that are carriers of tumors, various types of treatment and control their randomizer. In the case of treatment of tumors in the later stages of the tumors allowed to grow to the desired size, while animals in which tumors have received little development, eliminate. Animals selected randomly distributed to treatment and control. Animals that are not native swollen the lei, also can be subjected to the same treatment that animals and vehicles in order to distinguish the toxic effect from the effect on the tumor. Chemotherapy is usually started at 3-22 day after the inoculation of the tumor, depending on the type of tumor and the animals are daily observations. Different groups of animals weigh 3-4 times per week up to maximum weight loss, then weighed at least once a week until the end of the experiment.

The tumor measured 2-3 times per week up until the weight of the tumor will not be about 2 g, or until the animal dies, if it survives until then, until the weight of the tumor may reach 2, kill Animals and conduct an autopsy.

Antitumor activity is determined by various registered parameters.

To study the validity of the combinations against leukemia animals instill a certain number of cells and the antitumor activity is determined by the prolongation of survival of mice subjected to treatment, compared to control. The product is considered active if the prolongation of survival exceeds 27%, and very active, if it exceeds 75% in the case of leukemia R.

As examples the following tables show the results obtained with regard to combinations of VEGF Trap and 5-fluorouracil used in optimal doses.

On toadie the invention relates to pharmaceutical compositions, containing combinations according to the invention.

Products included in the combination can be administered simultaneously, separately or distributing in time to obtain the maximum efficiency of the combination; each injection may be of different lengths from the fast complete introduction to continuous perfusion.

Therefore, according to the present invention, the combination is not limited to those produced by the physical Association of the components, but also those that are suitable for individual administration, performed simultaneously or distribution in time.

Compositions according to the invention are preferably compositions for parenteral administration. However, these compositions can be administered orally.

Compositions for parenteral administration are typically sterile pharmaceutically acceptable solutions or suspensions, which may get directly at the time of application. To obtain a non-aqueous solutions or suspensions can be used natural vegetable oils, such as olive oil, sesame oil or paraffin oil, or organic esters, suitable for injection, such as etiloleat. Aqueous sterile solutions can consist of a solution of the product in water. Aqueous solutions of prigodin the intravenous provided the pH is adjusted accordingly and reached isiconnect, for example, by using a sufficient amount of sodium chloride or glucose. Sterilization can be accomplished by heating or any other method that does not change the composition. Combinations can also be in the form of liposomes or in Association with the media, such as cyclodextrin or glycols.

In the combinations according to the invention, components which can be applied simultaneously, separately or distributing in time, the number of derived VEGF Trap is preferably from 2 to 80 wt.% combination, and the content may vary depending on the nature of the associated substances, the required efficiency and the nature of the subject to treat cancer.

The combinations according to the invention is particularly suitable for the treatment of cancer of the colon and/or stomach. In particular, their advantage lies in the possibility to use the components in a distinctly smaller doses than their separate application.

The following example illustrates the combination according to the invention.

EXAMPLE

In accordance with conventional technology for subcutaneous injection is prepared ampoules of 1 cm3containing 25 mg of VEGF Trap, dissolved in phosphate buffer.

In accordance with conventional technology for intravenous injection and the rate of 0.2 ml per mouse cook 5 cm 3commercial solution containing 250 mg of 5FU, which is diluted with 5%glucose in water.

After appropriate dilution of these solutions are injected simultaneously by perfusion.

The introduction can be repeated several times a day or a week before the partial or complete remission or until recovery.

1,9
The dosage in mg/kg/dayDeath as a result of treatment% weight loss at NadirT/C %T-dayslck
scVEGF Trap (day 4,7, 11, 14, 18, 21)Iv 5-FU (day 4,11,18)
40 (240)-0/52,34a 12.71,4
25 (150)-0/51,1813,91,5
10 (60)-0/51,1 912,11,3
2,5 (15)-0/50,9325,20,6
-145 (435)1/58,7Toxic--
-90 (270)0/54,8012,51,3
-55,8 (167,4)0/51,1127,80,8
-34,6 (103,8)0/5+2,3344,60,5
40 (240)90 (270)0/58,00 25,22,7
25 (150)90 (270)0/59,6024,82,7
10 (60)90 (270)0/57,4023,12,5
10(60)55,8(167,4)0/54,4016,51,8
10(60)34,6(103,8)0/5of 5.4120,02,2
2,5(15)90(270)0/57,0020,42,2
2,5(15)55,8(167,4)0/52,0018,0
2,5(15)34,6(103,8)0/52,0611,71,3

HSR-1428 (05/28/04-07.30.2004): the doubling Time of tumor size = 2.8 days. The average time with a weight of 750 mg for the control group = 22,2 day. The treatment duration = 18 days for VEGF Trap, and combinations and 15 days for 5-FU.

Used abbreviations thereof: T/S=inhibition of tumor growth on day 24; (T-C) duration of tumor growth, lck=log destroyed cells.

1. Combination containing VEGF Trap and 5-fluorouracil for use in the treatment of tumors.

2. The combination according to claim 1, characterized in that it further comprises polynovo acid.

3. The combination according to claim 1, characterized in that it contains from 2 to 80 wt.% VEGF Trap.

4. The product containing VEGF Trap and 5-fluorouracil, suitable for use as a combined preparation for simultaneous, separate or distributed in time use in the treatment of cancer.



 

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