ACTIVITY ENHANCER FOR ANTICANCER AGENT
|Posted date||Apr 26, 2013|
|International application number||2012JP056186|
|International publication number||WO 2012124641|
|Date of international filing||Mar 9, 2012|
|Date of international publication||Sep 20, 2012|
|Title||ACTIVITY ENHANCER FOR ANTICANCER AGENT|
|Abstract||Provided is an activity enhancer for an anticancer agent, containing, as an active ingredient, a D-amino acid residue-containing FNIII14 polypeptide, which is a polypeptide FNIII14 having an amino acid sequence represented by sequence No. 1, in which at least one of the amino acid residues at positions 1 to 13 is a D-amino acid residue. Also provided is an anticancer composition containing an anticancer agent and the activity enhancer for an anticancer agent.|
|Outline of related art and contending technology||
Chemotherapy, tumor development in the current medical treatment of cancer may still occupy an important position. In particular, in the treatment of leukemia which is adjacent to the center of the chemotherapy, the solid cancer is higher than the therapeutic effect is obtained. In particular acute myeloid leukemia (AML) cells, a cell showing a high drug sensitivity is known. For this reason, an acute myeloid leukemia therapy as a treatment for induction of remission in a case, the number of cases of complete remission and about 80%. However, recurrence is often long-term survival in has to be in 30% -40%. Complete remission after chemotherapy the patient's remaining bone marrow relapse of leukemia cells remaining in the minute are considered to be the cause of. Peripheral blood in body fluids/non-adhesive state leukemia cells were, killed by the anticancer agent is relatively efficiently. On the other hand, is of leukemic cells in bone marrow, extracellular matrix (such as fibronectin (FN) or bone marrow stromal cells) to, adhesion molecules (for example integrin) and via an adhesive, and thereby render the bacteria resistant to an anticancer agent, chemotherapy remain after having minute also known. This phenomenon is, drug resistance (CAM-DR) bond dependant referred to, to be overcome in leukemia of an anticancer therapy is one of the most important issues.
Fibronectin is involved in cell adhesion or the detachable, a typical one of the extracellular matrix protein molecule, distributed in nearly all tissues, the role of the tissue as well as serving as a frame building, is bonded to the adhesion molecules on the cell membrane, for regulation of the cell function also function as signaling molecules. A polypeptide molecule is fibronectin, type I, type II, type III is constituted from a repeating sequence. Among them, fibronectin type III-like repeats (FN), is (FNIII), known a variety of functions.
For example, is FNIII, cell adhesion inhibitory activity (for example, JP-10-147600 and Japanese Patent Application No. JP-2000-26490, reference) are known to have. JP-10-147600 describes, the effect of limiting the possibilities for the metastasis of cancer is referred to, the description of Examples is not. In addition, based on the activity of inducing tumor cell death FNIII enhancing effect has anti-cancer activity, International Publication No. 01/08698 are disclosed. However, International Publication No. 01/08698 in vitro by Example is only the test results and, to the efficacy of in vivo has not been investigated, such as stability in blood completely unknown.
Further, is described in International Publication No. 01/08698, disclosed in vitro test for only, does not disclose the effect of in vivo, therefore, based on the activity of inducing tumor cell death FNIII of enhanced intensified a practical one for anti-cancer activity can not be determined. Specifically International Publication No. 01/08698 1 - to 8 is described in which Fig. FIG., with respect to the number of cancer cells, and vincristine or actinomycin D, a polypeptide represented by SEQ ID NO:2 examined the mixing effect, the effect of addition in Fig. 1, 2, 3, 4 and 8 about or at most 30%, at a concentration effect as Fig. 2 and inversion or, practical promising data is not shown. 5 And 7 in Fig. the addition effect of the drug is shown, since it is not concentration-dependent effect of the drug itself, cannot be determined to be effective. As shown in Fig. 6 only, in the case of using cancer cells derived from GT3TKB, with respect to the vincristine, in the polypeptide shown in SEQ ID NO:2 there is a tendency that the effect of the addition of. In this way, actually take into consideration the use in a medical field and, in the polypeptide set forth in SEQ ID NO:2, of a specific cancer type and the particular agent and the effect of added only to, all of the medicament to enhance the effect of this polypeptide is not considered. Further, the polypeptide shown in SEQ ID NO:2, of an anticancer agent, different mechanism of action of the pyrimidine metabolism antagonist, such as the effect of the cytarabine has not been shown.
JP-2006-327980 describes, in experimental animals FNIII-like peptide in combination with leukemia therapeutic agent aiming at a remission of mice described in the embodiments. However, the concentration of the embodiment and 1 mg FNIII-like peptide, at a lower concentration effect is not confirmed. In addition, both of which are hereby Leukemia (2008), Vol.22,353-360 JP 2006-327980 in similar experiments is reported, even modified FNIII-like peptide, not being biologically active improved shown.
Such chemical modifications with respect to some reports. Is described in JP-2010-043087, the native E. coli HBHA (E.Coli) may be produced in genetic recombination of the, mycobacteria HBHA is produced physiologically active is different, methylated lysine C-terminus of the original can be reproduced in the physiological activity of and reported. This is because, in methylating activity inherent in a low-pass filter can be a recoverer, intrinsically has the effects of biologically active or more was not. Is described in JP-6-73093, ' does not have the opioid analgesic dependence, resistance or the like to solve drawbacks' in, as the amino acid D Trp, His, Phe is introduced will such as have been reported. However, as described in JP-6-73093 and as, stability and activity of the compound to attain an improvement of an image is not. In addition, the use of the amino acid D, generally for not recognized by the protease, will not experience what degradation, also changes the conformation of the peptide obtained, failing in maintaining the physiological activity is estimated. Biochem Pharmacol. 1999 Dec 1; 58 (11): in 1775-80, one end of the end N D C changed to 2 amino acid residues, in increasing the stability of the enzyme-treated serum reported but, had high physiological activity. Neuropeptides. 1984 Dec; 5 (1-3): in 177-80, an opioid peptide group, for example enkephalin (Tyr-Gly-Gly-Phe-Leu) Tyr-D-Ala-Gly-Phe-Leu 2 of modified amino acids may be substituted, a higher activity did not is reported.
|Scope of claims||
(In Japanese)請求の範囲 [請求項1]
|IPC(International Patent Classification)||
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
Contact Information for " ACTIVITY ENHANCER FOR ANTICANCER AGENT "
- Tokyo University of Science University Research Administration Center
- URL: https://www.tus.ac.jp/ura/
- Address: 1-3 kagurazaka, Shinjuku-ku, Tokyo, Japan , 162-8601
- Phone: 81-3-5228-7431
- Fax: 03-5228-7442