NZ751051B2 - Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit - Google Patents
Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit Download PDFInfo
- Publication number
- NZ751051B2 NZ751051B2 NZ751051A NZ75105117A NZ751051B2 NZ 751051 B2 NZ751051 B2 NZ 751051B2 NZ 751051 A NZ751051 A NZ 751051A NZ 75105117 A NZ75105117 A NZ 75105117A NZ 751051 B2 NZ751051 B2 NZ 751051B2
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- NZ
- New Zealand
- Prior art keywords
- paclitaxel
- tumor
- salt
- compound
- cytosine
- Prior art date
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Abstract
The present invention provides the use of paclitaxel and 1-(2-deoxy-2-fluoro-4-thio-?-D-arabinofuranosyl)cytosine or methanesulfonate thereof in the manufacture of medicaments for treating pancreatic cancer, wherein the medicaments are to be co-administered, wherein the amount of the 1-(2-deoxy-2-fluoro-4-thio-?-D-arabinofuranosyl)cytosine or methanesulfonate thereof used is 0.01 to 100-fold molar amount of the paclitaxel, and wherein the paclitaxel is an albumin-bound paclitaxel injection suspension of nanoparticle preparation encapsulating paclitaxel with albumin (nab-paclitaxel). uoro-4-thio-?-D-arabinofuranosyl)cytosine or methanesulfonate thereof used is 0.01 to 100-fold molar amount of the paclitaxel, and wherein the paclitaxel is an albumin-bound paclitaxel injection suspension of nanoparticle preparation encapsulating paclitaxel with albumin (nab-paclitaxel).
Description
ANTI-TUMORAGENT, ANTI-TUMOR EFFECT ENHANCER, AND ANTI-TUMOR Field of the Invention The present ion relates to an anti-tumor agent, an anti—tumor effect enhancer, and an anti-tumor kit.
Description of the Related Art It is known that 1-(2-deoxyfluorothio-[3-D-arabinofuranosyl)cytosine (hereinafter, mes referred to as "Compound A") has excellent anti—tumor activity and is therefore useful as an anti—tumor agent (Patent Documents 1 and 2). It is also known that Compound A has potent umor activity also in the case of oral administration thereof to mice (Non-Patent Documents 1 and 2). A salt of Compound A and a method for producing the same are also known (Patent Documents 2 to 4).
In chemotherapy of malignant tumors, —based anti—tumor agents such as paclitaxel and nab-paclitaxel are also used as useful drugs. However, it is known that the response rate to tumor with a taxane—based anti-tumor agent alone is as low as 10% to 25%, and the al period of cancer patients is short (survival period of 12 to 15 months) (Non—Patent Document 3).
In a al setting, a multidrug combination therapy has been carried out for the purpose of compensating for differences in susceptibility of each anti—tumor agent to tumor and of enhancing the drug efficacy, and a medicine ing paclitaxel and other drugs is also known (Patent Document 5). For example, combination use of gemcitabine and nab-paclitaxel to pancreatic cancer ts has a response rate of 23% and a median survival period of 8.5 months (Non—Patent Document 4), which cannot be said that the therapeutic effect is sufficiently high.
Prior Art Documents Patent Documents Patent Document 1: W01997/038001A Patent Document 2: W02013/146833A Patent Document 3: W02011/074484A Patent Document 4: WO2014/027658A Patent Document 5: WO2013/100014A tent Documents tent nt 1: Cancer Letters, 1999, Vol. 144, pp. 177 to 182 Non-Patent nt 2: Oncology Reports, 2002, Vol. 9, pp. 1319 to 1322 Non—Patent Document 3: Journal of Clinical Oncology, 2005, Vol. 23, pp. 7794 to 7803 Non—Patent Document 4: New England Journal of Medicine, 2013, Vol. 369, pp. 1691 to 1703 SUMMARY OF THE INVENTION In recent years, a combination therapy has been widely d out rather than administering an anti—tumor agent alone. However, it is completely unknown whether any anti-tumor effect will be enhanced or the effect will be offset in the case Where any anti-tumor agents are used in combination.
An object of the present invention is to provide an anti-tumor agent and an anti-tumor kit which have superior anti—tumor effect as compared with a therapy with gemcitabine, paclitaxel or a combination thereof; as well as an anti-tumor effect enhancer.
In View of the above, the present inventors have studied combination use of various drugs, and as a , have found that combination use of paclitaxel and Compound A exhibits significant anti-tumor effect. The present invention has been completed based on these findings.
That is, the present invention provides the following. (1) An anti—tumor agent comprising paclitaxel or a salt thereof and l—(2-deoxyfluorothio—B-D—arabinofuranosyl)cytosine or a salt or prodrug thereof. (2) The anti-tumor agent according to (1), in which the amount of the 1-(2-deoxyfluorothio-B-D-arabinofi1ranosy1)cytosine or the salt or prodrug thereof used is 0.01 to 100—fold molar amount of the axel or the salt f. (3) The anti—tumor agent according to (1) or (2), in which the anti-tumor agent is for pancreatic cancer. (4) The anti-tumor agent according to any one of (1) to (3), in which the paclitaxel is a nanoparticle containing paclitaxel and albumin. (5) The anti—tumor agent according to any one of (1) to (4), in which the paclitaxel is nab-paclitaxel. (6) An anti-tumor effect er, comprising 1-(2-deoxy—2~fluorothio-B-D-arabinofuranosyl)cytosine or a salt or prodrug thereof to be used in combination with paclitaxel or a salt thereof. (7) An anti-tumor kit comprising a preparation containing paclitaxel or a salt f and a preparation containing l-(2-deoxy—2—flu0rothio-|3-D-arabinofuranosyl)cytosine or a salt or prodrug thereof. (8) An anti—tumor agent comprising 1-(2-deoxy—2-fluorothio—[3-D-arabinofuranosy1)cytosine or a salt or prodrug thereof to be used in combination with paclitaxel or a salt thereof. (6-1) The umor effect enhancer according to (6), in which the paclitaxel is a nanoparticle containing paclitaxel and albumin. (6-2) The anti-tumor effect enhancer according to (6) or (6—1), in which the paclitaxel is nab-paclitaxel. (7-1) The anti-tumor kit according to (7), in which the paclitaxel is a nanoparticle containing axel and albumin. (7-2) The umor kit according to (7) or (7-1), in which the paclitaxel is nab-paclitaxel. (8-1) The anti—tumor agent according to (8), in which the paclitaxel is a nanoparticle containing paclitaxel and albumin. (8—2) The anti-tumor agent according to (8) or (8-1), in which the paclitaxel is nab-paclitaxel. (9) A method for use of paclitaxel or a salt thereof and 1-(2—deoxy—2—fluoro—4—thio—B—D—arabinofuranosyl)cytosine or a salt or prodrug f in the treatment of a tumor, preferably the treatment of pancreatic cancer, comprising a step of administering a therapeutically effective dose thereof to a subject (a mammal including a human) in need of such treatment. (10) A method for treating a tumor, characterized in that a therapeutically ive dose of l-(2-deoxy—2—fluorothio-[3-D-arabinofi1ranosyl)cytosine or a salt or prodrug thereof in the case of being used in combination therapy and a therapeutically ive dose of paclitaxel or a salt thereof in the case of being used in combination therapy are administered in ation to a t. (11) A method for treating a tumor, characterized in that a therapeutically ive dose of l—(2-deoxy—2-fluorothio-B-D-arabinofuranosyl)cytosine or a salt or prodrug thereof in the case of being used in combination therapy and a therapeutically effective dose of paclitaxel or a salt thereof in the case of being used in combination therapy are administered to a subject aneously, separately, sequentially, or at intervals. (12) Use of 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or a salt or prodrug thereof for the production of an anti-tumor agent in combination with paclitaxel or a salt thereof. (13) Use of 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or a salt or prodrug thereof for an anti-tumor agent in combination with paclitaxel or a salt thereof. (14) 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or a salt or prodrug thereof for treating a tumor by administration thereof as a single dosage form with axel or a salt thereof or as a dosage form separate from paclitaxel or a salt thereof.
Compound A or a salt or prodrug thereof exhibits significant anti-tumor effect in the case of being used in combination with paclitaxel. That is, the anti-tumor agent and anti-tumor kit of the present invention have or tumor regression and tumor growth inhibitory s as ed with gemcitabine alone, axel alone, or a combination of gemcitabine and paclitaxel. The anti-tumor effect enhancer of the present invention can be administered in combination with paclitaxel or a salt thereof to enhance anti-tumor effect.
In a particular aspect, the present ion provides use of paclitaxel; and 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or methanesulfonate thereof in the manufacture of medicaments for treating pancreatic cancer, wherein the amount of the 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or methanesulfonate thereof used is 0.01 to 100-fold molar amount of the paclitaxel, and wherein the paclitaxel is an albumin-bound paclitaxel injection suspension of nanoparticle preparation encapsulating paclitaxel with albumin (nab-paclitaxel), wherein the medicaments are to be stered in combination therapy with each other.
BRIEF DESCRIPTION OF THE GS Fig. 1 is a graph showing the transition of tumor volume in a human pancreatic cancer cell line Capan-1 subcutaneously implanted tumor-bearing model mouse.
Fig. 2 is a graph showing the transition of body weight in a human pancreatic cancer cell line Capan-1 subcutaneously implanted tumor-bearing model mouse.
Fig. 3 is a graph g a combinational effect of inhibiting tumor growth in a human pancreatic cancer cell line Capan-1 aneously implanted tumor-bearing model mouse.
[FOLLOWED BY PAGE 4a] DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, the numerical value represented by "%" is based on the mass unless otherwise stated. In on, the range expressed by "to" includes the values at both ends unless otherwise stated.
The term "subject" is a mammal such as a human, a mouse, a monkey, or a livestock in need of prevention or ent thereof, preferably a human in need of prevention or treatment thereof.
The term "preventing" refers to inhibition of disease onset, reduction of disease onset risk, or delay of disease onset.
The term "treating" refers to ement of, or inhibition (maintenance or delay) of [FOLLOWED BY PAGE 5] progression of a target disease or ion.
The term "treatment" refers to preventing, treating, or the like of a variety of diseases.
The term "tumor" refers to a benign tumor or a malignant tumor.
The term "benign tumor" refers to a tumor in which a tumor cell and a sequence thereof take a form close to a normal cell from which such a tumor cell is derived, and which is free of invasiveness or metastatic properties.
The term "malignant tumor" refers to a tumor in which the morphology and sequence of a tumor cell are different from a normal cell from which such a tumor cell is derived, and which exhibits invasiveness or metastatic properties.
Hereinafter, the present ion will be described in detail.
The present invention relates to an anti—tumor agent including paclitaxel or a pharmaceutically acceptable salt thereof (hereinafter, sometimes ed to as a "salt thereof") and 1-(2-deoxyfluoro-4—thio-B-D—arabinofuranosyl)cytosine (Compound A) or a salt or prodrug thereof. Further, the present invention also relates to an anti-tumor agent including paclitaxel or a salt thereof in combination with Compound A or a salt or prodrug thereof.
First, Compound A or a salt or g thereof will be described.
The salt may be, for example, a pharrnaceutically acceptable salt and specific examples thereof include a l acid salt, an organic carboxylate, and a sulfonate.
Preferred examples of the salt include a mineral acid salt and a sulfonate.
Examples of the mineral acid salt include hloride, hydrobromide, hydroiodide, e, phosphate, and sulfate, among which hydrochloride, hydroiodide, nitrate, or sulfate is preferable, and hydrochloride is more preferable. Examples of the organic carboxylate e formate, e, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate, and trifluoroacetate. es of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate, among which methanesulfonate is preferable.
The salt of Compound A may be an anhydride, a hydrate, or a solvate. In the case where the term "salt" is simply used in the t specification, it may be in the form of anhydride, hydrate, or solvate. As for the term "anhydride" used in the present specification, it refers to the salt in a state where it is not a hydrate or a solvate, unless ise stated.
Even though it is a substance which ally does not form a hydrate or a solvate, the salt of nd A which does not have crystallization water, hydration water and an interacting t is also included in the "anhydride" referred to in the present invention. Anhydride may also be referred to as "anhydrate". In the case where the salt of nd A is a hydrate, the molecular number of hydration water is not particularly limited, and the hydrate may be a monohydrate, a dihydrate, or the like. Examples of the solvate include methanol solvate, ethanol solvate, propanol solvate, and anol solvate.
Particularly preferred specific examples of Compound A are as follows: methanesulfonate of 1-(2-deoxy—2-fluorothio—B-D—arabinofuranosyl)cytosine; hydrochloride of 1-(2-deoxy—2-fluoro-4—thio-B-D-arabinofuranosyl)cytosine; 1/2 sulfate of l-(2-deoxy—2-fluoro-4—thio-B-D—arabinofuranosyl)cytosine; nitrate of eoxy—2-fluoro—4—thio—B—D—arabinofuranosyl)cytosine; and hydroiodide of 1-(2-deoxy—2—fluorothio-[3-D-arabinofuranosyl)cytosine; as well as anhydrides of the foregoing salts.
The prodrug refers to a compound or a salt f which is ted into a compound exhibiting a desired cological activity, following ge of a functional group functioning as a prodrug by a reaction with an enzyme, gastric juice, or the like in the body after administration f.
Examples of groups forming a prodrug include the groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Scientists.
The prodrug of Compound A refers to a compound or a salt thereof which converts into Compound A or a phosphate compound thereof by a reaction with an enzyme, gastric juice, or the like under physiological conditions in Vivo.
As to the prodrug of Compound A, the description of WO2016/068341A, the contents of which are incorporated , can be incorporated and referred to.
More specifically, for example, a thionucleoside derivative represented by l Formula [1] or a salt thereof described in W02016/O68341A is incorporated herein, and a preferred range thereof is also the same as that described in W02016/068341A.
In the tinvention, Compound A or a salt or prodrug thereof may be used alone or in combination of two or more thereof.
Next, a method for producing Compound A or a salt or g thereof will be described. Compound A can be produced, for example, by the method described in W01997/038001A or Journal of Organic Chemistry, 1999, V01. 64, pp. 7912 to 7920. The salt of Compound A or a hydrate or solvate thereof can be produced, for e, by the method described in W02014/027658A. The prodrug of nd A can be produced, for example, by the method described in WO2016/068341A.
Compound A or a salt or prodrug thereof according to the present invention can be used as an anti-tumor agent or as an active ingredient of a pharmaceutical composition.
In the present invention, axel or a salt thereof may be used alone or in combination of two or more thereof. Paclitaxel or a salt thereof may be a composition containing them, in on to paclitaxel or a salt thereof.
The salt may be, for example, a pharrnaceutically acceptable salt and specific examples f include salts in commonly known basic groups such as amino group, and salts in commonly known acidic groups such as hydroxyl group and carboxyl group.
Examples of salts in basic groups e salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, oroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylene sulfonic acid, and naphthalene sulfonic acid.
Examples of salts in acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen—containing organic bases such as trimethylamine, triethylamine, ylamine, pyridine, N,N-dimethylaniline, N—methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N—benzyl—B-phenethylamine, 1- mine, and N,N’ -dibenzy1ethylenediamine.
Examples of the ition containing paclitaxel or a salt thereof include a nanoparticle containing paclitaxel and albumin rably human serum albumin) (albumin-bound paclitaxel injection suspension of rticle preparation encapsulating paclitaxel with albumin (nab-paclitaxel, trade name "Abraxane")); a polymeric micelle (NK 105) in which paclitaxel is encapsulated in a block mer of polyethylene glycol and polyaspartic acid; a prodrug in which fatty acid docosahexaenoic acid (DHA) is conjugated to paclitaxel (Taxoprexin); a g in which polyglutamic acid is conjugated to paclitaxel (trade name "Opaxio"); and a prodrug in which a monoclonal antibody targeting a tumor cell is conjugated to paclitaxel.
Paclitaxel is preferably a nanoparticle containing paclitaxel and n and more preferably nab-paclitaxel.
Compound A is an anti—tumor agent having an excellent DNA synthesis inhibitory effect. In the case where Compound A is used in combination with paclitaxel, it is expected that such a combination will have an effect of enhancing the anti-tumor effect of paclitaxel without showing significant exacerbation of toxicity.
(Anti—tumor agent) According to the present invention, provided are an anti-tumor agent ing paclitaxel or a salt thereof and 1-(2-deoxy—2-fluorothio-B-D-arabinofuranosyl)cytosine or a salt or prodrug thereof; and an anti-tumor agent ing 1—(2—deoxyfluoro-4—thio-B-D—arabinofuranosy1)cytosine or a salt or prodrug f to be used in combination with paclitaxel or a salt thereof.
Typically, the anti-tumor agent of the embodiment of the present ion may contain additives such as an excipient, a binder, a lubricant, a disintegrant, a coloring agent, a flavoring agent, an fier, a surfactant, a solubilizing agent, a suspending agent, a ty agent, a buffering agent, a preservative, an antioxidant, a stabilizer, and an absorption er, which have been used in the formulation.
The anti-tumor agent of the embodiment of the present invention including paclitaxel or a salt thereof and Compound A or a salt or prodrug thereof may be a single dosage form containing paclitaxel or a salt f and Compound A or a salt or g thereof, or may be a binary dosage form containing paclitaxel or a salt thereof and Compound A or a salt or prodrug thereof. Preferably, the anti—tumor agent of the embodiment of the present invention is a binary dosage form in which paclitaxel or a salt thereof and nd A or a salt or prodrug f are separately formulated.
In the case where paclitaxel or a salt thereof and Compound A or a salt or prodrug thereof are used as separate preparations, dual preparations can be administered to a subject simultaneously, separately, sequentially, or at intervals. In addition, the means for administering a composition containing paclitaxel and the means for administering a composition containing Compound A may be the same or different (for example, oral administration and injection).
The route of administration of the anti—tumor agent of the embodiment of the present ion may be, for example, a method such as intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, ermal administration and/or through suppositories.
Parenteral administration is preferred as the route of administration. For e, enous injection venous on) such as drip infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection and/or intrathecal injection can be mentioned as the parenteral administration. The method of administration includes administration by syringe or drip on.
The dose or blending amount of paclitaxel or a salt thereof and Compound A or a salt or prodrug thereof contained in the anti—tumor agent of the ment of the present invention is not particularly limited as long as it exerts an effect of enhancing the anti—tumor effect, but Compound A or a salt or prodrug thereof may be used in an amount of 0.01 to 100 mol, preferably 0.1 to 50 mol, and more preferably 1 to 40 mol per 1 mol of paclitaxel.
With respect to the dosage and administration frequency of paclitaxel or a salt thereof, for example, for an adult, for example a dose of 1 to 1000 day can be stered once or in l divided portions by oral or parenteral administration (for example, injection, drip infusion, or rectal administration).
With respect to the dosage and administration frequency of Compound A or a salt or prodrug thereof, a dose of l to 2000 mg/m2/day can be administered once or in several divided portions. However, it is not limited to these doses and administration frequencies.
Examples of dosage forms of the anti-tumor agent of the embodiment of the present invention include a tablet, a capsule, a powder, a syrup, a granule, a pill, a suspension, an emulsion, a solution, a itory, an eye drop, a nasal drop, an ear drop, a patch, an ointment, and an injection, among which an ion is preferred. Each of these dosage forms can be ed by a formulation method conventionally known to those skilled in the art.
The anti-tumor agent of the embodiment of the present invention can be effectively used for the treatment of various types of tumors including, for example, melanoma, liver cancer, glioma, neuroblastoma, sarcoma, and tumors of the lung, colon, breast, bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine and other organs. The anti-tumor agent of the embodiment of the present invention is preferably an antineoplastic agent, can be used as an ncer agent, and is particularly effective for the treatment of pancreatic cancer.
(Anti-tumor kit) The anti-tumor kit of the embodiment of the present invention is a kit ing a combination of (a) axel or a salt thereof and (b) Compound A or a salt or prodrug thereof.
In the kit, (a) paclitaxel or a salt thereof and (b) Compound A or a salt or prodrug thereof can each be in various known preparation forms, and depending on the preparation form, (a) and (b) are contained in various commonly used containers.
Further, in the kit, (a) paclitaxel or a salt thereof and (b) Compound A or a salt or prodrug thereof may be contained in separate containers or may be mixed and stored in the same container. It is preferred that (a) paclitaxel or a salt thereof and (b) Compound A or a salt or prodrug thereof are contained in separate containers.
(Anti—tumor effect enhancer) The anti-tumor effect enhancer of the embodiment of the present invention is an anti-tumor agent including 1-(2-deoxy—2-fluorothio-[3-D—arabinofiiranosyl)cytosine or a salt or prodrug thereof to be used in combination with paclitaxel or a salt thereof.
Typically, the anti—tumor effect enhancer of the embodiment of the present invention may contain additives such as an excipient, a binder, a lubricant, a disintegrant, a coloring agent, a flavoring agent, an emulsifier, a surfactant, a lizing agent, a suspending agent, a ty agent, a buffering agent, a preservative, an antioxidant, a stabilizer, and an absorption er, which have been used in the formulation.
The anti-tumor effect enhancer of the embodiment of the present invention can be administered to a subject simultaneously with, separately from, sequentially with, or at intervals with paclitaxel or a salt thereof.
Parenteral stration is preferred as the route of administration of the anti-tumor effect enhancer of the embodiment of the present invention. For example, intravenous injection (intravenous infusion) such as drip infusion, intramuscular injection, eritoneal injection, subcutaneous injection, intraocular injection and/or intrathecal ion can be mentioned as the parenteral administration. The method of administration includes administration by syringe or drip infusion.
The dose or ng amount of Compound A or a salt or prodrug thereof contained in the anti-tumor effect enhancer of the embodiment of the present ion is not particularly limited as long as it exerts an effect of enhancing the anti-tumor effect, but Compound A or a salt or g thereof may be used in an amount of 0.01 to 100 mol, preferably 0.1 to 50 mol, and more ably 1 to 40 mol per 1 mol of paclitaxel.
With respect to the dosage and stration ncy of Compound A or a salt or g thereof contained in the anti—tumor effect enhancer of the embodiment of the present invention, a dose of 1 to 2000 mg/mz/day can be administered once or in several divided portions. However, it is not d to these doses and administration frequencies.
The anti-tumor effect er of the embodiment of the present invention can be effectively used for the treatment of various types of tumors including, for example, melanoma, liver cancer, , neuroblastoma, sarcoma, and tumors of the lung, colon, , bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine and other organs. The umor effect enhancer of the embodiment of the present invention is preferably an oplastic effect enhancer, and is ularly effective for the treatment of pancreatic cancer.
The present invention provides a method for use of paclitaxel or- a salt thereof and eoxy—2-fluorothio-B—D—arabinofuranosy1)cytosine or a salt or prodrug thereof in the treatment of a tumor, preferably the treatment of pancreatic cancer, including a step of administering a therapeutically effective dose thereof to a subject (a mammal including a human) in need of such treatment.
Further, the present invention provides a method for treating a tumor, characterized in that a therapeutically effective dose of l-(2-deoxyfluoro—4—thio—[3—D—arabinofuranosyl)cytosine or a salt or prodrug f in the case of being used in combination therapy and a therapeutically effective dose of paclitaxel or a salt f in the case of being used in combination therapy are administered in ation to a subject.
Further, the present invention provides a method for ng a tumor, characterized in that a eutically effective dose of l-(2-deoxy—2-fluorothio-B-D—arabinofuranosyl)cytosine or a salt or prodrug thereof in the case of being used in combination therapy and a eutically effective dose of paclitaxel or a salt thereof in the case of being used in combination therapy are administered to a subject simultaneously, separately, sequentially, or at intervals.
Use of l—(2-deoxy—2-fluorothio-[3—D-arabinofuranosyl)cytosine or a salt or prodrug thereof can be made for the production of an anti-tumor agent in combination with paclitaxel or a salt thereof.
Use of l-(2-deoxy—2-fluorothio-[3-D-arabinofi1ranosy1)cytosine or a salt or prodrug thereof can be made for an anti-tumor agent in combination with paclitaxel or a salt thereof.
According to the present invention, it is possible to obtain l-(2-deoxy—2-fluorothio-[3-D-arabinofuranosyl)cytosine or a salt or prodrug thereof for treating a tumor by stration thereof as a single dosage form with paclitaxel or a salt thereof or as a dosage form separate from paclitaxel or a salt thereof.
Further, according to the present invention, it is possible to obtain an anti-tumor agent ing l-(2-deoxy-2—fluorothio-[3-D-arabinofuranosyl)cytosine or a salt or prodrug thereof, which is used in combination with paclitaxel or a salt thereof.
Hereinafter, the present invention will be described in more detail with nce to Examples and Test Examples, but the present invention is not limited to these Examples and the like. In addition, the maximum tolerated dose (MTD) indicated by paper reports and the like was used for setting doses of various anti-tumor agents whose anti—tumor effect is enhanced as shown in the following Test Examples.
(Example 1) Methanesulfonate of l—(2—deoxy—2—fluoro—4—thio—B—D—arabinofuranosyl)cytosine (Compound A) was synthesized by the method described in W02013/146833A.
(Test Example 1) Combinational effect test in Capan-l aneously implanted tumor-bearing model mouse Gemcitabine (hereinafter, also referred to as Gem), Abraxane (hereinafter, also ed to as Abx), and methanesulfonate of nd A were used as test nces.
Gemcitabine was prepared by dissolving gemcitabine hydrochloride (manufactured by Teva Pharmaceutical Industries Limited) in physiological saline. Abraxane was prepared by dissolving ne (manufactured by Celgene Corporation) in logical saline.
Capan-l cell, a human pancreatic cancer cell line, was subcutaneously injected into the posterior flank of 5 to 6—week old female BALB/cA Jcl-nu mice. After tumor implantation, the major diameter (mm) and minor diameter (mm) of the tumor were measured, and the tumor volume (TV) was calculated. Mice were assigned to each group so that the average TV of each group was equal, and the day on which this grouping (n = 8) was carried out was taken as Day 1.
The test liquid in Abraxane alone group was prepared to be 30 mg/kg/day as the stration dose. In addition, the test liquid in Compound A alone group was prepared to be 480 mg/kg/day. Compound A was administered from the mouse tail vein a total of three times from Day 1 once a week, and Abraxane was similarly administered from the mouse tail vein a total of three times from Day 1 once a week. In the combined administration group, Compound A was administered at 480 mg/kg/day and Abraxane was administered at 30 mg/kg/day.
As a ative experiment, gemcitabine was used as a control. The test liquid of abine alone group was prepared to be 240 mg/kg/day. Gemcitabine was administered from the mouse tail vein a total of three times from Day 1 once a week. In the combined administration group, gemcitabine was administered at 240 mg/kg/day and Abraxane was administered at 30 day.
In this test, doses of Compound A and gemcitabine were set using MTD of each drug. ne was used at the maximum dose usable in combination with each drug. An anti—tumor agent exhibits that the dose exhibiting the maximum drug efficacy is very close to the dose expressing toxicity, and the anti-tumor agent is generally evaluated in the vicinity of MTD in order to evaluate the maximum anti—tumor effect possessed by the drug in an animal model. In this test example, the MTD and the maximum effect dose are almost synonymous.
As an index of anti—tumor effect, TV at Day 33 was measured in each drug administration group. According to the following equation, a ve tumor volume (RTV) with respect to Day 1 and T/C (%) were calculated to evaluate the anti-tumor effect.
Evaluation judgment of combinational effect was made as having a combinational effect in the case where the average RTV value of the combined administration group was statistically significantly (Welch’s IUT, over all maximum ) smaller than the average RTV value of each individual administration group. The results are shown in Table 1 and Fig. 1. In the table, * indicates that a statistically cant difference was ed in the control group and Gem or Compound A alone group.
TV (mm3) = (major er >< minor diameter2)/2 RTV = (TV at Day V at Day 1) T/C (%) = [(average RTV value of test liquid administered group)/(average RTV value of control group)] X 100 [Table 1] Dose RTV I T/C Group name vs. control vs. alone (mg/kg/day) (meanzzstandard deviation) (%) Control 0 4.012021 Abx 30 2.03i1.ll Gem 240 2.74i0.4l 68.3 Abx+Compound A *: statistically significant Compound A significantly enhanced the anti—tumor effect of Abraxane. At 480 mg/kg/day, which is a high dose (maximum effect dose) in nude mice, combination use thereof induced significant reduction in the size of the tumor. The effect was thought to be larger than that of the ng drug gemcitabine. A more detailed explanation will be given later.
Also, body weight (BW) was measured over time as an index of toxicity and an average %body weight change (BWC (%)) up to Day 33 relative to Day 1 was calculated by the ing equation (n: weight measurement day, last ement day corresponds to Day 33 which is the final evaluation day). The results are shown in Fig. 2.
BWC (%) = [(BW at Day n) - (BW at Day 1)]/(BW at Day 1)><100 No exacerbation of body weight loss was observed in ed administration.
On the ational effect of the present invention, the results of evaluation using a combination index (CI) which is a quantitative index of the combinational effect are shown.
The CI can be calculated by the following equation according to Cancer Research, 2010, Vol. 70, pp. 440 to 446.
That is, in the case where the drugs to be used in combination are drugs 1 and 2, CI = (T/C at the time of combination use)+100/{[(T/C of drug l)+100]X[(T/C of drug 2)+100]} CI = l: additive effect C1 > 1: antagonistic effect CI < 1: synergistic effect The CI in the case where Abraxane and gemcitabine were used in combination was 0.80, and the CI in the case where Abraxane and Compound A were used in combination was 0.32. Since CI < l, a synergistic effect by combination use is observed, and the synergistic effect of Compound A can be said to be more significant than that of the existing drug gemcitabine.
In addition, on the combinational effect of the present invention, the results of evaluation using a tumor growth tory effect h of control (GC)) are shown. For the evaluation method, the same method as in B of Fig. 5 of Molecular Cancer Therapeutics, 2013, Vol. 12‘, pp. 2585 to 2696 was used.
As bed in the above document, the GC can be calculated by the following equation.
In the case where RTV > 1 GC (%) = [(corresponding drug RTV-1)/(control RTV—1)]><100 In the case where RTV S 1 GC (%) = (corresponding drug RTV—1)>< 100 Combinational effect was estimated from the drug efficacy with Abraxane and Compound A or gemcitabine alone by the following calculation equation. The results are shown in Fig. 3 and Table 2.
The ted combination use GC (%) = [GC (%) of AbraxaneXdrug alone GC (%)]+100 For example, in this test example, from Table 1, GC (%) ofAbraxane alone is [(2.03-1)/(4.01-1)]><100=34.2 (%) since RTV > 1, GC (%) of abine is [(2.74—1)/(4.01—1)]X100=57.8 (%) since RTV > 1.
Therefore, the estimated combination use GC (%) is (34.2X57.8)+100=19.8 (%).
On the other hand, the actual GC (%) of the combination use of Abraxane and gemcitabine is [(1.11-1)/(4.01-1)]><100=3.7 (%) from RTV > 1.
As a result, since the estimated combination use GC (%) is 19.8 (%), s the actual combination use GC (%) is 3.7 (%), it is thought that there is a significant combinational effect exceeding the assumed combinational effect.
In the case where the same calculation is d out also for Compound A, GC (%) of Compound A is -1)/(4.01-1)]><100=9.6 (%) since RTV > 1 for single drug.
Therefore, the estimated combination use GC (%) is (34.2 ><9.6)+100=3.3 (%) The actual GC (%) is (0.21—1)><100=-79.0 (%) from RTV S 1. The solid arrow in Fig. 3 indicates the combinational effect of gemcitabine and the dotted arrow indicates the combinational effect of Compound A.
As a result, also in nd A, the estimated ation use GC (%) is 3.3 (%), whereas the actual ation use GC (%) is -79.0 (%), from which it is thought that there is a significant combinational effect exceeding the assumed combinational effect. It can be said that the degree of combinational effect is more prominent than the existing drug gemcitabine.
[Table 2] Dose RTV Estimated combination use GC (%) (mg/kg/day) (meanistandard deviation) GC (%) 0 4.01:0.21 2.03:t1.ll 274::0.41 Compound A l ..29:t0 59 bx+C0mpound A 480+30 0,21i0.12 -79.0 3 .3 The present invention is useful as an anti—tumor agent and an anti—tumor kit which t significant anti-tumor effect, as well as an anti—tumor effect enhancer.
Claims (4)
1. Use of paclitaxel and 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or methanesulfonate thereof in the manufacture of ments for treating pancreatic cancer, wherein the amount of the 1-(2-deoxyfluorothio-β-D-arabinofuranosyl)cytosine or methanesulfonate thereof used is 0.01 to 100-fold molar amount of the axel, and wherein the paclitaxel is an albumin-bound paclitaxel injection sion of nanoparticle preparation encapsulating paclitaxel with albumin (nab-paclitaxel), wherein the medicaments are to be administered in combination therapy with each other.
2. The use of claim 1, wherein the medicaments are to be administered simultaneously, separately, sequentially, or at intervals.
3. The use of claim1 or claim 2, wherein the ments are in the form of a preparation.
4. The use of claim 1, substantially as herein described with reference to any one of the Examples and/or
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JP2016-169167 | 2016-08-31 | ||
JP2016169167 | 2016-08-31 | ||
PCT/JP2017/031074 WO2018043530A1 (en) | 2016-08-31 | 2017-08-30 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
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NZ751051B2 true NZ751051B2 (en) | 2022-01-06 |
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