WO2004062687A1 - Pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof - Google Patents

Pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof Download PDF

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Publication number
WO2004062687A1
WO2004062687A1 PCT/KR2003/000085 KR0300085W WO2004062687A1 WO 2004062687 A1 WO2004062687 A1 WO 2004062687A1 KR 0300085 W KR0300085 W KR 0300085W WO 2004062687 A1 WO2004062687 A1 WO 2004062687A1
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cancer
protein
paclitaxel
administration
pharmaceutical composition
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PCT/KR2003/000085
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French (fr)
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Sung-Hoon Kim
Tae-Hee Kang
Soo-Young Choi
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Imagene Co., Ltd.
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Priority to PCT/KR2003/000085 priority Critical patent/WO2004062687A1/en
Priority to AU2003206144A priority patent/AU2003206144A1/en
Publication of WO2004062687A1 publication Critical patent/WO2004062687A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol

Definitions

  • composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof
  • the present invention relates to the pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same anduse thereof. More specifically, the present invention relates to the pharmaceutical composition, treatment method using the same, and their use in which p43 protein and paclitaxel are administered simultaneously, separately, or sequentially to obtain an increased anticancer effect.
  • anticancer agents Most common anticancer agents are doxorubicin and cisplatin, both developed during the 1970s. More recent anticancer agents include, paclitaxel, docetaxel, fiudarabine, cladribine and vinorelbine, and it has been reported that these agents are better than previously used agents in terms of their anticancer effects and application range.
  • Paclitaxel the most studied anticancer agent in recent days, contains a compound of taxane variety, which is isolated from plant stem of tctxus sp..
  • Paclitaxel is known to have treatment effect on leukemia and cancer by inhibiting spindle function during cell division.
  • paclitaxel is known to have cure rate of at least 30% on a patient with ovarian cancer, of at least 50% on a patient with breast cancer, and of at least 20% on a patient with lung cancer (refer to E. K. Rowinsky et al., J Natl. Cancer Inst., 82: 1247-1259, 1990).
  • the above-described anticancer agents have a drawback of losing their anticancer effects when the agents are administered repeatedly during a long period of time or when cancer recurs, and thus cancer cells develop a resistance to the anticancer agents.
  • most of the anticancer agents exert their anticancer effect by inhibiting the synthesis of nucleic acids in a cell, or by directly binding thereto and therefore damaging the functions of the nucleic acids. In doing so, the anticancer agents not only damage the cancer cells selectively but also hurt normal cells, especially tissue cells with active cell differentiation. Therefore, there is a risk of using such anticancer agents with side effects such as deterioration in bone marrow function, damage on gastrointestinal mucosa, and loss of hair, etc.
  • International patent publication No. 0152882 discloses a method of treating cancer by administering temozolomide and interferon alpha in combination to a cancer patient.
  • International patent publication No. 0234244 discloses a pharmaceutical composition for the treatment of cancer which comprises camptothecin and stilbene derivatives.
  • US patent No. 6,262,054 discloses a method of treating cancer by administering in combination publicly known anticancer agents edatrexate and taxane. Meanwhile, the present inventors described a new use of p43 protein as an anticancer and anti-angiogenic agent in International patent publication No.
  • the inventors of the present invention found that combined administration of said p43 protein and paclitaxel has much greater anticancer effect compared to a single administration of p43 protein or paclitaxel.
  • the present invention is accomplished, and therefore the new pharmaceutical composition comprising p43 protein and paclitaxel with an increased anticancer activity and cancer treatment method using the same are provided.
  • the object of the present invention is to provide a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for cancer treatment.
  • Figure 1 shows a change in survival ratio of nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel.
  • Figure 2 shows a body weight change in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 3 shows a change in the absolute tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 4 shows a change in the relative tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel(*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 5 shows a change in the tumor weight in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (A: negative control, B: p43 protein 25 mg/kg administered, C: p43 protein 50mg/kg administered, D: p43 protein 25mg/kg + taxol 5mg/kg administered, E: p43 protein 50mg/kg + taxol 5mg/kg administered).
  • Figure 6 shows a change in survival ratio of nude mouse grafted with human stomach cancer cell line NUGC-3, after with the single or combined administration of p43 protein and paclitaxel.
  • Figure 7 shows a body weight change in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 8 shows a change in the absolute tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01, a: five test animals from negative control group were dead on the 14 th day of the administration).
  • Figure 9 shows a change in the relative tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel.
  • the present invention provides a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for the cancer treatment.
  • the present invention provides a method of treating cancer which includes administering to a patient the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel.
  • the present invention provides a use of p43 protein and paclitaxel which can be used for the preparation of pharmaceutical composition which is administered to treat cancer.
  • the term "effective amount” as used herein means an amount of a compound that can be useful to treat cancer in mammalians.
  • the pharmaceutical composition comprising p43 protein and paclitaxel has a synergy effect on cancer treatment by having said agents administered in combination.
  • administered in combination means that a compound or component is administered together to a subject animal.
  • Administering each component or compound together means that, in order to obtain desired treatment effect, each component can be administered simultaneously, or sequentially at separate time in any order.
  • the present pharmaceutical composition for the treatment of cancer is characterized in that it comprises effective amount of p43 protein and paclitaxel.
  • p43 protein comprised in the pharmaceutical composition of the present invention has been disclosed in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108, each previously filed by the present inventors. Said two documents are incorporated by reference herein.
  • p43 protein comprised in the pharmaceutical composition of the present invention refers to either natural or recombinant p43 protein, or the protein with the substantially equivalent biological activity.
  • the protein with the substantially equivalent biological activity includes functional equivalents and functional derivatives of natural/recombinant p43 protein.
  • “Functional equivalent” mentioned above represents the mutant with modified amino acid sequence in which a whole or a part of natural type p43 protein is substituted, or in which a part of the amino acid sequences is deleted or added, and substantially equivalent biological activity to the natural type p43 protein.
  • “Functional derivative” represents the modified p43 protein with increased or decreased physical/chemical protein property and substantially equivalent biological activity to the natural p43 protein.
  • p43 protein of the present invention can be obtained from mammalian, preferably from human. Most preferably, it refers to the protein with the publicly known sequence as disclosed before (International patent publication No. 0195927 and Korean patent application publication No. 2001-112108).
  • p43 protein used in the present invention can be produced from the above-mentioned known sequence using genetic engineering techniques (see, Park et al., J. Biol. Chem. 274: 166673-166676, 1999).
  • said p43 protein can be prepared according to the genetic engineering techniques described in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108.
  • Paclitaxel comprised in the pharmaceutical composition of the present invention is well known in the art as an anticancer agent.
  • Paclitaxel comprised in the pharmaceutical composition of the present invention includes the extract from natural sources and chemically synthesized compounds according to US patent No. 5,440,056, and derivatives thereof. Chemical formula of paclitaxel is known (Kingston et al., Studies in Organic Chemistry, 26:219-235, 1986).
  • Paclitaxel can be prepared by known chemical synthesis method, extraction method, and culture method using a cell line producing paclitaxel, etc.
  • Paclitaxel is commercially available as the drug formulation.
  • the drug formulation containing paclitaxel mention can be made to TAXOL ⁇ which is distributed by Bristol-Myers Squibb of the United States.
  • GENEXOL which is commercially available from Samyang Genenx Korea, was used.
  • p43 protein and paclitaxel can be formulated into a form of a single composition, or a separate composition.
  • each component can be administered simultaneously, separately, or sequentially. For instance, when each component of the present pharmaceutical composition is in a single composition, all the components can be administered simultaneously. On the other hand, if the components are not in a single composition, one component can be administered before, or, after, and/or together with the administration of other components.
  • the administration order for the pharmaceutical composition of the present invention i.e., whether and at what point, simultaneous, separate or sequential administration take place, may be decided by a doctor or an expert in this field. The administration order varies greatly depending on many factors to be considered.
  • p43 protein is administered first and the other component, i.e., paclitaxel, is administered after the lapse of time. More preferably, p43 protein is administered everyday from the beginning day of the administration while paclitaxel is initially administered at the beginning day and continues to be administered later on every 2 or 3 days. For example, p43 protein is administered once everyday and paclitaxel is administered five times; at the beginning day, and 2 days, 5 days, 8 days and 11 days after the administration has began.
  • the pharmaceutical composition of the present invention can be administered either systemically or locally in the administration order as described before.
  • oral or parenteral administration can be considered.
  • Example of parenteral administration includes; intravenous, subcutaneous, intraperitoneal, lateral, rectal, dermal, nasal, tracheal or bronchial administration and inhalation into lung .
  • a preferred route of administration is parenteral, more preferably intraperitoneal or dermal.
  • the pharmaceutical composition of the present invention which is administered according to the route of administration described above, it can be formulated into an appropriate form by further comprising a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes an inert diluent, a filling agent, water, or various kinds of organic solvents.
  • the pharmaceutical composition of the present invention can comprise additional components such as flavoring agent, binder and excipient, etc.
  • the pharmaceutical composition of the present invention can comprise a carrier for oral administration, for example, lactose, starch, cellulose derivative, magnesium stearate, and stearic acid, etc.
  • active compounds can be mixed with excipients and prepared into different forms such as tablet, lateral tablet, troche, capsule, elixir, suspension, syrup and wafer, etc.
  • the pharmaceutical composition of the present invention can comprise a carrier for parenteral administration, such as water, suitable oil, saline, aqueous glucose and glycol, etc.
  • Additional carrier for the parenteral administration may include a stabilizer and a preservative.
  • Suitable stabilizer includes an antioxidant such as sodium bisulphite, sodium sulphite or ascorbic acid.
  • Suitable preservative includes benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the pharmaceutical composition of the present invention can be formulated into the parenteral administration composition, for example, an injection formulation.
  • the injection formulation can be prepared according to the techniques known in the art, using an appropriate dispersant, humectant and emulsifier.
  • each component can be solubilized in saline or buffer solution and can be formulated into the injection formulation.
  • paclitaxel comprised in the pharmaceutical composition of the present invention can be prepared in an oily phase microemulsion in which lipid containing olive oil or sunflower oil and PEG-linked lipid are mixed with paclitaxel, as described in US patent No. 5,478,860.
  • paclitaxel can be encapsulated in liposomes.
  • it can be formulated with a solubilizer such as anhydrous ethanol and polyethoxylated castor oil, or prepared in formulation forms for oral administration or injection, as described in US patent No. 5,424,073.
  • p43 protein comprised in the pharmaceutical composition of the present invention can be formulated into the general protein formulation.
  • liquid type formulation For example, after p43 protein is freeze-dried and solubilized in the buffer solution, a liquid type formulation can be obtained.
  • liquid type formulation further comprising above-described stabilizer can be prepared.
  • formulation type, administration route and administration method there is no limit for formulation type, administration route and administration method.
  • Inhibitory effect of the pharmaceutical composition of the present invention on tumor growth was observed when p43 protein is administered once everyday in a dose of 25 ⁇ 50mg/kg/day and paclitaxel is administered at the beginning day of the administration and 2 days, 5 days, 8 days, and 11 days later on in a dose of 5mg/kg, that is considered to be a minimum amount for inhibiting cancer cell growth. Therefore, p43 protein can be administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg, and paclitaxel can be administered once or several times at the beginning day of the administration and later once or several times every two or three days from the beginning day of the administration, in a dose of 1 mg/kg to lOmg/kg.
  • said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel can be initially administered at once at the beginning day of the administration and every two or three days later on in once-a-day manner, in a dose of 5mg/kg.
  • final dose and dosing frequency can be adjusted within the allowed range that is clinically determined in view of characteristics of drug formulation, administration method and route , patient's condition, age, body weight, sex, nature of symptom, and severeness of sickness, etc.
  • the pharmaceutical composition of the present invention is very useful for the treatment of abnormal cell growth, i.e., cancer.
  • Example of cancer includes solid cancer such as lung cancer, stomach cancer, large intestinal cancer, liver cancer, bone cancer, spleen cancer, skin cancer, cephalic cancer, cervical cancer, cutaneous or intraocular melanoma, uterine sacoma , ovarian cancer, rectal cancer, cancer of anal region , colon cancer, breast cancer, Fallopian tube carcinoma, endometrium carcinoma, uterine cervical carcinoma, vagina carcinoma, vulval carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary track cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, kidney bone carcinoma, CNS tumor, primary CNS lymphoma, bone marrow tumor, brain stem nerve glioma, and pituitary adrenoma, and combination thereof in which more than one
  • xenograft model was employed.
  • xenograft model is commonly used for the development of new anticancer agent. It is usually carried out using a nude mouse.
  • a nude mouse free of specific pathogen is grafted with human lung cancer cell line or human stomach cancer cell line, respectively. After administering p43 protein and paclitaxel either alone or in combination, survival ratio, body weight and cancer size of the treated mouse was measured and anticancer activity for each case was determined.
  • the present invention provides the method of treating cancer including administration of pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient in need of such treatment.
  • the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient, in which the two components are formulated into either a single or a separate composition.
  • the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising p43 protein and paclitaxel to a patient simultaneously, separately, or sequentially.
  • the present invention provides the method of treating cancer including administration of p43 protein everyday from the beginning day of the administration while administering paclitaxel initially on the beginning day and keeping its administration every 2 or 3 days from the beginning day.
  • the present invention provides the method of treating cancer including administration of p43 protein once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days from the beginning day of the administration.
  • said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5mg/kg can be initially administered once on the beginning day of the administration and later on every two or three days in once-a-day manner.
  • the present invention provides the method of treating cancer which including administration of the pharmaceutical composition to a patient orally or parenterally.
  • Example of the oral or the parenteral administration is the same as described above.
  • the present invention also provides the method of treating cancer including administration of the pharmaceutical composition comprising effective amount of p43 protein and paclitaxel to a patient, and pharmaceutically acceptable carrier as an additional component.
  • the pharmaceutically acceptable carrier is the same as described above.
  • a 'patient' described above means a person diagnosed with the abnormal cell growth i.e., cancer. Cancer varieties are the same as those described in the above. Especially in the present invention, the term 'patient' refers to the patient diagnosed with a lung or stomach cancer.
  • the present invention also provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition used for cancer treatment in which the two components are administered in combination.
  • the present invention provides a use of p43 protein and Paclitaxel for preparing the pharmaceutical composition for cancer treatment in which said two components are formulated into either a single or a separate composition.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the two components are administered simultaneously, separately, or sequentially.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered everyday from the beginning day of the administration while paclitaxel is administered initially on the beginning day and is later being kept administered every 2 or 3 days.
  • this invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel is administered once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days. More preferably, the p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5 mg/kg can be initially administered once on the beginning day of the administration and later every two or three days in once-a-day manner.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition is administered orally or parenterally.
  • Example of the oral or parenteral administration is the same as described above.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition comprises the effective amount of p43 protein and paclitaxel, and further comprises pharmaceutically acceptable carrier.
  • Cancer varieties are the same as those described in the above. Especially in the present invention, it can be a lung or stomach cancer.
  • Example 1 Anticancer activity in the lung cancer xenograft mouse model by single or combined administration of p43 protein and paclitaxel
  • a nude mouse with BALB/C origin and specific pathogen free (SPF) was used as a test animal for the present invention (5 weeks old, Daehan Biolink Inc). After obtaining said animals, their appearance was visually examined. Animals were deemed for seven days in the animal room where tests will be carried out. General things were checked and only the healthy animals were chosen for the test. Said animals were kept in the animal keeping room where under condition had been maintained as temperature of 23+ 3 ° C, relative humidity of 50+ 15%, 12 hour of lighting (from 8AM to 8PM), ventilation frequency of 10-20 times/hr and light intensity of 150 ⁇ 300Lux.
  • NCI-H460 cell line was obtained from Cancer cell line Bank of the Korean Research Institute of Bioscience and Biological and used as a human ling cancer cell line for the present invention.
  • Cancer cell lines obtained as described above were cultured in a CO 2 incubator (Forma, USA) at temperature of 37 ° C and CO 2 concentration of 5%.
  • RPMI-1640 in which FBS (Fetal bovine serum, GibcoBRL, 16000-044) was added to the final concentration of 10% and 10% peniciline-streptomycin solution (GibcoBRL, 15140-122) was also added, was used as a the culture medium.
  • cancer cells isolated from the culture medium was stored in cold temperature . On the final day of culturing, all the cells were collected and counted. Then, using PBS (phosphate buffered saline), cell concentration was adjusted to 3x 10 7 cells /ml. Adjusted cell culture solution was subcutaneously injected to fifty opted and healthy mice in the amount of 3 ml/animal at axillia region between right side shoulder and chest wall.
  • PBS phosphate buffered saline
  • Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the lung cancer cells, as described in the above step 1-2).
  • the size of cancer found in the nude mouse grafted with the cancer cells was measured and ranked.
  • the measurement of cancer was carried out by determining width, length and thickness of the cancer cells using Vernier calipers.
  • the body weight of the animal was measured at the same time. Animals were put in order with their cancer size estimated from said measurements. Among the test animals, forty animals with the cancer size similar to the mean value were selected and allocated into a separate group using a computer so that the size of cancer is evenly distributed among each group.
  • p43 protein was administered either alone or in a combination with paclitaxel. Specifically, 25mg/kg of p43 protein was administered alone (low dose p43 administration group), 50mg/kg of p43 protein was administered alone (high dose p43 administration group), 25mg/kg of p43 protein was administered in combination with 5mg/kg of paclitaxel (GENEXOL , Samyang Genex Inc.) (combined administration group of low dose p43 and paclitaxel), or 50mg/kg of p43 protein was administered in combination with 5mg/kg paclitaxel (combined administration group of high dose p43 and paclitaxel).
  • paclitaxel GENEXOL , Samyang Genex Inc.
  • PBS phosphate buffered saline
  • glycerol 20% glycerol (Sigma)
  • Administration method involves fixing a mouse with an abdominal skin fixing method and administering the test compositions to the mouse in an intraperitoneal route .
  • p43 Protein was administered once everyday for 28 days " and paclitaxel was administered total of five times, i.e., at the beginning day of the administration, and 2 days, 5 days, 8 days and 11 days later. Test groups and administered dose are summarized in the following table.
  • V.C. lx PBS (Phosphate buffered saline) solution containing 20%) of glycerol
  • the body weight of all the animals in the above step 1-3 was measured on the beginning day of the administration, and twice per week during the administration period, and once per week during the observation period after the administration had been terminated.
  • Tumor size was measured on the beginning day of the administration and every other day during the administration period. Width, length and thickness of the tumor were measured using a vernier calipers. Tumor volumes were calculated using the equation described below. In addition, change in the relative tumor size was calculated by dividing the tumor size measured every other day with the tumor size before the administration, and is described in percentage value. Tumor weight was measured with the autopsied mouse after the test has been terminated. After the mean values for the body weight, tumor size and tumor weight and standard deviation values thereof were obtained for each test group, their statistical significance was determined using the student-t test.
  • the body weight of the test animal decreased in a dose dependent manner till the 3 rd day of the administration, except for the negative control group.
  • the body weight loss ratio for the test groups compared to the negative control group is as follows; 87% loss for the low-dose p43 protein administration group, 84% loss for the high-dose p43 protein administration group, 84% loss for the combined administration group of the low-dose p43 protein and paclitaxel, and 81% loss for the combined administration group of the high-dose p43 protein and paclitaxel. After three days of the administration, normal body weight gain was observed. Still, the body weight of the animals in all of the test groups is lower than that of the negative control group.
  • the tumor growth ratio for the negative control group and the test groups at the end of the administration, i.e., on 28 th day, is as follows; 5192% for the negative control group,
  • Table 2 and Figure 5 represent the test result for tumor weight change.
  • the results demonstrate that, compared to the control group, the tumor weight decreased in a dose dependent manner for both of the test groups; i.e., p43 protein single administration group (Gl: low-dose p43 protein administration group, G2: high-dose p43 protein administration group) and the combined administration group of p43 protein and Paclitaxel (G3: low-dose p43 protein and Paclitaxel, G4: high-dose p43 protein and Paclitaxel).
  • the tumor weight decreased most dramatically for the combined administration group of p43 protein and Paclitaxel.
  • the reason for having smaller weight gain ratio for the combined administration of p43 protein and paclitaxel compared to the single administration of p43 protein is believed to be due to the fact that, since the tumor weight decreased more in the combined administration group, the overall weight gain ratio becomes smaller than that of the single administration group.
  • tumor growth can be more significantly and more quickly inhibited by the combined administration of p43 protein and Paclitaxel than by the single administration of p43 protein.
  • human stomach cell line NUGC-3 was obtained from Cancer cell line Bank of the Korean Research Institute of
  • Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the human stomach cancer cells as described in the above step 2-1). Since the tumor growth varied a lot among the test mice grafted with the human stomach cancer cells, the test groups were formed by carrying our said measurements every other day. Total of 24 mice with the tumor size of 50 ⁇ 100mm 3 were selected and allocated into a separate test group using a computer so that the size of cancer is evenly distributed among each test group. After two days, another group of 24 mice with a similar tumor size were selected from the rest of the mice and allocated into the test group using the computer. To each of said groups constituted as described above, p43 protein was administered alone or in combination with paclitaxel following the same method as described in Example 1. Constitution of test groups and dose are described in Table 3 below. An animal group administered with 5ml kg of paclitaxel was taken as a positive control.
  • V.C lx PBS(Phosphate buffered saline) solution containing 20% of glycerol
  • the survival ratio for each test groups is as follows; 25%> for the negative control group to which the excipient was administered on the final day of administration (Day 28), 63% for the low dose p43 protein administration group, 25% for the high dose p43 protein administration group, 100%) for both of the combined administration groups of the low-dose p43 protein and paclitaxel and the high-dose p43 protein and paclitaxel, and 63 % for the positive control in which Paclitaxel is administered only.
  • survival ratio of more than 50% was observed for the combined administration group of p43 protein and paclitaxel. For other test groups, most of the test animals were perished.
  • the change in the body weight of the test animals is shown in Figure 7.
  • the body weight of the test animals was temporarily decreased after two days from the administration of p43 protein and paclitaxel in a single or combination. These are the same results as those observed for the mouse grafted with the human lung cancer cell line.
  • the test animals slowly started to regain their body weight from the 5 th day of the administration, and eventually recovered fully the original weight around the 10 th day.
  • the negative control group no such gain was observed and the body weight of the test animals kept decreasing.
  • the tumor weight cannot be compared between the control group and the test group, due to the high mortality among the control group and the single administration group of p43 protein. Since the high mortality, continuing weight loss and high incidents of tumor growth over the beginning period of the test were found for the test animals of the control group grafted with the human stomach cancer cell line, it is believed that the cancer cells grafted therein cause the animal death. Moreover, with respect to the high survival ratio and the inhibition of tumor growth at the early stage of the experiment for the group administered with p43 protein and paclitaxel in combination, it is believed that they are caused by the anticancer activity of said drugs. Taken together, it is found that the combined administration of p43 protein and paclitaxel is more efficient than the single administration of p43 protein or Paclitaxel, in terms of anticancer activity against stomach cancer.
  • the pharmaceutical composition comprising p43 protein and paclitaxel and the treatment method using the same of the present invention are advantageous in that, compared to the single administration, tumor growth can be more significantly inhibited by administering the two components in combination, and therefore can provide synergistic treatment effect.
  • the pharmaceutical composition and the treatment method using the same of the present invention can minimize the use of paclitaxel, of which side effects are in concern, and therefore can reduce the undesirable effects of the anticancer agents.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, a therapy method using the same and a use thereof. More particularly, the present invention relates to the pharmaceutical composition, which is characterized in that p43 protein is administered in combination with a paclitaxel simultaneously, separately or sequentially, the therapy method using the same and the use thereof. The pharmaceutical composition and therapy method according to the present invention, in which the p43 protein is administered in combination with the paclitaxel, can enhance the effectiveness of cancer treatment by inhibiting the growth of cancer cells significantly over the short period of time. In addition, the present invention can decrease drug toxicity by minimalizing dosage of paclitaxel.

Description

Pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof
Technical Field
The present invention relates to the pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same anduse thereof. More specifically, the present invention relates to the pharmaceutical composition, treatment method using the same, and their use in which p43 protein and paclitaxel are administered simultaneously, separately, or sequentially to obtain an increased anticancer effect.
Background Art
Presently, surgical operation, radiation therapy, and chemical therapy are used to treat cancer. Among these, chemical therapy employs an anticancer agent to treat cancer. The chemical therapy has been widely used since a perfect cure of choriocarcinoma using methotrexate. About 60 kinds of various anticancer agents have being used in these days. As much information has been obtained for carcinogenegis and characteristics of cancer cells, active researches have been conducted on the development of new anticancer agents.
Most common anticancer agents are doxorubicin and cisplatin, both developed during the 1970s. More recent anticancer agents include, paclitaxel, docetaxel, fiudarabine, cladribine and vinorelbine, and it has been reported that these agents are better than previously used agents in terms of their anticancer effects and application range.
Paclitaxel, the most studied anticancer agent in recent days, contains a compound of taxane variety, which is isolated from plant stem of tctxus sp.. Paclitaxel is known to have treatment effect on leukemia and cancer by inhibiting spindle function during cell division. Especially, paclitaxel is known to have cure rate of at least 30% on a patient with ovarian cancer, of at least 50% on a patient with breast cancer, and of at least 20% on a patient with lung cancer (refer to E. K. Rowinsky et al., J Natl. Cancer Inst., 82: 1247-1259, 1990). However, the above-described anticancer agents have a drawback of losing their anticancer effects when the agents are administered repeatedly during a long period of time or when cancer recurs, and thus cancer cells develop a resistance to the anticancer agents. In addition, most of the anticancer agents exert their anticancer effect by inhibiting the synthesis of nucleic acids in a cell, or by directly binding thereto and therefore damaging the functions of the nucleic acids. In doing so, the anticancer agents not only damage the cancer cells selectively but also hurt normal cells, especially tissue cells with active cell differentiation. Therefore, there is a risk of using such anticancer agents with side effects such as deterioration in bone marrow function, damage on gastrointestinal mucosa, and loss of hair, etc. In order to overcome the problems associated with the resistance to the anticancer agents as described above, it is preferred to employ a combined chemotherapy to a single-kind-anticancer agent therapy, in which different kinds of drug formulations with different reaction mechanisms and no cross-resistance are used. In another way of overcoming the side effects of anticancer agents, it has been suggested to develop a new drug with no side effect or to use existing drugs in a minimal effective concentration.
International patent publication No. 0152882 discloses a method of treating cancer by administering temozolomide and interferon alpha in combination to a cancer patient. International patent publication No. 0234244 discloses a pharmaceutical composition for the treatment of cancer which comprises camptothecin and stilbene derivatives. US patent No. 6,262,054 discloses a method of treating cancer by administering in combination publicly known anticancer agents edatrexate and taxane. Meanwhile, the present inventors described a new use of p43 protein as an anticancer and anti-angiogenic agent in International patent publication No.
0195927 and Korean Patent Application Publication No. 2001-112108.
In this connection, while developing new kind of anticancer agents, the inventors of the present invention found that combined administration of said p43 protein and paclitaxel has much greater anticancer effect compared to a single administration of p43 protein or paclitaxel. As a result, the present invention is accomplished, and therefore the new pharmaceutical composition comprising p43 protein and paclitaxel with an increased anticancer activity and cancer treatment method using the same are provided.
Detailed Description of the Invention
The object of the present invention is to provide a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for cancer treatment.
Another object of the present invention is to provide a method of treating cancer which includes administering to a patient the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel. Yet another object of the present invention is to provide a use of p43 protein and paclitaxel which can be used for the preparation of the pharmaceutical composition which is administered to a patient to treat cancer.
Brief Description of Drawing
Figure 1 shows a change in survival ratio of nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel.
Figure 2 shows a body weight change in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p<0.05, **: significant difference for the values obtained from negative control group p<0.01).
Figure 3 shows a change in the absolute tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p<0.05, **: significant difference for the values obtained from negative control group p<0.01).
Figure 4 shows a change in the relative tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel(*: significant difference for the values obtained from negative control group p<0.05, **: significant difference for the values obtained from negative control group p<0.01). Figure 5 shows a change in the tumor weight in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (A: negative control, B: p43 protein 25 mg/kg administered, C: p43 protein 50mg/kg administered, D: p43 protein 25mg/kg + taxol 5mg/kg administered, E: p43 protein 50mg/kg + taxol 5mg/kg administered). Figure 6 shows a change in survival ratio of nude mouse grafted with human stomach cancer cell line NUGC-3, after with the single or combined administration of p43 protein and paclitaxel.
Figure 7 shows a body weight change in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p<0.05, **: significant difference for the values obtained from negative control group p<0.01).
Figure 8 shows a change in the absolute tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p<0.05, **: significant difference for the values obtained from negative control group p<0.01, a: five test animals from negative control group were dead on the 14th day of the administration).
Figure 9 shows a change in the relative tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel.
Preferred Embodiment of the Invention Accordingly, the present invention provides a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for the cancer treatment.
Further, the present invention provides a method of treating cancer which includes administering to a patient the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel.
Still further, the present invention provides a use of p43 protein and paclitaxel which can be used for the preparation of pharmaceutical composition which is administered to treat cancer.
The term "effective amount" as used herein means an amount of a compound that can be useful to treat cancer in mammalians. The pharmaceutical composition comprising p43 protein and paclitaxel has a synergy effect on cancer treatment by having said agents administered in combination.
The term "synergy" described in the above means that the effect of the two components when administered in combination is greater than additive effect of the each component when administered alone (Chou and Talalay, Adv. Enzyme. Regul, 22:27-55, 1984).
The term "administered in combination" (or, "combined administration") means that a compound or component is administered together to a subject animal. Administering each component or compound together means that, in order to obtain desired treatment effect, each component can be administered simultaneously, or sequentially at separate time in any order.
The present invention is descried in detail herein below. The present pharmaceutical composition for the treatment of cancer is characterized in that it comprises effective amount of p43 protein and paclitaxel. p43 protein comprised in the pharmaceutical composition of the present invention has been disclosed in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108, each previously filed by the present inventors. Said two documents are incorporated by reference herein. p43 protein comprised in the pharmaceutical composition of the present invention refers to either natural or recombinant p43 protein, or the protein with the substantially equivalent biological activity. The protein with the substantially equivalent biological activity includes functional equivalents and functional derivatives of natural/recombinant p43 protein.
"Functional equivalent" mentioned above represents the mutant with modified amino acid sequence in which a whole or a part of natural type p43 protein is substituted, or in which a part of the amino acid sequences is deleted or added, and substantially equivalent biological activity to the natural type p43 protein. "Functional derivative" represents the modified p43 protein with increased or decreased physical/chemical protein property and substantially equivalent biological activity to the natural p43 protein. p43 protein of the present invention can be obtained from mammalian, preferably from human. Most preferably, it refers to the protein with the publicly known sequence as disclosed before (International patent publication No. 0195927 and Korean patent application publication No. 2001-112108). p43 protein used in the present invention can be produced from the above-mentioned known sequence using genetic engineering techniques (see, Park et al., J. Biol. Chem. 274: 166673-166676, 1999). For example, said p43 protein can be prepared according to the genetic engineering techniques described in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108.
Paclitaxel comprised in the pharmaceutical composition of the present invention is well known in the art as an anticancer agent. Paclitaxel comprised in the pharmaceutical composition of the present invention includes the extract from natural sources and chemically synthesized compounds according to US patent No. 5,440,056, and derivatives thereof. Chemical formula of paclitaxel is known (Kingston et al., Studies in Organic Chemistry, 26:219-235, 1986).
Paclitaxel can be prepared by known chemical synthesis method, extraction method, and culture method using a cell line producing paclitaxel, etc. In addition, Paclitaxel is commercially available as the drug formulation. As an example of the drug formulation containing paclitaxel, mention can be made to TAXOL ω which is distributed by Bristol-Myers Squibb of the United States. In the examples of the present invention, GENEXOL , which is commercially available from Samyang Genenx Korea, was used.
With respect to the pharmaceutical composition of the present invention, p43 protein and paclitaxel can be formulated into a form of a single composition, or a separate composition.
With respect to the pharmaceutical composition of the present invention comprising p43 protein and paclitaxel, each component can be administered simultaneously, separately, or sequentially. For instance, when each component of the present pharmaceutical composition is in a single composition, all the components can be administered simultaneously. On the other hand, if the components are not in a single composition, one component can be administered before, or, after, and/or together with the administration of other components. The administration order for the pharmaceutical composition of the present invention, i.e., whether and at what point, simultaneous, separate or sequential administration take place, may be decided by a doctor or an expert in this field. The administration order varies greatly depending on many factors to be considered. Preferably, for the pharmaceutical composition, which is not formulated in a single administering unit, p43 protein is administered first and the other component, i.e., paclitaxel, is administered after the lapse of time. More preferably, p43 protein is administered everyday from the beginning day of the administration while paclitaxel is initially administered at the beginning day and continues to be administered later on every 2 or 3 days. For example, p43 protein is administered once everyday and paclitaxel is administered five times; at the beginning day, and 2 days, 5 days, 8 days and 11 days after the administration has began.
The pharmaceutical composition of the present invention can be administered either systemically or locally in the administration order as described before. With respect to the administration route, oral or parenteral administration can be considered. Example of parenteral administration includes; intravenous, subcutaneous, intraperitoneal, lateral, rectal, dermal, nasal, tracheal or bronchial administration and inhalation into lung . A preferred route of administration is parenteral, more preferably intraperitoneal or dermal.
In addition, for the pharmaceutical composition of the present invention which is administered according to the route of administration described above, it can be formulated into an appropriate form by further comprising a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes an inert diluent, a filling agent, water, or various kinds of organic solvents. If necessary, the pharmaceutical composition of the present invention can comprise additional components such as flavoring agent, binder and excipient, etc. The pharmaceutical composition of the present invention can comprise a carrier for oral administration, for example, lactose, starch, cellulose derivative, magnesium stearate, and stearic acid, etc. For the oral administration, active compounds can be mixed with excipients and prepared into different forms such as tablet, lateral tablet, troche, capsule, elixir, suspension, syrup and wafer, etc. Furthermore, the pharmaceutical composition of the present invention can comprise a carrier for parenteral administration, such as water, suitable oil, saline, aqueous glucose and glycol, etc. Additional carrier for the parenteral administration may include a stabilizer and a preservative. Suitable stabilizer includes an antioxidant such as sodium bisulphite, sodium sulphite or ascorbic acid. Suitable preservative includes benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Following document can be referred to for an additional pharmaceutical carrier; Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995. Preferably, the pharmaceutical composition of the present invention can be formulated into the parenteral administration composition, for example, an injection formulation. The injection formulation can be prepared according to the techniques known in the art, using an appropriate dispersant, humectant and emulsifier. For example, each component can be solubilized in saline or buffer solution and can be formulated into the injection formulation.
Especially, paclitaxel comprised in the pharmaceutical composition of the present invention can be prepared in an oily phase microemulsion in which lipid containing olive oil or sunflower oil and PEG-linked lipid are mixed with paclitaxel, as described in US patent No. 5,478,860. In addition, as described in the International patent publication No. 9318757, paclitaxel can be encapsulated in liposomes. Further, it can be formulated with a solubilizer such as anhydrous ethanol and polyethoxylated castor oil, or prepared in formulation forms for oral administration or injection, as described in US patent No. 5,424,073. p43 protein comprised in the pharmaceutical composition of the present invention can be formulated into the general protein formulation. For example, after p43 protein is freeze-dried and solubilized in the buffer solution, a liquid type formulation can be obtained. In addition, the liquid type formulation further comprising above-described stabilizer can be prepared. However, as long as the effect of the present invention is preserved, there is no limit for formulation type, administration route and administration method.
Inhibitory effect of the pharmaceutical composition of the present invention on tumor growth was observed when p43 protein is administered once everyday in a dose of 25~50mg/kg/day and paclitaxel is administered at the beginning day of the administration and 2 days, 5 days, 8 days, and 11 days later on in a dose of 5mg/kg, that is considered to be a minimum amount for inhibiting cancer cell growth. Therefore, p43 protein can be administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg, and paclitaxel can be administered once or several times at the beginning day of the administration and later once or several times every two or three days from the beginning day of the administration, in a dose of 1 mg/kg to lOmg/kg. Preferably, said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel can be initially administered at once at the beginning day of the administration and every two or three days later on in once-a-day manner, in a dose of 5mg/kg. However, final dose and dosing frequency can be adjusted within the allowed range that is clinically determined in view of characteristics of drug formulation, administration method and route , patient's condition, age, body weight, sex, nature of symptom, and severeness of sickness, etc.
Meanwhile, when two kinds of compounds are administered in combination for the treatment of cancer, actual administration amount for each component can be only 70 to 80% of those in single administration, due to the synergy effect. Therefore, by administering paclitaxel with p43 protein obtained from living organisms, the administration amount of paclitaxel, of which side effects are frequently in concern, is minimized while anticancer effect is synergistically increased. As described before, the pharmaceutical composition of the present invention is very useful for the treatment of abnormal cell growth, i.e., cancer. Example of cancer includes solid cancer such as lung cancer, stomach cancer, large intestinal cancer, liver cancer, bone cancer, spleen cancer, skin cancer, cephalic cancer, cervical cancer, cutaneous or intraocular melanoma, uterine sacoma , ovarian cancer, rectal cancer, cancer of anal region , colon cancer, breast cancer, Fallopian tube carcinoma, endometrium carcinoma, uterine cervical carcinoma, vagina carcinoma, vulval carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary track cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, kidney bone carcinoma, CNS tumor, primary CNS lymphoma, bone marrow tumor, brain stem nerve glioma, and pituitary adrenoma, and combination thereof in which more than one type of cancer is involved.
In order to confirm the anticancer activity of the pharmaceutical composition of the present invention, xenograft model was employed. As an in vivo test, xenograft model is commonly used for the development of new anticancer agent. It is usually carried out using a nude mouse. In the present invention, a nude mouse, free of specific pathogen is grafted with human lung cancer cell line or human stomach cancer cell line, respectively. After administering p43 protein and paclitaxel either alone or in combination, survival ratio, body weight and cancer size of the treated mouse was measured and anticancer activity for each case was determined. As a result, for the mouse grafted with human lung cancer cells, there was greater inhibition on tumor growth in a significant sense by the combined administration of p43 protein and paclitaxel, compared to a single administration case. Furthermore, for the mouse grafted with human stomach cancer cells, the inhibition on tumor growth by the combined administration of p43 protein and paclitaxel was huge, compared to the single administration case, and the survival ratio was increased in a significant sense by the combined administration. Especially for the test animals grafted with stomach cancer cells, there was increased survival ratio up to four times for the combined administration of p43 protein and paclitaxel, compared to the single administration group.
The present invention provides the method of treating cancer including administration of pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient in need of such treatment.
Specifically, the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient, in which the two components are formulated into either a single or a separate composition.
More specifically, the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising p43 protein and paclitaxel to a patient simultaneously, separately, or sequentially.
Still more specifically, the present invention provides the method of treating cancer including administration of p43 protein everyday from the beginning day of the administration while administering paclitaxel initially on the beginning day and keeping its administration every 2 or 3 days from the beginning day. In addition, the present invention provides the method of treating cancer including administration of p43 protein once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days from the beginning day of the administration. More preferably, said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5mg/kg can be initially administered once on the beginning day of the administration and later on every two or three days in once-a-day manner. In addition, the present invention provides the method of treating cancer which including administration of the pharmaceutical composition to a patient orally or parenterally. Example of the oral or the parenteral administration is the same as described above.
The present invention also provides the method of treating cancer including administration of the pharmaceutical composition comprising effective amount of p43 protein and paclitaxel to a patient, and pharmaceutically acceptable carrier as an additional component. The pharmaceutically acceptable carrier is the same as described above.
A 'patient' described above means a person diagnosed with the abnormal cell growth i.e., cancer. Cancer varieties are the same as those described in the above. Especially in the present invention, the term 'patient' refers to the patient diagnosed with a lung or stomach cancer.
The present invention also provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition used for cancer treatment in which the two components are administered in combination.
Specifically, the present invention provides a use of p43 protein and Paclitaxel for preparing the pharmaceutical composition for cancer treatment in which said two components are formulated into either a single or a separate composition.
More specifically, the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the two components are administered simultaneously, separately, or sequentially.
Still more specifically, the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered everyday from the beginning day of the administration while paclitaxel is administered initially on the beginning day and is later being kept administered every 2 or 3 days.
In addition, this invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel is administered once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days. More preferably, the p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5 mg/kg can be initially administered once on the beginning day of the administration and later every two or three days in once-a-day manner. In addition, the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition is administered orally or parenterally. Example of the oral or parenteral administration is the same as described above. In addition, the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition comprises the effective amount of p43 protein and paclitaxel, and further comprises pharmaceutically acceptable carrier.
Cancer varieties are the same as those described in the above. Especially in the present invention, it can be a lung or stomach cancer.
Preferred embodiments of the present invention are given below. However, in no way the present invention will not be limited thereto.
Example 1 Anticancer activity in the lung cancer xenograft mouse model by single or combined administration of p43 protein and paclitaxel
1-1) Quarantine, acclimation and keeping of the test animals A nude mouse with BALB/C origin and specific pathogen free (SPF) was used as a test animal for the present invention (5 weeks old, Daehan Biolink Inc). After obtaining said animals, their appearance was visually examined. Animals were acclaimed for seven days in the animal room where tests will be carried out. General things were checked and only the healthy animals were chosen for the test. Said animals were kept in the animal keeping room where under condition had been maintained as temperature of 23+ 3 °C, relative humidity of 50+ 15%, 12 hour of lighting (from 8AM to 8PM), ventilation frequency of 10-20 times/hr and light intensity of 150~300Lux. During the acclimation and quarantine period, ten animals were kept in each keeping box (260Wx 420Lx 180H mm). During the period of administering the test composition and observation thereafter, four or fewer animals were kept in the keeping box (200WX 260Lx 13 OH mm). Solid feed stuff for a test animal, sterilized with radiation (Daehan Biolink), was freely fed to the test animals.
1-2) Grafting the test animal with cancer cells
To each of the individual mouse prepared in accordance with the above step 1-1), human lung cancer cell line was grafted. NCI-H460 cell line was obtained from Cancer cell line Bank of the Korean Research Institute of Bioscience and Biological and used as a human ling cancer cell line for the present invention. Cancer cell lines obtained as described above were cultured in a CO2 incubator (Forma, USA) at temperature of 37 °C and CO2 concentration of 5%. RPMI-1640, in which FBS (Fetal bovine serum, GibcoBRL, 16000-044) was added to the final concentration of 10% and 10% peniciline-streptomycin solution (GibcoBRL, 15140-122) was also added, was used as a the culture medium. For the grafting of said cancer cell lines to the mouse, cancer cells isolated from the culture medium was stored in cold temperature . On the final day of culturing, all the cells were collected and counted. Then, using PBS (phosphate buffered saline), cell concentration was adjusted to 3x 107cells /ml. Adjusted cell culture solution was subcutaneously injected to fifty acclaimed and healthy mice in the amount of 3 ml/animal at axillia region between right side shoulder and chest wall.
1-3) Single or combined administration of p43 protein and paclitaxel
Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the lung cancer cells, as described in the above step 1-2).
First of all, the size of cancer found in the nude mouse grafted with the cancer cells was measured and ranked. The measurement of cancer was carried out by determining width, length and thickness of the cancer cells using Vernier calipers.
The body weight of the animal was measured at the same time. Animals were put in order with their cancer size estimated from said measurements. Among the test animals, forty animals with the cancer size similar to the mean value were selected and allocated into a separate group using a computer so that the size of cancer is evenly distributed among each group.
To each group prepared as described above, p43 protein was administered either alone or in a combination with paclitaxel. Specifically, 25mg/kg of p43 protein was administered alone (low dose p43 administration group), 50mg/kg of p43 protein was administered alone (high dose p43 administration group), 25mg/kg of p43 protein was administered in combination with 5mg/kg of paclitaxel (GENEXOL , Samyang Genex Inc.) (combined administration group of low dose p43 and paclitaxel), or 50mg/kg of p43 protein was administered in combination with 5mg/kg paclitaxel (combined administration group of high dose p43 and paclitaxel). As a negative control, PBS (phosphate buffered saline) comprising 20% glycerol (Sigma) was administered. Administration method involves fixing a mouse with an abdominal skin fixing method and administering the test compositions to the mouse in an intraperitoneal route . As to the number and period of the administration, p43 Protein was administered once everyday for 28 days" and paclitaxel was administered total of five times, i.e., at the beginning day of the administration, and 2 days, 5 days, 8 days and 11 days later. Test groups and administered dose are summarized in the following table.
Table 1
Test groups and dose administered
Figure imgf000022_0001
V.C. : lx PBS (Phosphate buffered saline) solution containing 20%) of glycerol
1-4) Observation of the change in the general symptom and mortality of the test animals by single or combined administration of p43 protein and paclitaxel
General symptom and mortality of the test animals were observed everyday before and after the administration of p43 protein and paclitaxel. The observation had been carried out for 7 days after termination of administration.
The experimental result shows that, in connection with the administration of p43 protein and Paclitaxel, no change was observed for the general symptom of the test animals. However, there were tumor necrosis and dropped body temperature for the test animals right before their death. Furthermore, as shown in Figure 1, there was no change in death ratio in a significant sense in accordance with the administration of p43 protein and paclitaxel.
1-5) Measurement of the change in the body weight, tumor size and tumor weight of the test animals by single or combined administration of p43 protein and paclitaxel
The body weight of all the animals in the above step 1-3) was measured on the beginning day of the administration, and twice per week during the administration period, and once per week during the observation period after the administration had been terminated. Tumor size was measured on the beginning day of the administration and every other day during the administration period. Width, length and thickness of the tumor were measured using a vernier calipers. Tumor volumes were calculated using the equation described below. In addition, change in the relative tumor size was calculated by dividing the tumor size measured every other day with the tumor size before the administration, and is described in percentage value. Tumor weight was measured with the autopsied mouse after the test has been terminated. After the mean values for the body weight, tumor size and tumor weight and standard deviation values thereof were obtained for each test group, their statistical significance was determined using the student-t test.
{width (mm)x length (mm)x thickness (mm)}/2=tumor size (mm3)
As it is indicated in Figure 2, the body weight of the test animal decreased in a dose dependent manner till the 3rd day of the administration, except for the negative control group. The body weight loss ratio for the test groups compared to the negative control group is as follows; 87% loss for the low-dose p43 protein administration group, 84% loss for the high-dose p43 protein administration group, 84% loss for the combined administration group of the low-dose p43 protein and paclitaxel, and 81% loss for the combined administration group of the high-dose p43 protein and paclitaxel. After three days of the administration, normal body weight gain was observed. Still, the body weight of the animals in all of the test groups is lower than that of the negative control group.
Meanwhile, change in tumor size is indicated in Figure 3 and Figure 4. The tumor growth ratio for the negative control group and the test groups at the end of the administration, i.e., on 28th day, is as follows; 5192% for the negative control group,
4231% for the low-dose p43 protein administration group, 4941% for the high-dose p43 protein administration group, 3629%) for the combined administration group of the low-dose p43 protein and paclitaxel, and 3301%) for the combined administration group of the high-dose p43 protein and paclitaxel. Such results indicate that when the tumor growth ratio for the low-dose p43 protein administration group, the high-dose p43 protein administration group, the combined administration group of the low-dose p43 protein and paclitaxel, and the combined administration group of the high-dose p43 protein and paclitaxel is compared to that of the negative control group, there is inhibition on the tumor growth of 19%, 5%, 30%, or 36%, respectively. The tumor growth inhibition ratio for the test groups compared to that of the control group is further calculated using the following equation.
(Relative tumor growth ratio for the negative control group - Relative tumor growth ratio for the test group) x 100 / Relative tumor growth ratio for the negative control group Therefore, it is found that tumor growth is inhibited more for the combined administration of paclitaxel and p43 protein compared to the single administration of p43 protein. Moreover, from the 8th day to the end of the administration, the tumor size of the test group administered with p43 protein alone seems to be smaller than that of the control group. On the other hand, for the test group administered with p43 protein and paclitaxel in combination, the tumor size started to decrease in a statistically significant sense from the 4th or 6th day of the administration, compared to the control group. Therefore, it is obvious that the combined administration of p43 protein and paclitaxel can significantly inhibit the tumor growth in relatively short period of time. Even for the test group administered with p43 protein alone, the tumor size seems to decrease during the entire test period compared to the control group.
Table 2 and Figure 5 represent the test result for tumor weight change. The results demonstrate that, compared to the control group, the tumor weight decreased in a dose dependent manner for both of the test groups; i.e., p43 protein single administration group (Gl: low-dose p43 protein administration group, G2: high-dose p43 protein administration group) and the combined administration group of p43 protein and Paclitaxel (G3: low-dose p43 protein and Paclitaxel, G4: high-dose p43 protein and Paclitaxel). The tumor weight decreased most dramatically for the combined administration group of p43 protein and Paclitaxel.
Table 2
Tumor weight change for the single administration group of p43 protein or the combined administration group of p43 protein and paclitaxel
Figure imgf000026_0001
- : animals perished
N.C.: lx PBS(Phosphate buffered saline) solution containing 20%) of glycerol
The reason for having smaller weight gain ratio for the combined administration of p43 protein and paclitaxel compared to the single administration of p43 protein is believed to be due to the fact that, since the tumor weight decreased more in the combined administration group, the overall weight gain ratio becomes smaller than that of the single administration group.
In conclusion, tumor growth can be more significantly and more quickly inhibited by the combined administration of p43 protein and Paclitaxel than by the single administration of p43 protein.
Example 2
Anticancer activity in the stomach cancer xenograft mouse model by single or combined administration of p43 protein and paclitaxel2-l) Quarantine, acclimation and keeping of the test animals
Nude mouse for the test was quarantined and acclaimed according to the method as described in the above Example 1. Stomach cancer cells were grafted into
55 of said animals. For the stomach cancer cells, human stomach cell line NUGC-3 was obtained from Cancer cell line Bank of the Korean Research Institute of
Bioscience and Biological and used.
2-2) Single or combined administration of p43 protein and paclitaxel
Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the human stomach cancer cells as described in the above step 2-1). Since the tumor growth varied a lot among the test mice grafted with the human stomach cancer cells, the test groups were formed by carrying our said measurements every other day. Total of 24 mice with the tumor size of 50~100mm3 were selected and allocated into a separate test group using a computer so that the size of cancer is evenly distributed among each test group. After two days, another group of 24 mice with a similar tumor size were selected from the rest of the mice and allocated into the test group using the computer. To each of said groups constituted as described above, p43 protein was administered alone or in combination with paclitaxel following the same method as described in Example 1. Constitution of test groups and dose are described in Table 3 below. An animal group administered with 5ml kg of paclitaxel was taken as a positive control.
Table 3 Test groups and dose administered
Figure imgf000028_0001
V.C: lx PBS(Phosphate buffered saline) solution containing 20% of glycerol
2-3) Observation of the change in the general symptom and mortality of the test animals by administration of p43 protein and paclitaxel
To the mouse grafted with human stomach cancer cell according to the method described in the above Example 1, p43 protein was administered alone or in combination with paclitaxel. General symptom and mortality of the animals were then observed.
As a result, no general symptom change was found for the mouse grafted with the stomach cell after the administration of p43 protein and paclitaxel. Only right before the test animal was perished, there were sporadic death of tumor cells and drop of the body temperature. Survival ratio of the test animals by the administration of p43 protein and paclitaxel is shown in Figure 6. Specifically, the survival ratio for each test groups is as follows; 25%> for the negative control group to which the excipient was administered on the final day of administration (Day 28), 63% for the low dose p43 protein administration group, 25% for the high dose p43 protein administration group, 100%) for both of the combined administration groups of the low-dose p43 protein and paclitaxel and the high-dose p43 protein and paclitaxel, and 63 % for the positive control in which Paclitaxel is administered only. At the time of autopsy, survival ratio of more than 50% was observed for the combined administration group of p43 protein and paclitaxel. For other test groups, most of the test animals were perished. In addition, for the negative control group and the single administration group with p43 protein, death of the test animals was observed from the 5th day of the administration. In canse of the single administration of paclitaxel or the combined administration p43 protein and paclitaxel, death of the test animals was observed form the 19th day of the adminstration or from the 28th day after administration had been terminated, respectively. Therefore, the animals in the negative control group and single administration group with p43 protein were especially early dead observed in compared with the cases of the single administration of pacilitaxel or the combined administration of p43 protein and paclitaxel.
2-4) Measurement of the change in the body weight, tumor size and tumor weight of the test animals by single or combined administration of p43 protein and paclitaxel
Change in the body weight, tumor size and tumor weight of the test animals by single or combined administration of p43 protein and paclitaxel was measured according to the same method as described in Example 1.
As a result, the change in the body weight of the test animals is shown in Figure 7. For all of the test animal groups including the negative control group, the body weight of the test animals was temporarily decreased after two days from the administration of p43 protein and paclitaxel in a single or combination. These are the same results as those observed for the mouse grafted with the human lung cancer cell line. However, for the combined administration of p43 protein and paclitaxel and the positive control group in which paclitaxel is administered alone, the test animals slowly started to regain their body weight from the 5th day of the administration, and eventually recovered fully the original weight around the 10th day. Meanwhile, for the negative control group, no such gain was observed and the body weight of the test animals kept decreasing. For the test group administered with p43 protein only, no significant change in the body weight of the test animals was observed and the animals maintained to have temporarily lighter body weight. Change in the tumor size is shown in Figures 8 and 9. Until the 14th day of the administration when less than half of the test animals were perished in the negative control group, there was no specific inhibition for tumor growth in the group administered with p43 protein compared to the negative control group. However, for the group administered with p43 protein and paclitaxel in combination (i.e., combined administrations of low dose p43 protein plus paclitaxel and high dose p43 protein plus paclitaxel), there was tumor growth inhibition of 85% and 94%, respectively, in a significant sense on the 14th day of the administration compared to the control group. Therefore, such results indicate that the tumor size remained almost the same from the initiation of the administration. As such, it is obvious that, with the combined administration of p43 protein and paclitaxel, the tumor completely stops growing or even starts to disappear. In addition, for the group administered with paclitaxel alone, there was tumor growth inhibition of 58%) in a significant sense, on the 14th day of the administration. Meanwhile, for the experiments with the stomach cancer cell graft, accurate comparison of the control group with the test group during the second half of the test (i.e., after the 14th day of the administration) was not possible, due to the high mortality among the control group.
In conclusion, by having the combined administration of p43 protein and paclitaxel, more efficient inhibition of tumor growth can be achieved compared to the single administration of p43 protein or paclitaxel.
For the stomach cancer graft, the tumor weight cannot be compared between the control group and the test group, due to the high mortality among the control group and the single administration group of p43 protein. Since the high mortality, continuing weight loss and high incidents of tumor growth over the beginning period of the test were found for the test animals of the control group grafted with the human stomach cancer cell line, it is believed that the cancer cells grafted therein cause the animal death. Moreover, with respect to the high survival ratio and the inhibition of tumor growth at the early stage of the experiment for the group administered with p43 protein and paclitaxel in combination, it is believed that they are caused by the anticancer activity of said drugs. Taken together, it is found that the combined administration of p43 protein and paclitaxel is more efficient than the single administration of p43 protein or Paclitaxel, in terms of anticancer activity against stomach cancer.
Industrial applicability
The pharmaceutical composition comprising p43 protein and paclitaxel and the treatment method using the same of the present invention are advantageous in that, compared to the single administration, tumor growth can be more significantly inhibited by administering the two components in combination, and therefore can provide synergistic treatment effect. In addition, the pharmaceutical composition and the treatment method using the same of the present invention can minimize the use of paclitaxel, of which side effects are in concern, and therefore can reduce the undesirable effects of the anticancer agents.

Claims

What is claimed is:
1. Pharmaceutical composition for cancer treatment, which comprises the effective amount of p43 protein and paclitaxel.
2. The pharmaceutical composition according to Claim 1, which is characterized in that said p43 protein and paclitaxel are prepared in the form of a single or a separate composition.
3. The pharmaceutical composition according to Claim 1, which is characterized in that the p43 protein and paclitaxel are administered simultaneously, separately or sequentially.
4. The pharmaceutical composition according to Claim 2, which is characterized in that, for the separate composition, p43 protein is administered everyday from the beginning day of the administration and paclitaxel is initially administered on the beginning day of the administration and then kept being administered every two or three days after the administration has begun.
5. The pharmaceutical composition according to Claim 4, which is characterized in that the p43 protein is administered once or several times a day in a dose of lOmg/kg to 50mg/kg.
6. The pharmaceutical composition according to Claim 5, which is characterized in that the p43 protein is administered once a day in a dose of 25mg/kg to 50mg/kg.
7. The pharmaceutical composition • according to Claim 2, which is characterized in that, for the separate composition, paclitaxel in a dose of 1 mg/kg to lOmg/kg is initially administered once or several times on the beginning day of the administration and then kept being administered once or several times every two or three days after the administration has begun.
8. The pharmaceutical composition according to Claim 7, which is characterized in that for the separate composition, paclitaxel in a dose of 5mg/kg is firstly administered once on the beginning day of the administration and then kept being administered once every two or three days after the administration has begun.
9. The pharmaceutical composition according to Claim 1, which is characterized in that the composition is administered either orally or parenterally.
10. The pharmaceutical composition according to Claim 1, which is characterized in that the composition further comprises a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to Claim 1, wherein the cancer is solid cancer.
12. The pharmaceutical composition according to Claim 11, which is characterized in that the solid cancer is one selected from the group consisting of lung cancer, stomach cancer, large intestinal cancer, liver cancer, bone cancer, spleen cancer, skin cancer, cephalic cancer, cervical cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of anal region , colon cancer, breast cancer, Fallopian tube carcinoma, endometrium carcinoma, uterine sacoma vagina carcinoma, vulval carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary track cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, kidney bone carcinoma, CNS tumor, primary CNS lymphoma, bone marrow tumor, brain stem nerve glioma, and pituitary adrenoma, or combination thereof.
13. The pharmaceutical composition according to Claim 12, which is characterized in that the cancer is either a lung or stomach cancer.
14. Method of treating cancer, which comprises administering the pharmaceutical composition comprising effective amount of p43 protein and paclitaxel to a patient in need of the treatment.
15. The method of treating cancer according to Claim 14, which is characterized in that the p43 protein and paclitaxel are prepared in the form of a single or a separate composition.
16. The method of treating cancer according to Claim 14, which is characterized in that said p43 protein and paclitaxel are administered simultaneously, separately or sequentially.
17. The method of treating cancer according to Claim 15, which is characterized in that, for the separate composition, p43 protein is administered everyday from the beginning day of the administration and paclitaxel is initially administered on the beginning day of the administration and then kept being administered every two or three days after the administration has begun.
18. Use of p43 protein and paclitaxel for the preparation of the pharmaceutical composition, which are administered in combination to treat cancer.
19. Use of p43 protein and paclitaxel for the preparation of the pharmaceutical composition according to Claim 18, which is characterized in that that the p43 protein and paclitaxel are prepared in the form of a single or a separate composition.
20. Use of p43 protein and paclitaxel for the preparation of the pharmaceutical composition according to Claim 18, which is characterized in that the p43 protein and paclitaxel are administered simultaneously, separately or sequentially.
21. Use of p43 protein and paclitaxel for the preparation of the pharmaceutical composition according to Claim 19, which is characterized in that, for the separate composition, p43 protein is administered everyday from the beginning day of the administration and paclitaxel is initially administered on the beginning day of the administration and then kept being administered every two or three days after the administration has begun.
PCT/KR2003/000085 2003-01-15 2003-01-15 Pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof WO2004062687A1 (en)

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WO2008064596A1 (en) * 2006-11-29 2008-06-05 Sine Pharmaceutical Laboratories Pharmaceutical composition comprising p43 protein for the treatment of gastric adenocarcinoma
CN101824082A (en) * 2009-03-06 2010-09-08 信谊药厂 N-end deletion type p43 protein and application thereof in medicaments for treating tumors

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WO2001095927A1 (en) * 2000-06-14 2001-12-20 Imagene Co., Ltd. P43 anti-tumor therapeutic agent and three dimensional structure of its cytokine domain

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2008064596A1 (en) * 2006-11-29 2008-06-05 Sine Pharmaceutical Laboratories Pharmaceutical composition comprising p43 protein for the treatment of gastric adenocarcinoma
CN101824082A (en) * 2009-03-06 2010-09-08 信谊药厂 N-end deletion type p43 protein and application thereof in medicaments for treating tumors

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