Cancer treatment with application of viruses fluoropyrimidines and camptothecins

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to oncology, and can be applied for treatment of neoplasm, as well as for producing medication for it treatment. For this purpose virus of Newcastle disease in combination with gluoropyrimidine and camptothecin compound during one or more cycles in total quantity, effective for subject treatment.

EFFECT: application of claimed inventions results in stable regression of tumour due to synergetic anti-tumour effect from application of all three agents.

30 cl, 4 dwg, 7 tbl, 5 ex

 

The prior art inventions

The combined use of some viruses with 5-fluorouracil for the treatment of cancer are disclosed in WO 94/25627 (page 12).

The combined use of oncolytic viruses with camptothecine disclosed in WO 2005/113018 (Wellstat Biologies Corp.). Treatment of cancer with the use of some mutant herpes viruses in combination with any of a variety of anticancer agents, including irinotecan and topotecan, disclosed in published U.S. patent 2002/0071832 (Fong, and others), paragraphs 7 and 40. Treatment of neoplasms with the use of specific target cells adenoviral vectors in combination with antitumor agents, including irinotecan or topotecan, are disclosed in published U.S. patent No. 2003/0068307 (Yu, and others) page 13. Cm. also Nemunaitis, and others, Cancer Gene Ther. (2003) 10(5): 341-352; and Meek, and others, Cancer Res. (2001) 61(13): 5083-5089.

The combined use of irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) disclosed in: Teufel and others, 2004 (BMC Cancer 4:38); Tournigand and others, 2004 (J Clin Oncol 2:229-237); Andre and others, 1999 (Eur J Cancer 35:1343-7); Colucci and others, 2005 (J Clin Oncol 22); Bouche and others, 2004 (J Clin Oncol 22:4319-4328); Ducreux and others, 1999 (J Clin Oncol 17:2901-8); Kohne and others, 2005 (J Clin Oncol 23); Saltz and others, 1996 (J Clin Oncol 14:2959-67); Goto and others, 2004 (Int J Clin Oncol 9:354-8). Additional combinations of irinotecan and 5-FU are listed in Table 3 Vanhoefer and others, 2001 (J Clin Oncol 19:1501-18) and Sastre and others, 2005 (Cancer Chemother Pharmacol 55:453-60).

The invention

This invention provides a method of treating mammals is operauser, having a tumor, comprising an introduction to the subject of the virus, connection ftorpirimidinu and connecting camptothecin in the total amount, effective for the treatment of the subject; in which the virus is selected from the group including Newcastle disease virus, measles virus, vesicular stomatitis virus, influenza virus, Sindbis virus, picornavirus and virus myxoma.

This invention involves the use of a virus and/or connection ftorpirimidinu and/or camptothecin in the production of pharmaceuticals for the treatment, in combination with other mentioned components, the subject having neoplasm; the virus is selected from the group including Newcastle disease virus, measles virus, vesicular stomatitis virus, influenza virus, Sindbis virus, picornavirus and virus myxoma. The drug may contain one, two or all three of these components.

Brief description of drawings

Figure 1. Graph of the average volume of tumor xenografts carcinoma of the colon SW620 as a function of time after the start of treatment, comparing the activity of the triple combination NDV (1E+09 PFU) + irinotecan (25 mg/kg) + 5-FU (25 mg/kg) with each agent separately or only with the media.

Figure 2. Graph of the average volume of tumor xenografts carcinoma of the colon SW620 as a function of time after the start of treatment, comparing the activity of Troy is the first combination of NDV (1E+09 PFU)+irinotecan (25 mg/kg)+5-FU (25 mg/kg) from each dual combination (NDV+irinotecan; irinotecan+5-FU; NDV+5-FU) or from one carrier.

Figure 3. Graph of the average volume of tumor xenografts carcinoma of the colon SW620 as a function of time after the start of treatment, comparing the activity of the triple combination NDV (1E+09 PFU) + irinotecan (15 mg/kg)+5-FU (100 mg/kg) with each agent separately or only with the media.

Figure 4. Graph of the average volume of tumor xenografts carcinoma of the colon SW620 as a function of time after the start of treatment, comparing the activity of the triple combination NDV (1E+09 PFU)+irinotecan (15 mg/kg)+5-FU (100 mg/kg) from each dual combination (NDV+irinotecan; irinotecan+5-FU; NDV+5-FU) or only with the media.

Detailed description of the invention

Used the term "including" is not limiting. The claim that uses this term may contain other elements in addition to the requirements listed in this claim. Thus, for example, the formula of the invention may include treatment regimens, which also include other therapeutic agents or therapeutic dose of the virus, which specifically does not appear in it, provided that these elements or their equivalents are available.

Applied here, the abbreviation "NDV" is an abbreviation of Newcastle disease virus. Used the abbreviation "DLT" is an abbreviation to limitiruyuscyei toxicity. Used the term "plaque-forming unit (PFU) means one infectious virus particle. The applied symbols "BPFU" means billion PFU. The abbreviation "PP" means cleared of plaque. Thus, for example, PPMK107 means cleared of plaque strain MK107 of Newcastle disease virus. Used relationship PFU/m2"that is a standard unit for expressing the dose, mean PFU per square meter of surface area of the patient. Used the term "replication-competent virus" refers to a virus that causes infectious progeny in cancer cells.

In the embodiment of this invention, the virus is replication-competent.

In accordance with this invention, when the virus is Newcastle disease virus, it can have low (lentogenic), moderate (mesogenic) or high (Velogenic) virulence. The level of virulence are determined according to the test the average time of lethality in embryos (MDT). (Alexander, "Chapter 27: Newcastle Disease" in Laboratoiy Manual for the Isolation and Identification of Avian Pathogens, 3rd ed., Purchase et al. eds. (Kendall/Hunt, Iowa), page 117.) Viruses are classified using the MDT test as lentogenic (MDT> 90 hours); mesogenic (MDT from 60 to 90 hours) and viagenie (MDT <60 hours). Currently preferred are mesogenic NDV. In accordance with this invention, it is possible to apply any about CNY the path or route of administration of the virus to the subject. Examples of routes of administration refer to WO 00/62735. In one embodiment of this invention, the virus is administered systemically, such as intravenously. Intravenous therapeutic virus in accordance with this invention, it is preferable that the virus was mesogenic strain of Newcastle disease virus. In the preferred embodiment of this invention, the human subject is injected mesogenic strain of Newcastle disease virus from 12×109up to 120×109PFU/m2per dose, more preferably from 12×109up to 48×109PFU/m2on the dose. Applied here, the ratio of mg/m2" means milligrams per square meter of surface area of the patient.

In embodiments of this invention picornaviruses is poliovirus, Echovirus or Coxsackie virus. Examples of Coxsackie viruses, which are suitable in accordance with this invention include the following types: A21, A13, A15 and Al 8. Examples of suitable echoviruses include Echovirus 1 type.

The use of torpedinidae as anticancer agents considered Petty & Cassidy (2004) CUIT. Cancer Drug Targets, 4:191-204; and Lamont and Schilsky (1999) Clin. Cancer Res. 5:2289-2296. These agents are fluorinated pyrimidines, which have antitumor activity through multiple mechanisms, including inhibition of synthesis and function of RNA, the inhibition activity timedilation and incorporation into DNA.

The terms "ftorpirimidinu" or "connection ftorpirimidinu" means one or more of the following compounds: 5-fluorouracil (5-FU); capecitabine; 5-fluoro-2'-deoxyuridine (FudR); Ftorafur; Amateur; eniluracil/5-FU; S-I (a combination of prodrugs of 5-FU fioratura and two modulators of 5-FU, nazvyvaemy 5-chloro-2,4-dihydroxypyridine and aksonova acid in a molar ratio of 1:0,4:1); and UFT (a combination of ftorafura and uracil in a molar ratio of 1:4) (Lamont and Schilsky, 1999). 5-FU is often injected with a drug leucovorin to enhance the cytotoxic effects of 5-FU (see, for example, Jolivet, 1995, Eur J Cancer 3 IA: 1311-1315 and Rustum et al., 1998; Cancer J Sci Am 4:12 - 18). Methods of dosing and the introduction and application of torpedinidae and leucovorin are known in the art (see, for example. Vincent et al., 1999 (Anticancer Drugs 10:337-54); Jolivet, 1995), and their optimization for a particular patient are possible within the abilities of an experienced Clinician. Bolus 5-FU is usually produced by patients-people in a dose of from 370 to 500 mg/m2daily for 5 days every 4-5 weeks or more, preferably 500 mg/m2on a weekly basis. In the embodiment of this invention, one or more doses of 5-fu injected via continuous infusion for at least 22 hours per dose. Continuous introduction of 5-FU include intravenous bolus introduction the s 400 mg/m 2with the subsequent introduction of 600 mg/m2for more than 22 hours. In another embodiment, after bolus 400 mg/m2enter 2400 mg/m2for more than 46 hours. Leucovorin is usually administered to patients-people in a dose of from 200 to 500 mg/m2you enter directly before or during the administration of 5-FU.

The use of camptothecin as anticancer agents reviewed in Garcia-Carbonero and others, Clin. Cancer Res. (March 2002) 8: 641-661; and Pizzolato JF and Saltz LB, The camptothecins. Lancet 2003 361:2235-42. Camptothecine have antitumor activity, based on their binding and inhibition of topoisomerase I, nuclear enzyme that reduces torsional stress in DNA replication and plays an important role in DNA replication. Topotecan and irinotecan have been approved for clinical use by Management under the control over products and medicines (FDA). Other camptothecin are in development as anti-cancer therapeutic agent (Ulukan and Swaan, (Campothecins: a review of their chemotherapeutic potential. Drugs, 2002, 62:2039-57); and Garcia-Carbonero and Supko, 2002).

Used the term "connection camptothecin" means that the considered class of compounds, including camptothecin, analogs of camptothecin, derivatives camptothecin or conjugates of camptothecin. These compounds based on the characteristic of the main circuit of camptothecin, consisting of five rings:

In accordance with this invention can be applied to any connection camptothecin. Examples of compounds of camptothecin include irinotecan (CAMPTOSAR; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonylcontaining), topotecan (HYCAMPTIN; (S)-9-N,N-dimethylaminoethyl-10-hydroxycamptothecin), 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9-nitrocamptothecin (also called rubitecan), lurtotecan (7-(4-methylpiperazine)-10,11-Ethylenedioxy-20(S)-camptothecin), exatecan, krenitzin and gamecaptain. The structure and clinical information on some of the compounds of camptothecin can be found in Garcia-Carbonero, and others, Clin. Cancer Res. (March 2002) 8: 641-661. Examples of compounds of camptothecin can also be found in U.S. patent No. 4604463, No. 6403569, and No. 5004758, and in WO 2004/012661, WO 2003/101998, WO 2003/101996, WO 2003/101406, WO 2003/093274, WO 2003/086471, WO 01/76597, WO 01/64194, WO 00/70275, WO 00/53607, WO 99/17805, WO 99/17804, WO 99/05103, WO 98/35969, WO 97/28164, WO 97/25332, WO 97/16454, the contents of which are hereby incorporated by reference.

In accordance with the combination therapy of this invention the compound of camptothecin you can enter from one month before the introduction of the virus until after one month after administration of the virus. In more specific embodiments, the implementation of the connection camptothecin and the virus is administered to the subject within a period of twenty-four hours; or the connection of camptothecin injected from twenty four hours to one month, suppose the equipment from twenty four hours to one week prior to the introduction of the virus; or connection camptothecin introduce the subject of twenty-four hours to one month, preferably from twenty four hours to one week after administration of the virus. "Chemotherapy is mainly prescribed at regular intervals, called cycles. The cycle may include one dose, followed by several days or weeks without treatment. This allows time for the normal cells to recover from the side effects of the drug. Alternatively, the dose can enter multiple days in a row, or every other day for several days, followed by a rest period.. .. number of cycles... can be determined before treatment... or may be flexible in order to consider how the treatment affects the cancer." (From "Planning Drug Doses and Schedules"on the website of the American society of cancer, visited may 23, 2005.) In the embodiment of this invention the virus, connection ftorpirimidinu and camptothecin enter for one or more cycles, preferably for two or more cycles. One cycle can continue, for example, within 8 weeks, 6 weeks, 30 days or 3 weeks.

Below in Tables 3 through 6 present examples of modes of administration, which are also appropriate in relation to the introduction of viruses, torpedinidae and camptothecin in addition to presents, to the likesto, which correspond to or differ from those shown in the examples. Accordingly, in further embodiments of this invention viruses, connection ftorpirimidinu and camptothecin administered cyclically according to the injection mode shown in any of Tables 3 through 6.

Methods of dosing and injection modes and the introduction of camptothecin and cancer viruses known in the art (see, for example, Garcia-Carbonero, and others; WO 00/62735; WO 2004/000209; and Pecora, etc., J. Clin. Oncol. (2002) 20 (9): 2251-2266), and, thus, the optimization for a particular patient is within the abilities of an experienced Clinician. Irinotecan is usually administered to patients-people in a dose of from at 62.5 to 125 mg/m2four times a week, or more preferably from 80 to 125 mg/m2four times a week; or from 300 to 350 mg/m2once every three weeks, or more preferably from 300 to 350 mg/m2once every three weeks.

The subject, whose treatment in accordance with this invention can be either a human or a mammal, not a person. In accordance with this invention, it is possible to carry out the treatment of any tumor, including, but not limited to, the following: rectal cancer, pelvic cancer, colon cancer, lung cancer, breast cancer, prostate cancer, glioblastoma, kidney cancer, pancreatic cancer jelly is s, cancer of the head and neck, endometrial cancer, neuroblastoma, carcinoid, melanoma, ovarian cancer, sarcoma, cancer of the gastroesophageal junction, stomach cancer, esophagus cancer, liver cancer and cervical cancer.

Although the monitoring of treatment is not an essential aspect of the invention, there are methods of determining therapeutic effects of treatment. They include determining the size of the tumor after administration of the virus, and the tumor size is a positive result.

The invention will be better understood by reference to the following examples, which illustrate this invention, but not limit it. In the following examples NDV is triple purified from platelets MK107, which is attenuated (mesogenic) version of the Newcastle disease virus, described in more detail in international patent publication WO 00/62735, published on 26 October 2000 (Pro-Virus, Inc). All content WO 00/62735 and provisional application for U.S. patent No. 60/565,631, filed on April 27, 2004, are hereby incorporated by reference.

Examples

Example 1. NDV in combination with 5-fluorouracil. (5-FU).

Atipicheskim mice were injected subcutaneously with 10 million cells fibrosarcoma human HT 1080. Seven days later, when tumors were approximately 120 to 150 mm3the animals were randomized and received treatment one is C 10 different modes of treatment (see Table 1 for details), which included suboptimal dose intravenous NDV (2E+07 or 1E+08 PFU), 100 mg/kg bolus 5-fluorouracil (5-FU), administered intraperitoneally injected, and subcutaneous implantation pills containing 5 mg of 5-FU (catalogue #Z-190, Innovative Research of America; Sarasota, Florida), or pill placebo (catalog #C-111, Innovative Research of America; Sarasota, Florida) and other control options with the media. If produced implantation pills, it was carried out in the area, located on adalena distance from subcutaneous tumors. Date of the first administration of drugs designated as Day 0 in Table 1 below. Pill with 5-FU was used to provide a slower release of 5-FU than with bolus administration. These pills of 5-FU was used in order to approximate the effects of continuous infusion 5-FU or the introduction of oral analogue of 5-FU, such as capecitabine, in a few days.

11
Table 1
The treatment regimens tested for animicheskih mice, tumour
GroupThe number of mouseDay
treatment 0
Day
treatment 2
Day treatment 4
1M/La5FU bolusM/La
211M/LaPill controlM/La
311M/La5FU bolusNDV,1E+0,8
411M/LaPill controlNDV,1E+0,8
511M/La5FU bolus
611M/La5FU bolusM/La
711M/LaBolus controlbNDV,1E+0,8
811M/LaBolus controlb M/La
911NDV,2E+0,75FU bolusM/La
1011NDV,2E+0,7Bolus controlbM/La
aM/L: control media mannitol (5 %)/lysine (1 %)
bBolus control: Water for injections

The frequency of complete regression of the tumor (CR, 100% reduction in tumor size) were observed more frequently in the group treated with both NDV and 5-FU (either as a bolus or in the form of pills)than in the group treated only with 5-FU, or NDV. Cm. Tables 2a-c.

Table 2a
Treatment of mice, tumour, bolus administration of 5-FU in two days after treatment NDV leads to greater tumor response to treatment than in the application of any agent individually
GroupTreatmentThe response of the tumor to therapy (CR), %
6 Bolus 5-FU0
8Control the bolus0
9Both NDV and bolus 5-FU63
10NDV and control the bolus18

Table 2b
Treatment of mice, tumour, bolus administration of 5-FU for two days before the NDV treatment leads to greater tumor response to treatment than in the application of any agent individually
GroupTreatmentThe response of the tumor to therapy (CR), %
5Both NDV and bolus
5-FU
36
6Bolus 5-FU0
7NDV and control the bolus0
8Control the bolus0

Table 2c
Treatment of mice, tumour, pills with 5-FU for two days before treatment with NDV leads to greater tumor response to treatment than in the application of any agent individually
GroupTreatmentThe response of the tumor to therapy (CR), %
1Bolus 5-FU0
2Control pill0
3Both NDV and bolus 5-FU27
4NDV control pill0

Example 2. NDV in combination with irinotecan, 5-fluorouracil (5-FU) and leucovorin.

Patients suffering from cancer, was receiving treatment with NDV, followed by treatment with irinotecan, leucovorin and 5-fluorouracil. In each cycle of 6 weeks treatment of NDV included a total of from 9 to 12 intravenous drugs, conducted over 5 weeks, followed by a period of rest for one week (see Table 3 below). The first dose of each cycle contains from 12 to 24 billion PFU/m2(entered within 3 hours for 1 course and is within 1 hour for all other courses), followed by additional doses from 24 to 48 billion PFU/m2(each dose is administered within 1 hour). Irinotecan (180 mg/m2intravenously over 90 minutes) to introduce each subsequent week, starting from 2 weeks to 1 cycle (for example, see Table 8 below). Leucovorin (400 mg/m2intravenously over 120 minutes) was injected simultaneously with each dose of irinotecan followed immediately by intravenous bolus administration of 5-FU (400 mg/m2), and then continuous intravenous infusion of 5-FU (2400 mg/m2within 46 hours, with the use of the pump for intravenous injections. Patients also appoint an additional 6 week courses (also called loops) NDV, irinotecan, 5-FU and leucovorin.

Table 3
The combination of NDV treatment with the use of irinotecan
(80 to 125 mg/m2), leucovorin and 5-FU.
The cycles repeat treatment every 6 weeks
CycleWeekNDV?Irinotecan/Leucovorin/5FU
11Yes, two doseNo
2No
3Yes, from two to three dosesYes
4Yes, from one to 2 dosesNo
5Yes, two to 3 dosesYes
6NoNo
21Yes, two doseYes
2Yes, from two to three dosesNo
3Yes, from two to three dosesYes
4Yes, from one to 2 dosesNo
5Yes, from two to three dosesYes
6Nono

Example 3. NDV in combination with irinotecan, 5-fluorouracil (5-FU) and leucovorin.

Treated patients with colorectal cancer, as in the Use of the e 2, using NDV, irinotecan, leucovorin and 5-fluorouracil in the mode shown in Tables 4-6 below. In each cycle of 6 weeks treatment of NDV included a total of 10 intravenous drugs for 5 weeks followed by a rest period in one week (see Tables 4-6 below). The first dose in each cycle contained 12-24 billion PFU/m2(input for 3 hours for 1 year and within 1 hour for all other courses), and then further introduction from 24 to 48 billion PFU/m2(each dose was administered within 1 hour). Irinotecan (180 mg/m2intravenously over 90 minutes) was administered to each subsequent week, starting with 2 weeks 1 cycle. Leucovorin (400 mg/m2intravenously over 120 minutes) was administered simultaneously with each dose of irinotecan followed immediately by intravenous bolus administration of 5-FU (400 mg/m2and then a continuous intravenous infusion of 5-FU (2400 mg/m2within 46 hours, with the use of the pump for intravenous injections. Patients underwent an additional 6 week course introduction (also called loops) NDV, irinotecan, 5-FU and leucovorin.

Table 4
Combination for the treatment of patients with colorectal cancer, including NDV, irinotecan (80 to 125 mg/m2), Le is coverin and 5-FU. Cycles of treatment was repeated every 6 weeks
CycleWeekNDV?Irinotecan/Leucovorin/5FU
11Yes, two doses, administered with an interval in 3 daysNo
2Yes, 3 doses, administered with a break in 2 daysNo
3Yes, two doses, administered with an interval in 4 daysYes
4Yes, one doseNo
5Yes, two doses, administered with an interval in 4 daysYes
6NoNo
2 or more1Yes, two doses, administered with an interval in 4 daysYes
2Yes, two doses, administered with an interval in 4 daysNo
3 Yes, two doses, administered with an interval in 4 daysYes
4Yes, two doses, administered with an interval in 4 daysNo
5Yes, two doses, administered with an interval in 4 daysYes
6NoNo

Table 5
Usual treatment Cycle 1
MondayTuesdayEnvironmentThursdayFridaySaturdaySunday
1
NDV
Dose 1
23NDV
Dose 2
567
8
NDV
Dose 3
910 NDV
Dose 4
1112
NDV
Dose 5
1314
15
NDV
Dose 6
1617 irinotecan
LV/5FU
1819
NDV
Dose 7
2021
22
NDV
Dose
232425262728
29
NDV
Dose 9
3031 irinotecan
LV/5FU
3233
NDV
Dose 10
3435
36373839404142

Table 6
Usual treatment Cycles 2 and above:
MondayTuesdayEnvironmentThursdayToe the Itza SaturdaySunday
1
NDV
Dose 1
23 irinotecan
LV/5FU
45
NDV
Dose 2
67
8
NDV
Dose 3
9101112
NDV
Dose 4
1314
15
NDV
Dose 6
1617 irinotecan
LV/5FU
1819
NDV
Dose 6
2021
22
NDV
Dose
23242526
NDV
Dose 8
2728
29
NDV
Dose 9
3031 irinotecan
LV/5FU
3233
NDV
Dose 10
3435
36373839404142

Example 4

Atipicheskim the mice were injected subcutaneously 10 million carcinoma cells human colon SW620 (purchased from American Type Culture Collection, Manassas, VA). After five days (called day 0 below), when the size of the subcutaneous tumors were approximately 85 mm3, a group of 11-12 animals were randomized into 8 groups treated:

- NDV+Irinotecan

- NDV+5-FU-NDV+Irinotecan+5-FU

- Irinotecan

- 5-FU

- Irinotecan+5-FU

- Only media

During the Day 0 all mice received either NDV (1E+09 PFU), or media using the intravenous route of administration according to the principle of treatment presented above. Two days later, on Day 2, all mice performed the first intraperitoneally injection or irinotecan (25 mg/kg), or media, and then 1 hour later he performed the second intraperitoneally injection or 5-FU (25 mg/kg), or media in accordance with the principle of treatment presented above. A carrier for NDV was an aqueous solution of 5% mannitol/1% lysine. A carrier for irinotecan was saline. Carrier for 5-FU was water for injection. All mice were periodically determined by the size of the tumor, using a Vernier caliper.

As p is shown in figure 1, the combination of NDV+irinotecan+5-FU was significantly higher than that on the antitumor activity of the application of each agent separately or control of carrier. As shown in figure 2, the combination of NDV+irinotecan+5-FU was superior to anti-tumor activity of any of the combinations of the two drugs (NDV + Irinotecan; Irinotecan+5-FU; NDV+5-FU).

Example 5

This experiment was performed as in Example 4, except as follows: (1) treatment started within seven days after subcutaneous injection of tumor cells SW620; (2) subcutaneous tumors were approximately 100 mm3, (3) in the group treated was 13 mice; (4) the dose of irinotecan was 15 mg/kg instead of 25 mg/kg; and (5) the dose of 5-FU was 100 mg/kg instead of 25 mg/kg As before, animals were randomized into 8 groups treated:

- NDV-NDV+Irinotecan

- NDV+5-FU

- NDV+Irinotecan+5-FU

- Irinotecan

- 5-FU-Irinotecan+5-FU

- Only media

As before, in the course of the Day 0 all mice received either NDV (1E+09 PFU), or media using the intravenous route of administration according to the principle of treatment presented above. Two days later, on Day 2, all mice performed the first intraperitoneally injection or irinotecan (15 mg/kg), or media, and then after 1 hour was performed the second intraperitoneally injection or 5-FU (100 mg/kg), or media according to the principles of the in treatment, presented above. All mice were periodically determined by the size of the tumor, using a Vernier caliper.

As shown in figure 3, the combination of NDV+irinotecan+5-FU again was significantly higher than that on the antitumor activity of the application of each agent separately or media control. As shown in figure 4, the combination of NDV+irinotecan+5-FU was significantly higher than that for antitumor activity using any of a combination of two medicines (NDV+Irinotecan; Irinotecan+5-FU; NDV+5-FU). In addition, the data obtained about the synergistic antitumor effect of the use of all three agents is expressed in the resistant regression of the tumor. As shown in Table 7, were observed more complete regression of the tumors (CRs), which was stable (i.e., continued until Day 90) and the use of triple combination NDV+irinotecan+5-FU, unlike any other group treatment, including the use of any combination of two medicines (NDV+Irinotecan; Irinotecan+5-FU; NDV+5-FU) and each of the agents separately.

Table 7
When treating mice, tumour, using a triple combination NDV+Irinotecan+5-FU was observed more stable and complete reaction of puhala treatment than in the application of any of the agents alone or in any is combinatii of two medicines
TreatmentThe number of mousePersistent effect of CRs*,%
NDV130
NDV+Irinotecan1323
NDV+5-FU130
NDV+Irinotecan+ 5-F1346
Irinotecan130
5-FU130
Irinotecan+5-FU130
Only media130
*CRs, which lasted until Day 90

1. A method of treating a mammal having neoplasma, including introduction to the subject of Newcastle disease virus, ftorpirimidinu and connecting camptothecin for one or more cycle in the total amount effective to treat the subject.

2. The method according to claim 1, in which the virus is replicationcompetent.

3. The method according to claim 1, wherein the virus is a mesogenic strain of Newcastle disease virus.

4. The method according to claim 1, in which the virus is injected.

5. The method according to claim 1, in which the connection ftorpirimidinu is 5-fluorouracil.

6. The method according to claim 5, further comprising an introduction to the subject of leucovorin.

7. The method according to claim 5, in which 5-fluorouracil is administered via continuous infusion for at least 22 hours per dose.

8. The method according to claim 1, in which the connection of camptothecin selected from the group consisting of irinotecan, topotecan, 9-aminocamptothecin, exatecan, carniceria, rubitecan, lurtotecan and gamecaptain.

9. The method according to claim 8, in which connection camptothecin is irinotecan.

10. The method according to claim 1, wherein the virus is a mesogenic strain of Newcastle disease virus, torpedinidae is 5-fluorouracil, and connection camptothecin is irinotecan.

11. The method according to claim 1, in which Newcastle disease virus, ftorpirimidinu and connection camptothecin administered for two or more cycles.

12. The method according to claim 1, in which the connection of camptothecin administered to the subject from 24 hours to one month before the introduction of the virus.

13. The method according to item 12, in which the connection of camptothecin administered to the subject from 24 hours to one week prior to the introduction of Newcastle disease virus.

14. The method according to claim 1, in which the connection of the AC is of ptotein administered to the subject from 24 hours to one month after administration of the virus.

15. The method according to 14, in which the connection of camptothecin administered to the subject from 24 hours to one week after the introduction of Newcastle disease virus.

16. The use of Newcastle disease virus for the manufacture of a medicinal product for the treatment in combination with torpedinidae and connection camptothecin subject having neoplasma.

17. The use of ftorpirimidinu for the manufacture of a medicinal product for the treatment in combination with Newcastle disease virus and connection camptothecin subject having neoplasma.

18. The use of compounds of camptothecin for the manufacture of a medicinal product for the treatment in combination with Newcastle disease virus and connection ftorpirimidinu subject having neoplasma.

19. The use according to any one of p-18, in which the virus is replication-competent.

20. Use p in which the virus is a mesogenic strain of Newcastle disease virus.

21. The use according to any one of p-18, in which the virus is injected.

22. The use according to any one of p-18, in which connection ftorpirimidinu is 5-fluorouracil.

23. The use according to any one of p-18, in which the connection of camptothecin selected from the group consisting of irinotecan, topotecan, 9-aminocamptothecin, exatecan, carniceria, rubitecan, lurtotecan and gamecaptain.

24. Use the s on item 23, in which connection camptothecin is irinotecan.

25. The use according to any one of p-18, in which Newcastle disease virus is a mesogenic strain of Newcastle disease virus, torpedinidae is 5-fluorouracil, and connection camptothecin is irinotecan.

26. The use according to any one of p-18, in which Newcastle disease virus, ftorpirimidinu and connection camptothecin administered for two or more cycles.

27. The use according to any one of p-18, in which the connection of camptothecin administered to the subject from 24 hours to one month prior to the introduction of Newcastle disease virus.

28. The application of item 27, in which the connection of camptothecin administered to the subject from 24 hours to one week prior to the introduction of the virus.

29. The use according to any one of p-18, in which the connection of camptothecin administered to the subject from 24 hours to one month after the introduction of Newcastle disease virus.

30. The application of clause 29, in which the connection of camptothecin administered to the subject from 24 hours to one week after the introduction of Newcastle disease virus.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and is intended for relief of symptoms, prevention and/or treatment of cancer. Performed is introducion to subject, patient or person subjected to risk of cancer, one or several phosphate derivatives of one or more hydroxychromans, selected from group, which consists of 7:8-dimethyl-6-hydroxychromans, 8-methyl-6-hydroxychromans and their mixtures, together with one or more anticancer agents.

EFFECT: inventions make it possible due to application of effective quantity of composition of one or more hydrochromans with one or more anticancer agents and their combination to stimulate apoptosis of cancer cells, contributing to relief of symptoms, prevention and/or treatment of cancer.

24 cl, 4 dwg, 3 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: method of determining prognosis of disease development in patient with cancer includes estimation of level of choline kinase alpha gene expression in cancer tissue sample, taken from patient, and comparison of obtained value with value, corresponding to one or more samples of normal non-cancer tissue. Higher level of choline kinase alpha gene expression is used to differentiate patients with worse prognosis of disease development. Method of in vitro monitoring of anti-cancer therapy effect is realised by estimation of level of choline kinase alpha gene expression in cancer tissue sample, taken from patient, who is introduced anti-tumour agent, and comparison of obtained value with value, corresponding to one or more samples of normal non-cancer tissue. Efficient therapy reduces levels of choline kinase alpha gene expression or causes reversing the effects of high expression of said gene.

EFFECT: invention makes it possible to determine prognosis of disease development in patient with cancer or carry out monitoring of anti-cancer therapy in patient in efficient way.

6 cl, 47 dwg, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt - monohydrate of monohydrochloride of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide, having protein kinase inhibiting properties. The invention also relates to a method of obtaining said compound. The method involves the following steps: (a) merging 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in form of a free base and hydrochloric acid in methanol in a nitrogen atmosphere; (b) heating the reaction mixture to temperature in the range of approximately 42-50°C; (c) stirring the reaction mixture; (d) filtering the reaction mixture while maintaining temperature higher than 40°C to obtain a transparent solution; (e) cooling the transparent solution to approximately 30°C while stirring in a nitrogen atmosphere; (f) adding an inoculant to the solution; (g) cooling the solution containing the inoculant to approximately 23°C; (h) stirring the solution to obtain a suspension; (i) cooling the obtained suspension to approximately -10°C; (j) stirring the obtained suspension; (k) filtering solid substances, washing the solid substance with cold methanol; and (l) drying the solid substance at approximately 50-55°C and 10-20 torr to obtain the end product.

EFFECT: monohydrate of monohydrochloride of said compound has high solubility compared to a base and hydrochloride salt and has high bioavailability in vivo compared to said compounds.

4 cl, 17 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) (I), its N-oxide form, addition salt or stereochemically isomeric form, where m equals 0, 1, and m equals 0 denotes a direct bond; n equals 0, 1, 2 or 3, and n equals 0 denotes a direct bond; p equals; t equals 0 or 1, and t equals 0 denotes a direct bond; denotes -CR8=C<, and the dotted line denotes a bond, where R8 denotes hydrogen; R1 and R2 denotes hydrogen; R3 and R4 denote hydrogen; R5 denotes hydrogen; R6 and R7 each is independently selected from hydrogen or C1-6alkyl; Z denotes a radical selected from (a-1) (a-2) (a-4), where R10 and R11 are each independently selected from hydrogen, hydroxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkyl, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyloxy, hydroxy C1-6 alkyl. The invention also describes a pharmaceutical composition for treating cancer, based on the compound of formula I, as well as a method of preparing said composition and use of the compound of formula I, combination thereof with an anticancer agent and preparation method thereof.

EFFECT: improved properties of compounds.

14 cl, 6 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel imidazole derivatives of general formula (I), in which: Z' represents hydrogen atom or haloid radiacal; Z represents radical of formula -NH-X-NR1R2; R1 and R2 independently represent hydrogen atom, (C1-C6)alkyl radical, phenyl, optionally substituted by (C1-C6)alkyl radical, or benzyl, optionally substituted on ring by (C1-C6)alkyl radical; X represents SO2- or Y represents S, O or N-R; R represents CN or -NO2; or to its pharmaceutically acceptable salt. Invention also relates to methods of obtaining formula (I) compound, to pharmaceutical composition based on formula (I) compound, to application of formula (I) compound.

EFFECT: obtained are imidazole derivatives - inhibitors of tubulin polymerisation, useful in treatment of tumours and gout.

20 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to treatment of infectious diseases and oncology and can be used in treatment of persisting infection, angioimmunoblastic lymphoma or nodular with lymphoid prevalence Hodgkin's lymphoma. Method includes introduction of compound, which reduces activity or expression of member of family CD28, where said member of CD28 family is selected from group, consisting of PD-1, CTLA-4, BTLA and their functional fragment and version.

EFFECT: application of invention makes it possible to increase efficiency of treatment of persisting infection, angioimmunoblastic lymphoma or nodular with lymphoid prevalence Hodgkin's lymphoma.

36 cl, 8 dwg, 14 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be used in treatment of metastatic cancer of mammary gland. Method by invention includes introduction to patient with high expression of EpCAM, demonstrating total index of immune staining with respect to EpCAM more than 4, IgGl antibodies against EpCAM, containing SEQ ID NO: 3, 4, 5, 6, 7 and 8 in dose of saturation 6 mg/kg of body weight with further multiple supporting doses, each of which constitutes 6 mg/kg of body weight. IgGl antibody for application in treatment of metastatic cancer of mammary gland against EpCAM, contains SEQ ID NO: 3, 4, 5, 6, 7 and 8.

EFFECT: application of inventions makes it possible to increase period of survival without disease progressing in patients with high expression of EpCAM.

10 cl, 11 tbl, 8 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be used for treatment of cancer of rectum. For this purpose during operation in presacral space till its complete filling-in introduced is medication - "hydrogel napkins with 5-fluoruracyl and sodium alginate "Coletex -5-ftur" with addition of 50 mg of carboplatin. Two drainages of different diameter are installed into presacral space. After that, peritonisation with uninterrupted suture is carried out tightly. On 5-6 day after operation hydrogel "Coletex-gel-DNA" is introduced through drainages into presacral space until it is completely filled.

EFFECT: method ensures reduction of frequency of local recurrences and metastases after cancer of rectum surgery due to efficient intraoperative local chemical therapy in combination with reparative therapy after operation.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel conformationally stable compounds of general formula (I), which imitate the secondary structure of reverse-configuration regions of biologically active peptides and proteins which are reverse-configuration mimetics. The compounds can be used to inhibit or treat disorders modulated by Wnt-signalling pathway, such as cancer, especially colorectal cancer. The invention also relates to a library containing the disclosed compound. In general formula (I), A denotes -(C=O)-, B denotes -(CHR4)-, D denotes -(C=O)-, E denotes -(ZR6)-, G denotes -(XR7)-, Z denotes CH, X denotes a nitrogen atom, W denotes -(C=O)NH-, R1 denotes benzyl; R2 denotes a heterocyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms; a substituted hetercyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, an the ring has 1-3 substitutes independently selected from a group comprising halogen, piperidinyl, morpholinyl, C2-6alkenyl, phenyl, hydroxyphenyl, C1-6alkoxycarbonyl, dialkylamino, hydroxypiperidinyl, C1-6alkyl, hydroxyC1-6alkylpiperazinyl, amino, piperidinyl carbonyl; heterocyclyl-C1-6alkyl group having a 9-member condensed bicyclic ring which has one or two nitrogen atoms; and other values given in the claim. R4 denotes a substituted benzyl, having a substitute selected from disodium phosphate, monosodium phosphate, phosphate; R6 denotes hydrogen; R7 denotes: C1-6alkyl; C1-6alkynyl; C2-6alkenyl; substituted benzyl, having one or more substitutes independently selected from halogen and C1-6alkyl.

EFFECT: high efficiency of the compounds.

8 cl, 34 dwg, 19 tbl, 25 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary virology and biotechnology. As an active substance, a virus-vaccine contains antigen material of attenuated "VNIISZH 2003" strain of goat-pox virus (GPV) Variola vims caprmum of Poxviridae fam., Chordopoxvirinae subfam., Capripoxvirus genus deposited in collection of FGU "VGNKI", VNIISZH 2003 registration No. (reference) - DEP, in the effective amount. The strain is reproduced in a Ch-91 cell culture for 5-7 days and is collected in titre 5.5 lg "ТЦД"50/cm3 to 7.0 lg "ТЦД"50/cm3. The strain preserves initial characteristics when passing the Ch-91 cell culture for 35 passages.

EFFECT: virus-vaccine protects immunised animals from contact infection by epizootic goat-pox virus circulating in the territory of Russia.

4 dwg, 8 cl, 7 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: essence of the invention includes a way of inhibition of a mammal cancer cell with the defective antiviral response sensitive to interferon, including introduction of myxoma virus in a cell. The myxoma virus can be used at cancer treatment.

EFFECT: simplification of a way.

35 cl, 1 ex, 28 dwg, 1 tbl

FIELD: veterinary; veterinarian virology.

SUBSTANCE: production of dry cultural rinderpest virus-vaccine for minor ruminants includes growing of virus containing raw materials from "45G37/35-K" rinderpest virus strain in cell culture, introduction of protective medium and production of the end product. Passaged cell culture of saiga kidney is used as a cell culture. Infected culture is incubated under roller conditions during 5-7 days with the change of supporting medium each 2-3 days. Virus containing culture is mixed before freeze drying in proportion 1:1, and then freeze dried until moisture mass fraction is no more than 4%. Finally, it is packed into ampoules. The end product contains virus raw materials, peptone, sucrose, gelatine and demineralised water.

EFFECT: high-performance production of standard and innocuous rinderpest virus-vaccine for minor ruminants stable for storage conditions.

2 cl, 3 ex

FIELD: veterinary microbiology.

SUBSTANCE: according to the first variant, the vaccine suggested includes VGNKI-3/7 strain of hen's pox virus as a virus-containing material; as a stabilizer one should apply the mixture of peptone and lactose in 0.1-0.2M-phosphate buffer at pH being 7.0-7.4 at the following ratio of components, weight%: virus-containing material out of VGNKI-3/7 strain of hen's pox virus at infection activity being about 5.0-7.0 ID50/cu. cm 65.0-70.0; peptone 4.0-10.0; lactose 5.0-10.0; 0.1-0.2M-phosphate buffer at pH 7.0-7.4 - the rest. According to the second variant, the vaccine suggested contains VGNKI-3/7 strain of hen's pox virus as virus-containing material, and as a stabilizer - glycerol at the following ratio of components, weight%: glycerol 5-10; virus-containing material out of VGNKI-3/7 of hen's pox virus at infection activity of 6.0-7.5 lg ID50/cu. cm - the rest. The vaccine creates prolonged tense immunity.

EFFECT: higher efficiency.

3 cl, 9 ex, 1 tbl

FIELD: veterinary virology.

SUBSTANCE: the suggested vaccine contains a virus-containing material obtained at combined cultivation of avian smallpox virus upon cell culture of hen's fibroblasts "VGNKI-3" strain and virus of Newcastle disease "M-VNII VV&M" strain. Virus content in cell culture corresponds to 0.02-0.04 and 0.02-0.08 TCD/cell, correspondingly. The suggested virus vaccine is of high immunogenicity.

EFFECT: higher efficiency of vaccine application.

1 ex

FIELD: veterinary science, infectious diseases.

SUBSTANCE: invention relates to the development of dry cultural virus vaccine against plague in small ruminant animals that possesses high immunogenicity, harmlessness, areactogenic properties for sheep and goats and low cost. Virus vaccine comprises lyophilized virus-containing material prepared on base of the strain "45G37/35-K" and protective medium in the volume ratio 1:1. As protective medium virus vaccine comprises medium of the following composition, wt.-%: enzymatic peptone, 9.8-10.2; lactose, 1.8-2.2, and distilled water, the balance. Vaccine is harmless, shows highly immunogenic properties and stable in storage.

EFFECT: improved and valuable properties of vaccine.

2 cl, 3 ex

FIELD: biotechnology, vaccines.

SUBSTANCE: method involves preparing industrial strain, smallpox scrape off and virus-containing liquid. Virus-containing liquid is inactivated by gamma-radiation Co60. Integral (total) dose of irradiation is 1.75 x 106 R at the parent specific activity of virus-containing liquid from 1 x 109 to 1.9 x 109 OOE/ml and 1.9 x 106 R at the parent specific activity of virus-containing liquid from 2 x109 to 5 x 10 OOE/ml. The content of total protein is brought about to the concentration 100 mcg/ml and drying stabilizing agents are added. Vaccine elicits high immunogenicity, suitable in applying and absence of toxicity.

EFFECT: improved preparing method, improved and valuable properties of vaccine.

3 cl, 6 ex

FIELD: veterinary science.

SUBSTANCE: the present method deals with applying biological preparations for vaccinating farm animals and could be applied for protecting female goats against variola. The present innovation deals with a single subcutaneous injection of dry culture virus vaccine against ovine variola for female goats at the quantity of two vaccination dosages. The innovation enables to accelerate the development of tense immunity to variola virus in goats along the absence of post-vaccinal complications and prolong immunity by 8 mo, not less.

EFFECT: higher efficiency of prophylaxis.

3 ex, 1 tbl

The invention relates to the field of veterinary medicine

FIELD: medicine, veterinary science.

SUBSTANCE: invention refers to veterinary science. The method implies that the introduced vaccine is mixed with Myramistin. Myramistin is introduced intranasally by 0.2-0.3 ml into each nasal passage of a bird.

EFFECT: use of the offered method improves efficacy of vaccination.

2 tbl, 1 ex

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