CN102448454B - Comprise the Therapeutic combinations of PLK1 inhibitor and antitumor agent - Google Patents
Comprise the Therapeutic combinations of PLK1 inhibitor and antitumor agent Download PDFInfo
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- CN102448454B CN102448454B CN201080022643.6A CN201080022643A CN102448454B CN 102448454 B CN102448454 B CN 102448454B CN 201080022643 A CN201080022643 A CN 201080022643A CN 102448454 B CN102448454 B CN 102448454B
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Abstract
The invention provides a kind of combination, this combination comprises (a) formula (I) compound and (b) one or more antitumor agents, described antitumor agent is selected from antimetabolite, alkylating agent or class alkylating agent, intercalator, topoisomerase I or II inhibitor, antimitotic agent, inhibitors of kinases, proteasome inhibitor and the Developing restraint factor or the antibody of its receptor, the active component of wherein said combination is the most in a free form or presented in its pharmaceutically-acceptable salts or any hydrate or solvate, for the treatment of tumor.
Description
The present invention relates generally to field of cancer, and more specifically offer comprises PLK1 inhibitor and one or many
Planting the antineoplastic combinations of antitumor agent, this combination has good antitumor action.
Cancer is the cause of death that the mankind are main；Surgical operation, radiotherapy and chemotherapy are useful to anticancer
Method.Particularly, combined chemotherapy (it is intended to by combination or more than one medicine is used in combination treats cancer) is a kind of
The Therapeutic Method of widely accepted oncosis (such as cancer).In order to select antineoplastic combinations the most effectively and safely
Being applied to the patient suffering from cancer, people several times make great efforts and are still carrying out effort.In order to reduce single medicine alone
Time toxic action, and owing to having bigger effect when combining in some cases and be used alone than any one medicament,
Combine by using the known antitumoral compounds antineoplastic agent different from one or more, strengthen known antitumor chemical combination
The antitumor efficacy of thing is a kind of demand strongly experienced in field of anticancer therapy.
Expressing of PLK1 is the most visible in the normal structure of all propagation, but process LAN is but at a series of tumor (bag
Include breast carcinoma, carcinoma of prostate, ovarian cancer, pulmonary carcinoma, gastric cancer and colon cancer) in just observation obtain.Once PLK1 quilt in cancerous cell
RNAi exhaust, can be observed propagation suppression and reduction vigor (its cause cell cycle arrest the 4N DNA content stage with
Rear apoptosis).Although in the mankind, describe 4 kinds of different PLKs family members, but this inhibition of enzyme activity or the consumption of PLK1
Exhaust swelling in the G2/M cell cycle arrest and apoptosis and xenograft models being just enough in inducing tumor cell system
Tumor disappears.Additionally, for other PLKs, it has been described that the function of tumor suppressor gene, and report PLK2 and PLK3
(rather than PLK1) expresses in non-proliferative, differentiation postmitotic cells (such as neuron), and this points out PLK1 specificity
Compound be likely to be of more preferable safety (see for example: Strebhardt K, et al., Nat Rev Cancer 2006；6
(4): 321-30).
It is a kind of received for treating extensive human cancer for using mitotic inhibitor in treatment of cancer
Clinical strategy (see for example: Jackson JR, et al., Nature Reviews Cancer 2007；7,107-117).Purple
China fir alkanes (paclitaxel and docetaxel) and vinca alkaloids (vincristine and vinblastine) are by stablizing micro-pipe or making
Micro-pipe unstability (in by mitotic cell progression, there is catastrophic effect) and play a role.They are some tumor classes
The first-line treatment medicine of type (including Hokdkin disease, non_hodgkin lymphoma, carcinoma of testis, neuronal cell tumor and Wilms tumor)
Thing (vinca alkaloids) and be the second line treatment medicine in cisplatin-refractory ovarian, breast carcinoma, pulmonary carcinoma and the esophageal carcinoma
Thing (taxanes).But, due to the effect during such as cell migration, phagocytosis and axonal transport of micro-pipe, the most considerable
Observe these medicaments and there is some toxicity (such as peripheral neuropathy).
Protect with requirement described in patent application WO2008074788 (Nerviano Medical Sciences Srl.)
The pyrazoloquinazolines class protected is effective inhibitor of PLK1, and is therefore applicable to treat proliferative disorders, particularly cancer.
Formula (I) compound is described in the patent application indicated above and one of claimed compound.At this
Also its pharmaceutical composition of preparing, comprising it has been described and claimed as and in purposes pharmaceutically in application.
Have been surprisingly discovered that at present and be, when by formula (I) compound with known antitumor agent combined administration, formula (I)
Compound antitumor effect the most greatly strengthens.
The invention provides new combination, it comprises (a) formula (I) compound and (b) antitumor known to one or more
Agent.These combinations are particularly suitable for the treatment of proliferative disorders (especially cancer).
More specifically, combination of the present invention is highly suitable in the treatment as antitumor agent, and in toxicity and
The shortcoming that side effect aspect is the most relevant to currently available antineoplastic agent.
Therefore it is an object of the invention to a kind of combination, it comprises (a) formula (I) compound
(b) (it is different selected from antimetabolite, alkylating agent or class alkylating agent, intercalator, topology for one or more antitumor agents
Structure enzyme I or II inhibitor, antimitotic agent, inhibitors of kinases, proteasome inhibitor and the Developing restraint factor or its receptor
Antibody), the active component of wherein said combination the most in a free form or with its pharmaceutically-acceptable salts or appoint
Presented in what hydrate or solvate.
The combination according to the present invention that another aspect relates to simultaneously, individually or continuously uses.
Another aspect relates to treat proliferative disorders or postpone the combination according to the present invention of proliferative disorders progress.
Another aspect of the present invention relates to the purposes in prepared by medicine of the combination according to the present invention, wherein said medicine
For treat proliferative disorders or postpone proliferative disorders development, wherein said purposes include described Therapeutic combinations to needs its
Experimenter's using simultaneously, continuously or individually.
Additionally, the present invention relates to a kind of pharmaceutical composition, it comprises and pharmaceutically acceptable carrier, diluent or figuration
The combination according to the present invention of agent mixing.
Another aspect relates to the pharmaceutical composition according to the present invention, and it is used for treating proliferative disorders or postponing proliferative disorders
Progress.
Another aspect of the present invention relates to the purposes in prepared by medicine of the pharmaceutical composition according to the present invention, Qi Zhongsuo
State medicine for treat proliferative disorders or postpone proliferative disorders progress, wherein said purposes include described pharmaceutical composition to need
Want its experimenter using simultaneously, continuously or individually.
Additionally, the present invention relates to a kind of method treating proliferative disorders, described method include to needs its experimenter with
Time, continuously or individually use the combination of the present invention.
Another aspect relates to a kind of method treating proliferative disorders, described method include to needs its experimenter with
Time, continuously or individually use the pharmaceutical composition of the present invention.
Another aspect relates to a kind of method reducing side effect, and described side effect is by using the anti-swollen of antitumor agent
Tumor treatment causes in the mammal (including the mankind) needing it, and described method includes producing synergistic antitumor effect
Effective dose is to the preparation of described administration combination, and described preparation comprises (a) formula as defined in claim 1
(I) (it is selected from antimetabolite, alkylating agent or class alkylating agent, intercalator, topology for compound and (b) one or more antitumor agents
Isomerase I or II inhibitor, antimitotic agent, inhibitors of kinases, proteasome inhibitor and the Developing restraint factor or its be subject to
The antibody of body).
Present invention also offers the test kit of commercialization, it comprises: (a) in a suitable case is as above
Defined formula (I) compound, and (b) one or more antitumor agents (its selected from antimetabolite, alkylating agent or class alkylating agent,
Intercalator, topoisomerase I or II inhibitor, antimitotic agent, inhibitors of kinases, proteasome inhibitor and Developing restraint
The factor or the antibody of its receptor).
According in the test kit of the present invention, (a) formula as defined above (I) compound, and (b) one or more resist
Tumor agent (its selected from antimetabolite, alkylating agent or class alkylating agent, intercalator, topoisomerase I or II inhibitor, anti-have silk to divide
Split agent, inhibitors of kinases, proteasome inhibitor and the Developing restraint factor or the antibody of its receptor) it is present in single container dress
Put interior or be present in different cases.
Another embodiment of the invention is to comprise the commercial kit of pharmaceutical composition described above.
Test kit according to the present invention is intended to simultaneously, individually or be continually used for antineoplastic treatment.
Test kit according to the present invention is intended for anticancer treatment.
According to the preferred embodiment of the invention, the combination of the present invention comprises formula (I) compound and antimetabolite, described
Antimetabolite is selected from 5-fluorouracil, AzGR, capecitabine, cytosine arabinoside, gemcitabine, pemetrexed, methotrexate, depends on
Reach Qu Sha, hydroxyurea, fludarabine and mercaptopurine.
Preferably, the described antimetabolite for the present invention is gemcitabine or cytosine arabinoside.
According to presently preferred embodiment, combination of the present invention comprises formula (I) compound and alkylating agent
Or class alkylating agent, described alkylating agent or class alkylating agent selected from nitrogen mustards (chlormethine, cyclophosphamide, ifosfamide, melphalan and
Chlorambucil), aziridines (phosphinothioylidynetrisaziridine), nitrosoureas (carmustine, lomustine, semustine), Triazenes
(dacarbazine and temozolomide) and platinum derivatives (cisplatin, oxaliplatin, carboplatin and Satraplatin).
It is highly preferred that described alkylating agent or class alkylating agent for the present invention are cisplatin.
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound and intercalator；Excellent
Selection of land, described intercalator is bleomycin.
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound and topoisomerase
Enzyme I inhibitor, described topoisomerase I inhibitor is selected from hycamtin, SN-38, CPT11 and 9-nitrocamptothecin.
It is highly preferred that described topoisomerase I inhibitor is SN-38 or CPT11.
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound and topoisomerase
Enzyme II inhibitor, described Topoisomerase II inhibitors selected from doxorubicin, epirubicin, idarubicin, Nemorubicin,
Mitoxantrone, etoposide and teniposide.
Preferably, described Topoisomerase II inhibitors is doxorubicin.
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound has silk to divide with anti-
Splitting agent, described antimitotic agent is selected from paclitaxel, docetaxel, ipsapirone, vinblastine, vincristine, vindesine
And vinorelbine.
It is highly preferred that described antimitotic agent is paclitaxel.
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound and kinase inhibition
Agent, described inhibitors of kinases selected from Sorafenib, Dasatinib, gefitinib, Erlotinib, Sutent, imatinib,
AMN107 and Lapatinib.
According to another preferred embodiment, described inhibitors of kinases is Sorafenib or Dasatinib
According to another preferred embodiment of the present invention, the combination of the present invention comprises formula (I) compound and proteasome
Inhibitor；Preferably, described proteasome inhibitor is bortezomib.
According to presently preferred embodiment, the combination of the present invention comprises formula (I) compound and Developing restraint
(blood vessel endothelium is raw selected from Avastin for the factor or the antibody of its receptor, the described Developing restraint factor or the antibody of its receptor
The antibody of the long factor), Cetuximab, Victibix, horse trastuzumab, Buddhist nun's trastuzumab (EGF-R ELISA anti-
Body), Herceptin and pertuzumab (antibody of ErbB2).
According to another preferred embodiment, described antibody is Avastin.
Term " synergistic antitumor effect " means by using combination to mammal (including people) as used herein
Effective dose suppresses tumor growth, preferably makes completed tumor regression, wherein said is combined as formula as defined above (I) chemical combination
(it is selected from antimetabolite, alkylating agent or class alkylating agent, intercalator, topoisomerase I or II for thing and one or more antitumor agents
Inhibitor, antimitotic agent, inhibitors of kinases, proteasome inhibitor and the Developing restraint factor or the antibody of its receptor)
Combination.
Term " preparation of combination " is particularly defined as " test kits of parts " as used herein, combines in the sense that
Partner (partners) (a) can independently or (be had by the different fixed Combination of use with (b) (as defined above)
The difference amount of combination partner (a) and (b)) use (the most at the same time or in different time points).Then can be by Kit of parts
Parts use the most simultaneously or temporally stagger (be exactly any parts for Kit of parts, different time points and with
Equal or different time interval).It is highly preferred that select time interval so that unit construction uses treated disease
Effect is bigger than the effect that any one simply using combination partner (a) and (b) obtains.Such as in order to answer patient to be treated sub-
(different needs is due to the concrete disease of patient, age, sex, body weight for the needs of group or the needs of single patient
Deng), the ratio of the combination partner (a) to be administered in the preparation of combination and the total amount of combination partner (b) can be changed.Preferably
, there are the effect (the mutual potentiation of such as combination partner (a) and (b)) that at least one is useful, particularly synergism in ground
(such as, it is better than the effect of addition, additional beneficial effect, less side effect, in one or both of combination partner (a) and (b)
Ineffective dose under associating curative effect), and be most preferably the strong synergism of combination partner (a) and (b).
Term " is applied " or " using " means parenteral and/or Orally administered as used herein." parenteral "
Meant intravenous, subcutaneous and intramuscular administration.
Formula (I) compound is used, the course for the treatment of generally used be every dose about 5 to about 500mg, every day 1 to 5 time.
Formula (I) compound can be used with multiple dosage form, such as, and oral tablet, capsule, sugar-coat or Film coated tablets, liquid
Liquid solution agent or suspensoid；The suppository of rectal administration；Parenteral (such as, intramuscular) or by intravenous and/or sheath and/or ridge
The injection used in post or transfusion.
In the method for the invention, using for antimetabolite, preferably cytosine arabinoside or gemcitabine, generally adopt
The course for the treatment of be the 200mg/m of body surface area2To 5000mg/m2As using weekly.It is highly preferred that the course for the treatment of generally used is
The the 1st and the 8th day in 21-days cycles or the 1st, 8 and 15 days in 28-days cycles or in the cycle of 21-days the 1st day
Use about 500mg/m2To 1250mg/m2。
Using for alkylating agent, preferably temozolomide, the course for the treatment of generally used is daily body surface area
15mg/m2To 300mg/m2.It is highly preferred that the course for the treatment of generally used is the most continuous 42 days the most about 50mg/m2Extremely
150mg/m2。
Using for platinum derivatives, preferably cisplatin, the course for the treatment of generally used is daily surface of every 2-3 week
Long-pending 10mg/m2To 100mg/m2.It is highly preferred that the course for the treatment of generally used is every 2 weeks 1 time, used about 30mg/m at the 1st day2Extremely
85mg/m2。
Using for intercalator, preferably bleomycin, the course for the treatment of generally used is to execute 1 times a week or 2 times a week
1U/m2 to 100U/m2 with body surface area.
Using for topoisomerase I inhibitor, preferably CPT-11, the course for the treatment of generally used is continuous 2-10 days
The daily 1mg/m of body surface area2To 500mg/m2.It is highly preferred that the course for the treatment of generally used is weekly or every 2 weeks or every 3 weeks
Use about 50mg/m2To 350mg/m2。
Using for Topoisomerase II inhibitors, preferably doxorubicin, the course for the treatment of generally used is continuous 2-
The 0.1mg/m of 10 days daily body surface areas2To 500mg/m2.It is highly preferred that the course for the treatment of generally used is the week at 21-days
Interim continuous 3-5 days the most about 0.5mg/m2To 100mg/m2。
Using for antimitotic agent, preferably paclitaxel, the course for the treatment of generally used is to use surface in every 3 weeks
Long-pending about 50mg/m2To 100mg/m2, or use weekly 30mg/m2Rise.
Inhibitors of kinases is used, preferably Sorafenib, the course for the treatment of generally used can be 1mg extremely
5000mg.It is highly preferred that the course for the treatment of used is about 10mg to 2000mg.Proteasome inhibitor is used, preferably
Bortezomib, the course for the treatment of generally used is every 0.1mg/m using body surface area for 3 weeks2To 30mg/m2。
Finally, for the using of antibody of the Developing restraint factor or its receptor, preferably Avastin, generally use
The course for the treatment of can be 0.1mg/kg to 100mg/kg.More preferably, the course for the treatment of of employing is to execute for the 1st day in the cycle of 3 weeks
With 1mg/kg to 20mg/kg.
When the active component of the preparation combined according to the present invention provides together with pharmaceutically acceptable carrier or excipient
Time, define pharmaceutical composition.This pharmaceutical composition constitutes another embodiment of the invention.
Select pharmaceutically acceptable carrier and excipient, so that the side effect of medical compounds minimizes but do not cancels
Or suppress effect of this compound to the degree making failure in treatment.
For carry out the technical staff of compound formulation art with the form of pharmaceutical composition, in preparation according to this
Pharmaceutically acceptable carrier used in bright pharmaceutical composition or excipient are that they are known.Such as, " pharmaceutically may be used
The carrier accepted " mean solid or liquid filler, diluent or the encapsulating substance of one or more compatibilities, it is suitable to suckling
Animal (including the mankind) is used.Such as, " pharmaceutically acceptable excipient " means to be intentionally added in dosage formulation be used as
The diluent of active substance or any inert substance of medium.This term includes binding agent, filler, disintegrating agent and lubricant.
But, the combination of the present invention can be added without the auxiliary agent of any lasting-release and use.
Pharmaceutical preparation and application technique can be at " Remington ' s Pharmacological Sciences "；Mack
Publishing Co., Easton, PA, find in latest edition.
The pharmaceutical composition of suitable parenteral administration is made as aseptic form.Therefore this aseptic compositions can be
Sterile solution agent in the acceptable diluent of nontoxic parenteral or solvent or suspensoid.
May change according to the amount containing active component in the pharmaceutical composition of the present invention, depend on to a great extent
In many factors (example route of administration as mentioned and described medium).
Combination according to the present invention and described pharmaceutical composition are applicable to anticancer therapy.
The antineoplaston of the present invention is particularly suitable for treating the cancer of form of ownership, and it includes but not limited to: cancer example
Such as bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, include the pulmonary carcinoma of small cell lung cancer, esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, pancreas
Adenocarcinoma, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate and include the skin carcinoma of squamous cell carcinoma；The hematopoietic system cancer of lymphatic system
(hematopoietic tumor), described cancer includes that leukemia, acute lymphoblastic leukemia, acute lymphoblast are white
Disorders of blood, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphomas, non Hodgkin lymphom, hairy cell lymphoma and
Burkitt's lymphoma；The hematopoietic system cancer of medullary system, described cancer includes that acute and chronic myelogenous leukemia, myeloproliferative disorder are combined
Simulator sickness and promyelocytic leukemia；The cancer originated including the mesenchyme of fibrosarcoma and rhabdomyosarcoma；Mesothelioma；Maincenter and
Peripheral nervous system cancer, described cancer includes astrocytoma, neuroblastoma, glioma and schwannoma；Its
Its cancer, described cancer includes mesothelioma, melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratinization spine skin
Tumor (keratoxanthoma), thyroid follicular cancer and Kaposi sarcoma.
Due to PLK1 pivotal role in cell proliferation regulates, combination of the present invention and described pharmaceutical composition
Apply also for treating various kinds of cell proliferative disorders, such as, benign prostatic hyperplasia, familial adenomatosis, polyposis, nerve fiber
Tumor, psoriasis, (relevant to atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis
) vascular smooth muscle cell proliferation (vascular smooth cell proliferation).
Combination of the present invention and described pharmaceutical composition, as apoptosis regulators, it is also possible to be applicable to treat cancer
Disease, virus infect, and prevent the development of AIDS in the individuality that HIV-infects, autoimmune disease and neural degeneration obstacle.
The antitumor action of combination preparation of the present invention is such as shown by following in vitro tests, described in vitro tests meaning
The present invention to be illustrated and it is not done any restriction.
Embodiment
Material and method:By the human pancreas cancer (Mia-PaCa, Capan-1) of exponential growth, human colon carcinoma (HCT-116),
Leukemia (HL60) and multiple myeloma (KMS11) cell line are inoculated and 5%CO moistening at 37 DEG C2The middle temperature of environment
Educate.Medicine is added in experimental culture, and incubation 72 hours in dark at 37 DEG C.MCF7 breast cancer cell line is connect
Plant and 5%CO moistening at 37 DEG C2Incubation in environment.Medicine is added in experimental culture, and at 37 DEG C
Incubation 120 hours in dark.Inoculate latter 24 hours, the scalar dosage of formula (I) compound and antitumor agent is added in culture medium.
Test by two parts of referrals: use simultaneously (by two kinds of medicament administrations in cell 72/120 hour) and continuous administration (
Within after using other medicaments 24 hours, use described formula (I) compound).Drug solution faces with now joining.At the end for the treatment of, by making
System (CellTiterGlo-Promega) is monitored by the intracellular adenosine triphosphate of Envision (PerkinElmer) reader
Measure cell proliferation.Use test probe (Assay Explorer) (MDL) program comparison therapy data and contrasting data
Evaluate inhibitory activity.S-shaped interpolation curve is used to calculate the dosage of suppression 50% cell growth.Based on mutually without exclusiveness medicine
Chou-Talalay equation (Adv Enzyme Regul 1984；22:27-55), use multiple medicine function analysis is special
Having computer program to calculate association index (C.I.), wherein C.I. ＜ 1 shows to be better than summation action；C.I.:＞ the last 3 antagonism is made
With；1.3-3 antagonism；1.2-0.8 summation action；0.8-0.3 synergism；＜ the last 0.3 synergism.
Embodiment 1: formula (I) compound and the cell in vitro neurotoxin active of gemcitabine combination.
The result showing formula (I) compound and gemcitabine synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 1 is
The report of Capan-1 human pancreatic cancer cell.
Table 1
Embodiment 2: formula (I) compound and the cell in vitro neurotoxin active of cisplatin combination.
The result showing formula (I) compound and cisplatin synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 2 is HCT-116 people
The report of colon carcinoma cell line.
Table 2
Embodiment 3: formula (I) compound and the cell in vitro neurotoxin active of SN-38 combination.
The result showing formula (I) compound and SN-38 synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 3 is HCT-116
The report of CCL188.
Table 3
Embodiment 4: formula (I) compound and the cell in vitro neurotoxin active of doxorubicin combination.
The result showing the synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) of formula (I) compound and doxorubicin in table 4 is HL-
The report of 60 human leukemia cell lines.
Table 4
Embodiment 5: formula (I) compound and the cell in vitro neurotoxin active of Paclitaxel combinations.
The result showing formula (I) compound and paclitaxel synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 5 is HCT-116
Human colon carcinoma, HL60 human leukemia and the report of KMS11 people's multiple myeloma cell line.
Table 5
Embodiment 6: formula (I) compound and the cell in vitro neurotoxin active of Sorafenib combination.
The result showing formula (I) compound and Sorafenib synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 6 is HCT-
116 human colon carcinomas and the report of Mia-PaCa human pancreatic cancer cell.
Table 6
Embodiment 7: formula (I) compound and the cell in vitro neurotoxin active of Dasatinib combination.
Table 7 shows formula (I) compound and Dasatinib synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) result for
The report of the MCF7 breast cancer cell line after treatment in 120 hours.
Table 7
Embodiment 8: formula (I) compound and the cell in vitro neurotoxin active of bortezomib combination.
The result showing formula (I) compound and bortezomib synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) in table 8 is KMS11
People's multiple myeloma and the report of Mia-PaCa human pancreatic cancer cell.
Table 8
Embodiment 9: formula (I) compound and the cell in vitro neurotoxin active of cytosine arabinoside combination.
The result showing the synergism (i.e. 0.3 ＜ C.I. ＜ 0.8) of formula (I) compound and cytosine arabinoside in table 9 is HL-
The report of 60 human promyelocytic leukemia cell lines.
Table 9
Embodiment 10: formula (I) compound and the cells in vivo neurotoxin active of CPT11 combination.
According to Council of the European Communities's directive/guide (European Communities Council Directive) the 86/th
No. 609/EEC, by being placed in purchased from the Balb Male nude mice of Harlan (Italy), there is sterilized paper filter cover (paper
Filter cover), in the cage of food and bedding and padding and acidifying water.
It is subcutaneously implanted HT29 human colon carcinoma tumor fragment.Treatment is started when tumor tangibly.By oral route by formula
(I) compound is used at the 2nd, 3,4,6,7 and 8 days with the dosage of every day 45 and 60mg/kg.By intravenous route by CPT11
Use at the 1st, 5,9 days with the dosage of 45mg/kg.During combination, formula (I) compound was used at the 2nd, 3,4,6,7 and 8 days, and
And CPT11 used at the 1st, 5,9 days.Within every 3 days, measure tumor growth and body weight.Tumor growth is assessed by caliper.Record two
Bar diameter and according to following equation calculate tumor weight: length (mm) x width2/2.The evaluation of effect of antineoplaston is for prolonging
The generation of the late exponential growth of tumor (see document Anticancer drugs 7:437-60,1996).This delay (T-C
Value) it is defined as the difference of time (unit: sky) required for the size (1g) that the tumor for the treatment of group (T) and matched group (C) reaches predetermined
Different.It is accredited as synergism when the T-C value that T-C value is the mono-medicine of ＞ of drug regimen is added.
Toxicity is evaluated based on losing weight.Table 10 reports this result.
Table 10
*Oral medication is carried out at 2,3,4,6,7,8 days
**Treated by intravenous route at 1,5,9 days
***At 2,3,4,6,7,8 days with formula (I) compounds for treating；Treated with CPT11 at 1,5,9 days
Clear and definite synergism is created with formula (I) compound of CPT11 combination.When formula (I) compound combines with CPT11
Viewed T-C is simply added more than the intended T-C obtained by single therapy.Any one treatment group is not the most seen
Observe toxicity.
Embodiment 11: formula (I) compound and the cells in vivo neurotoxin active of 5FU combination.
According to Council of the European Communities's directive/guide the 86/609/EECth, will be male purchased from the Balb of Harlan (Italy)
Nude mouse is placed in the cage with sterilized paper filter cover, food and bedding and padding and acidifying water.It is subcutaneously implanted HT29 people's colon
Tumor fragment.Treatment is started when tumor tangibly.By oral route by formula (I) compound with the agent of 45mg/kg every day
Amount was used at the 2nd, 3,4,6,7 and 8 days.By intravenous route, 5FU is used at the 1st, 5 and 9 days with the dosage of 50mg/kg.
During combination, formula (I) compound was used at the 2nd, 3,4,6,7 and 8 days, and 5FU used at the 1st, 5 and 9 days.Within every 3 days, measure
Tumor growth and body weight.Tumor growth is assessed by caliper.Record two diameters and calculate tumor weight according to following equation
Amount: length (mm) x width2/2.The evaluation of effect of antineoplaston is that the generation of the exponential growth postponing tumor (sees document
Anticancer drugs 7:437-60,1996).This delay (T-C value) is defined as the swollen for the treatment of group (T) and matched group (C)
Tumor reaches the difference of time (unit: sky) required for predetermined size (1g).The T-C that T-C value is the mono-medicine of ＞ when drug regimen
Value is accredited as synergism when being added, and is accredited as summation action when the T-C value of drug regimen is added equal to the T-C value of single medicine.
Toxicity is evaluated based on losing weight.Table 11 reports this result.
Table 11
*Oral medication is carried out at 2,3,4,6,7,8 days
**Treated by intravenous route at 1,5,9 days
***At 2,3,4,6,7,8 days with formula (I) compounds for treating；Treated with 5FU at 1,5,9 days
When formula (I) compound combines with 5FU, viewed T-C is simple with the intended T-C obtained by single therapy
It is added similar, prompts for summation action.
Embodiment 12: formula (I) compound and the cells in vivo neurotoxin active of Avastin combination.
According to Council of the European Communities's directive/guide the 86/609/EECth, will be male purchased from the Balb of Harlan (Italy)
Nude mouse is placed in the cage with sterilized paper filter cover, food and bedding and padding and acidifying water.
It is subcutaneously implanted HT29 human colon carcinoma tumor fragment.Treatment is started when tumor tangibly.By oral route by formula
(I) compound was used at the 2nd, 3,4,6,7,8,10,11 and 12 days with the dosage of every day 45 and 60mg/kg by 10ml/kg volume.
By intraperitoneal routes, Avastin is used at the 1st, 5,9 and 13 days with the dosage of 20mg/kg.During combination, formula (I) is changed
Compound was used at the 2nd, 3,4,6,7,8,10,11 and 12 days, and Avastin was used at the 1st, 5,9 and 13 days.Within every 3 days, survey
Amount tumor growth and body weight.Tumor growth is assessed by caliper.Record two diameters and calculate tumor according to following equation
Weight: length (mm) x width2/2.The evaluation of effect of antineoplaston is that the generation of the exponential growth postponing tumor (sees document
Anticancer drugs 7:437-60,1996).This delay (T-C value) is defined as the swollen for the treatment of group (T) and matched group (C)
Tumor reaches the difference of time (unit: sky) required for predetermined size (1g).The T-C that T-C value is the mono-medicine of ＞ when drug regimen
Value is accredited as synergism when being added, and is accredited as summation action when the T-C value of drug regimen is added equal to the T-C value of single medicine.
Toxicity is evaluated based on losing weight.Table 12 reports this result.
Table 12
*Oral medication is carried out at 2,3,4,6,7,8,10,11,12 days.
**Treated by intravenous route at 1,5,9,13 days.
***At 2,3,4,6,7,8,10,11,12 days with formula (I) compounds for treating, used Avastin at 1,5,9,13 days
Treatment.
Viewed T-C is obtained by single therapy with intended when formula (I) compound combines with Avastin
T-C is simply added similar.Toxicity is not the most observed in any one treatment group.
Embodiment 13: formula (I) compound and the cells in vivo neurotoxin active of cytosine arabinoside combination.
According to Council of the European Communities's directive/guide the 86/609/EECth, will be female from the SCID of Harlan (Italy)
Mice is placed in the cage with sterilized paper filter cover, food and bedding and padding and acidifying water.0.2ml is injected in mouse vein
Containing 5x106AML-PS acute myeloid leukemia cells.
By oral route by formula (I) compound with the dosage of 120mg/kg at the 2nd, 3,14,15,26,27,38,39 days
Use.By intraperitoneal routes by cytosine arabinoside with the dosage of 75mg/kg the 2nd, 3,4,5,6,14,15,16,17,18,26,
27, within 28,29,30,38,39,40,41,42 days, use.During combination, by formula (I) compound the 2nd, 3,14,15,26,27,38,
Within 39 days, use, and cytosine arabinoside the 2nd, 3,4,5,6,14,15,16,17,18,26,27,28,29,30,38,39,40,41,
Within 42 days, use.Within every 3 days, measure body weight.Measure treatment animal and evaluate antineoplaston relative to the mean survival time of matched group
Effect.Table 13 reports this result.
Combination group has significance statistically relative to the antitumor efficacy of single therapy group, points out formula (I) chemical combination
The therapeutic alliance of thing and cytosine arabinoside has potential synergism.Do not observe toxicity.
Table 13
*Oral medication is carried out at 2,3,14,15,26,27,38,39 days,
**Intraperitoneal is passed through at 2,3,4,5,6,14,15,16,17,18,26,27,28,29,30,38,39,40,41,42 days
Approach is treated.
***Carried out oral medication at 2,3,14,15,26,27,38,39 days with formula (I) compound, 2,3,4,5,6,14,
15, within 16,17,18,26,27,28,29,30,38,39,40,41,42 days, intraperitoneal routes treatment is carried out with cytosine arabinoside.
Claims (7)
1. a combination preparation, it comprises (a) formula (I) compound
(b) one or more antitumor agents, described antitumor agent selected from gemcitabine, cytosine arabinoside, cisplatin, SN-38,
CPT11, doxorubicin, paclitaxel, Sorafenib, Dasatinib and bortezomib, the active component of wherein said combination preparation
The most in a free form or presented in its pharmaceutically-acceptable salts or any hydrate.
2. a pharmaceutical composition, its comprise mix with pharmaceutically acceptable carrier, diluent or excipient according to right
Require the combination preparation described in 1.
Combination preparation the most according to claim 1 or pharmaceutical composition according to claim 2, the while of being used for,
Single or continuous print uses.
4. a commercial kit, it is included in the group as defined in claim 1 in a suitable case
Close preparation or pharmaceutical composition, for it while, single or continuous print use as defined in claim 2.
Combination preparation the most according to claim 1 or pharmaceutical composition according to claim 2 are in prepared by medicine
Purposes, described medicine is used for treating or postponing proliferative disorders.
Combination preparation the most according to claim 1 or pharmaceutical composition according to claim 2 are in prepared by medicine
Purposes, described medicine is used for reducing side effect, described side effect be by use antitumor agent antineoplaston feed
Breast animal causes.
Purposes the most according to claim 6, wherein mammal is the mankind.
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| EP09161111 | 2009-05-26 | ||
| EP09161111.1 | 2009-05-26 | ||
| PCT/EP2010/057027 WO2010136394A1 (en) | 2009-05-26 | 2010-05-21 | Therapeutic combination comprising a plk1 inhibitor and an antineoplastic agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826343A (en) * | 2003-05-22 | 2006-08-30 | 法玛西雅意大利公司 | Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
| WO2008074788A1 (en) * | 2006-12-21 | 2008-06-26 | Nerviano Medical Sciences S.R.L. | Substituted pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826343A (en) * | 2003-05-22 | 2006-08-30 | 法玛西雅意大利公司 | Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
| WO2008074788A1 (en) * | 2006-12-21 | 2008-06-26 | Nerviano Medical Sciences S.R.L. | Substituted pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
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