WO2001003738A1 - Agents de type polymeres destines a la prevention de metastases et de la recurrence du cancer et methode de prevention de metastases et de la recurrence du cancer - Google Patents

Agents de type polymeres destines a la prevention de metastases et de la recurrence du cancer et methode de prevention de metastases et de la recurrence du cancer Download PDF

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Publication number
WO2001003738A1
WO2001003738A1 PCT/JP2000/004307 JP0004307W WO0103738A1 WO 2001003738 A1 WO2001003738 A1 WO 2001003738A1 JP 0004307 W JP0004307 W JP 0004307W WO 0103738 A1 WO0103738 A1 WO 0103738A1
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recurrence
cancer
metastasis
cancer metastasis
surgery
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PCT/JP2000/004307
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English (en)
Japanese (ja)
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Hiroshi Maeda
Toshimitsu Konno
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Hiroshi Maeda
Toshimitsu Konno
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Publication of WO2001003738A1 publication Critical patent/WO2001003738A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Definitions

  • the present invention is intended to prevent cancer metastasis and recurrence during or after solid tumor resection surgery in the body cavity, before, during or after surgery, in the body cavity near the site where metastasis or recurrence is most likely to occur, or in metastasis or recurrence.
  • the present invention relates to a high molecular weight cancer metastasis' relapse prevention agent administered to a metastatic route to a site of origin. More specifically, when administered to a cancer patient, it stays in the body cavity for a long time, and effectively prevents the recurrence of the primary cancer apparently cured by surgery or metastasis from the primary cancer.
  • Molecular cancer metastasis ⁇ Relapse prevention agent is intended to prevent cancer metastasis and recurrence during or after solid tumor resection surgery in the body cavity, before, during or after surgery, in the body cavity near the site where metastasis or recurrence is most likely to occur, or in metastasis or recurr
  • Lung cancer, stomach cancer, and other solid cancers are the main carcinomas of the thoracic cavity and intraperitoneal organs (lung, stomach, liver, colon, etc.). Treatment of these cancers is surgery, chemotherapy, radiation therapy, immunotherapy, etc. Alternatively, various treatments using them in combination have been performed.
  • the mainstream of cancer treatment is still surgery or chemotherapy, and the progress of surgery has recently increased the cure rate of primary cancer significantly.
  • it even if it is visually undetectable and apparently cured, it completely prevents the recurrence of cancer due to extremely small cancer cells, or metastasis to other organs during or after surgery It is difficult to do so.
  • recurrence and metastasis often lead to death, and recurrence after surgery often accounts for more than 50% of surgical cases.
  • Metastatic cancer is often difficult to treat surgically, and most are treated with chemotherapy or I have to rely on radiation therapy. Therefore, it is rational to deposit the drug in advance at the site where metastasis / recurrence occurs before these metastasize.
  • the recurrence of cancer after surgery is mainly due to the dissemination of small adherent tumors that have not been completely removed at the time of surgery into the body cavity, or the cancer cells passing through the blood or lymphatic fluid (lymphoid system).
  • Mediated lymphatic mechanisms Considering that cancer cells migrate to other organs and proliferate at the metastasis site and cause recurrence, anticancer drugs that can extinguish cancer cells that remain in the body cavity and adhere to Sprayed or retained in body cavities such as the thoracic cavity and abdominal cavity where expected normal organs and normal cells are located, or administered to blood vessels and lymph nodes that are pathways for metastasis and remain in the body cavities for a long time If the dissemination of disseminated cancer is removed, metastasis and recurrence can be greatly controlled.
  • the inventor of the present invention solves this problem by using a polymerized drug and, moreover, an oily drug. It is considered that the most effective means is to use a formulated drug, and if a high-molecular-weight drug is used, it will stay in the body cavity for a long time without spreading to other organs or moving into blood vessels. Kills tumor cells that come in contact with it And it was focused on the fact to exert a relapse prevention effect of disseminated.
  • the body cavity is the place where the immune inflammatory cells (macrophages, neutrophils and lymphocytes) are most abundant and has the ability to activate these cells. Focusing on the fact that if a drug is administered into the body cavity as a polymerized and oily anticancer drug, it is the optimal method to increase the immunity of the host most efficiently. We tried to solve this problem by using
  • NCS neocarzinostatin
  • SMA styrene-maleic acid copolymer residue
  • SMANCS high-molecular-weight anticancer agent
  • Smantas is a high-molecular-weight anticancer drug, unlike conventional drugs, metastasis is expected in advance. If administered to a body cavity near the normal organ or a blood vessel that is a metastatic route, such as the portal vein or lymphatic vessel, before, during, or after surgery, it diffuses into other healthy organs other than the administration site and moves into the blood vessel The tumor remains in the organs and tissues of the normal part where relapsed or disseminated tumor cells are apt to engraft without prolonged invasion. It has been found that such a high molecular weight anticancer agent is particularly effective when used as a cancer metastasis preventive agent, since it exhibits a metastatic recurrence preventive effect.
  • the present inventors have also found out that a conventional low-molecular compound type anticancer drug is also effective for preventing recurrence of metastasis of cancer by binding it to a high-molecular compound to polymerize it, and arrived at the present invention.
  • the present invention relates to an anticancer drug in which a drug having an anticancer action is combined with a polymer compound, and is used for preventing cancer metastasis and recurrence to normal organs or cells during or after solid tumor resection surgery. It is a high-molecular-weight cancer metastasis / relapse prevention agent administered before, during, or after surgery in the body cavity near metastatic sites or in metastatic routes to metastatic sites.
  • the present invention is also a method for preventing cancer metastasis / relapse using such a high molecular weight cancer metastasis / recurrence preventive agent.
  • the present invention is particularly directed to the use of "Smanx" (dinostatin stimaramamer), a neocarzinostatin derivative in which neocarzinostatin (NCS) is bonded to a styrene-maleic acid copolymer residue (SMA) as an active ingredient. And a method for preventing cancer metastasis using the same.
  • "Smanx" dinostatin stimaramamer
  • NCS neocarzinostatin derivative in which neocarzinostatin
  • SMA styrene-maleic acid copolymer residue
  • FIG. 1 is a graph showing the intraperitoneal survival rate and the time course of blood translocation when the high-molecular weight anticancer drug Smantas was administered intraperitoneally to a cancer-bearing (AH136 tumor) rat.
  • FIG. 2 shows the low-molecular weight anticancer drug doxorubicin in cancer-bearing (AH136 tumor) rats.
  • FIG. 3 is a graph showing the intraperitoneal residual rate and the time course of blood transit when administered intraperitoneally.
  • FIG. 3 is a graph showing the intraperitoneal survival rate and the time course of blood transit when mitomycin was administered intraperitoneally to a cancer-bearing (AH136 tumor) rat.
  • FIG. 4 is a graph showing the intraperitoneal survival rate and the time course of blood translocation when radioactive albumin as a model compound of macromolecule was administered intraperitoneally to a cancer-bearing (AH 136 tumor) rat.
  • the polymer-type cancer metastasis / recurrence preventive agent of the present invention comprises a component having an anticancer effect as an active ingredient, which is bound to a polymer compound by a covalent bond, an ionic bond, or the like, to form a polymer. can get.
  • any one of a polymer and a low-molecular compound may be used as long as it has biocompatibility and can bind to a polymer compound to form a polymer-type cancer metastasis preventive agent
  • neocarzinostatin, mitomycin, doxorubicin, cisplatin and the like can be exemplified.
  • Polymeric compounds for forming high-molecular-weight cancer metastasis / recurrence preventive agents include styrene-maleic acid copolymer, polyamino acid, hydroxypropyl.methacrylate copolymer, polyvinylpyrrolidone, and polyethylene. Examples include glycol, polyvinyl alcohol, soluble gelatin, chitins, pullulan, dextrans, and starch.
  • Table 1 can be given as an example of a high molecular weight anticancer agent obtained by combining these high molecular compounds and drugs. [table 1 ]
  • HMPA Hydroxypropylmethacrylate copolymer
  • PVP Polyvinylpyrrolidone
  • the behavioral molecular weight in vivo is 40,000 or more. If the behavioral molecular weight is lower than this, it will not stay at the target site in the body cavity for a long time, will diffuse freely into the blood and other organs, and will not be able to increase the concentration of the cancer metastasis / relapse prevention agent in the body cavity.
  • the molecular weight of the cancer metastasis preventive agent itself needs to be high molecular weight, and the average molecular weight is preferably 10,000 or more, but even if it is less than that, it binds to albumin etc. Then, the object of the present invention can be achieved as long as the behavioral molecular weight in vivo becomes 40,000 or more.
  • SMANC S neocarzinostatin
  • SMA styrene-maleic acid copolymer
  • Neocarzinostatin is derived from Streptomyces carzinostaticus var.
  • F-41-Kuroya is a proteinaceous anti-cancer substance produced in a culture of the present invention (Japanese Patent Publication No. 42-21752, US Pat. No. 3,334,022), and its primary structure is one of the present invention.
  • Japanese Patent Publication No. 42-21752, US Pat. No. 3,334,022 Japanese Patent Publication No. 42-21752, US Pat. No. 3,334,022
  • a certain Maeda reported that the total number of amino acid residues was 109, with an estimated molecular weight of 10,700 (Science 178, 875-876 (1972)), and Arch. Biochem, Biophys., 163, 379-385).
  • NCS neocarzinostatin
  • SMA styrene-maleic acid copolymer
  • [NCS] is the primary amino group in the alanine residue at position 1 of neocarzinostatin or the primary amino group in the lysine residue at position 20 with one hydrogen atom removed from each. Means a monovalent neocarzinostatin residue.
  • [SMA] is
  • R represents a hydroxyl group from an alkyl alcohol having 1 to 4 carbon atoms, an ethylene glycol monoalkyl ether having 1 or 2 carbon atoms in an alkyl group, or a glycerin dialkyl ether having 1 or 2 carbon atoms in an alkyl group. This is an alcohol residue excluding.
  • [SMA] refers to a maleic acid residue represented by the above formulas (5) and (6) and a carbonyl group in which a hydroxyl group is removed from a carboxyl group in a Z or half-esterified maleic acid residue. It has a bond of a carbon atom, whereby it is combined with [NCS] to form a polymer type anticancer drug.
  • a typical example of Sumantas is a compound (Bu-SMANCS) in which the half-esterified styrene maleic acid copolymer residue in the SMA is a half butyl esterified styrene maleic acid copolymer residue. .
  • Sumantas is a drug that is particularly excellent in activating the immune system in the body cavity where the immune inflammatory cells (macrophages, neutrophils, and lymphocytes) are most abundant. Therefore, it readily binds to serum albumin in body cavities, has a higher apparent molecular weight, stays in body cavities for a long time, and maximizes the effect of preventing the recurrence of cancer metastasis. It is the most suitable cancer metastasis preventive agent.
  • Polymeric cancer metastasis preventive agents that are conjugates with high molecular compounds, such as Sumantas, further include higher fatty acid glyceride, medium chain fatty acid triglyceride, diglyceride, soybean oil, olive oil, other vegetable oils or oil-based contrast agents (for example, it can be used by suspending and dissolving with, for example, Piridol. Also If necessary, other refined oils can be blended. For example, for Smanx, 1 mg of 1 mg is suspended and dissolved in 2 ml of an oil-based contrast medium by ultrasonic waves, and the suspension is usually used in an amount of 1 to 4 mg in the thoracoabdominal cavity.
  • aqueous solution such as physiological saline, an 8% sodium bicarbonate solution, and a 5% glucose solution.
  • Other fatty acid triglycerides, fatty acids and their esters, olive oil, cottonseed oil, oleic acid, soybean oil, and other vegetable oils may be used.
  • the polymer-type cancer metastasis / recurrence preventive agent of the present invention is used for preventing metastasis and recurrence during surgery for solid cancer, and is performed by visual inspection of normal tissues and normal organs in which cancer cells are not yet found, and normal surgery. Is intended to be retained for a long time in the apparently cured area, and is therefore administered to body cavities such as the abdominal cavity and thoracic cavity or blood vessels that serve as a metastatic pathway for cancer, for example, portal vein and lymph vessels.
  • body cavities such as the abdominal cavity and thoracic cavity or blood vessels that serve as a metastatic pathway for cancer, for example, portal vein and lymph vessels
  • it is used as a metastasis preventive agent administered in the body cavity near the metastatic site or in the metastatic route to the metastatic site. Is valid.
  • the administration is performed immediately before, during or immediately after the surgery, and the administration can be carried out using a syringe, a spray, or the like, or the composition can be soaked in gauze and applied.
  • the substance may be administered in the form of a sponge or a film absorbed in a substance that dissolves in the body, for example, fibrin, gelatin, pullulan, or the like. It can be administered to blood vessels such as the portal vein, which is a route of hematogenous or lymph node dissemination and metastasis, or into the blood vessels.
  • the resection of the tumor was performed on 10 egrets, and the stump was sutured.
  • the control group was treated with 1.0 ml of saline without administration of an anticancer drug. Administer, suture and close as above.
  • the group to which the high-molecular-weight anticancer drug Smanx was administered was more effective in preventing recurrence after surgery for lung tumors than the mitomycin-administered group and the group without the anti-cancer agent. .
  • Example 2 Intraperitoneal dissemination after resection of liver cancer in a rat model using the high-molecular weight anticancer drug Sumantas) ⁇ Preventive chemotherapy for cancerous peritonitis
  • 230 g to 310 g of donryulat, 30 males or females were anesthetized by intravenous injection of pentobarbutyrate and sodium, incised and opened about 5 cm in the upper abdomen, the liver was exposed, and ascites cancer was developed in another donryurat. Then, 2 ⁇ 10 6 / ml of AH136B tumor subcultured in the abdominal cavity was suspended in 1 ml of Dulbecco's MEM medium and dispersed on the liver membrane to create a rat model of disseminated intraperitoneal metastasis. That is, this is used as a tumor dissemination model during surgery. The rats are then divided into the following three groups and treated separately.
  • the first group is a group administered with the high-molecular-weight anticancer drug Sumantas / Lipiodol suspension.
  • the smux is 1.0 mg / kg, and the amount of SMIV is 1.0 ml (containing about 0.3 mg) of Libiodol.
  • the second group is a group to which mitomycin C (Kyowa) is administered, which is a typical example of a low-molecular-weight anticancer drug. 1. About 0.3 mg of this drug was dissolved in 2 ml of 5% glucose at a dose of Omg / kg. Spray intraperitoneally and administer.
  • the third group is a control group to which no anticancer drug was administered and only 2 ml of 5% glucose was administered.
  • the drugs in groups 1 and 2 are less than 1/2 to 1/3 of the maximum tolerated dose.
  • Example 3 Adjuvant chemotherapy at the time of surgical resection for human lung cancer
  • the tumor was an isolated tumor about 3 cm in diameter at the lower left lobe of the lung. I had.
  • a complete healing resection of the lung tumor was performed by normal thoracotomy. Then, in the chest cavity during thoracotomy, inhaled sumantas / libiodol into a plastic syringe and spread about 3 ml (containing 3 mg of sumantas) widely.
  • a small amount of 0.05 ml to 0.1 ml was sprayed into the thoracic cavity and then sutured, and the prognosis was observed over a long period of time.
  • X-ray and other diagnostic imaging chest X-ray or CT
  • ultrasound imaging are performed, and X-ray chest radiographs are taken every month at the beginning of administration and once every 3 to 6 months after 6 months.
  • X-ray chest radiographs are taken every month at the beginning of administration and once every 3 to 6 months after 6 months.
  • Example 4 Time-dependent changes in intraperitoneal and blood concentrations after drug administration
  • the low-molecular-weight anticancer drugs mitomycin C and doxorubicin, and the high-molecular-weight anticancer drugs Sumantas and radioactive compounds as model compounds for macromolecules Using a total of four compounds of labeled serum albumin, rats with AH136B ascites-type hepatoma (ascites carcinoma) were injected into the abdominal cavity of each rat after administration of these various drugs. The relationship between temporal changes was examined.
  • the doxorubicin used was due to the radioactivity of the radioactive 14 C derivative (NEN, Boston, MA, USA), and the mitomycin (Sigma) and smux were due to the antibacterial activity against the gram-positive bacteria Micrococcus luteus. In all cases, ascites (intraperitoneal) and blood concentration were measured.
  • the chelating agent diethylene 'triamine' pentaacetic acid (DTPA) anhydride was added in an equimolar ratio to the amino group of lysine in serum albumin, and pH 8.5-5
  • the addition reaction of DTPA was performed in a sodium bicarbonate solution to obtain DTPA-bound albumin.
  • the line radioactive chromium trichloride to (5 1 CrCl 3) was added DTPA equimolar amounts, were chelated. Radioactive chromium in the DTPA groups Adding chromium (5 1 Cr) is you bond immediately. This reaction mixture is fractionated on a Sephadex G-50 column.
  • Fig. 4 shows the intraperitoneal survival rate and the time course of blood transit after intraperitoneal administration.
  • . 1 to 4 the horizontal axis represents time, while the vertical axis represents biological activity (antibacterial activity) in FIGS. 1 and 3, and radioactivity in FIGS. 2 and 4. More represented.
  • ⁇ indicates intraperitoneal concentration and ⁇ indicates blood concentration.
  • the high molecular weight anticancer agent is advantageous for removing cancer cells seeded in the pleural cavity or intraperitoneal cavity by intracavitary administration, as long as the drug concentration in the body cavity is sufficiently high for a long period of time.
  • a high-molecular-weight anticancer drug that does not shift to systemic (hematogenic) has fewer systemic side effects.
  • low-molecular-weight mitomycin and doxorubi Syn is almost completely transferred into the blood within 30 to 60 minutes from the intraperitoneal cavity, and the intraperitoneal concentration and the blood concentration are balanced. That is, since these drugs spread throughout the body in a short time and disappear from the abdominal cavity, the efficacy (efficacy) in the target body cavity is reduced, while systemic side effects may be exhibited. it is obvious .
  • Example 5 Prophylactic chemotherapy for liver metastasis during resection of human colorectal cancer
  • cancer cells became hematogenous through the portal vein during the surgical procedure. It is thought that it is often spread and spread to the liver.
  • the portal vein which is considered to be the pathway of the metastasis
  • 2 to 4 ml of smantas / lipiodol (lmg / ml) and a pulse of a syringe are pushed slowly at 0.1 ml / time. The injection took 5-10 minutes.
  • three out of 15 patients had metastatic cancer in the liver three years after the operation, and no other patients had such metastatic liver cancer.
  • Surgical resection is still the mainstay of treatment for colorectal and rectal cancer.
  • 50-60% of them develop metastatic liver cancer mainly in the liver, which causes death.
  • rectal cancer cells detached during surgery and formed metastatic tumor daughter nodules in the liver This is thought to be primarily due to the hematogenous dissemination of cancer cells through the portal vein during the surgical procedure.
  • a 2 to 3 mm square piece of VX-2 cancer was transplanted into the liver capsule of a white rabbit, and when the tumor diameter reached 10 to 20 mm, it was divided into two groups, A and B.
  • Sumantas Z Lipiodol The comparison was made between the case where only therapeutic treatment was performed and the case where prophylactic treatment was used in combination.
  • group A (8 birds), according to the conventional therapeutic administration method, 1 mg of sumantas was suspended and dissolved in 1 ml of ribiodol in the hepatic artery of each rabbit opened under ether anesthesia. 2 ml were administered.
  • the present invention is to disperse a high-molecular-weight anticancer drug, which is a conjugate with a high-molecular compound such as Sumantas, into the thoracic cavity and the abdominal cavity during a surgical operation for solid tumors, thereby distributing the compound to the body cavity.

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Abstract

L'invention concerne des agents de type polymères destinés à la prévention de métastases et de la récurrence d'un cancer, ces agents étant administrés dans des sites où se développent fréquemment des métastases de cancer (par exemple une cavité corporelle ou une veine porte autour d'un site où se développent fréquemment des métastases) avant, pendant ou après une intervention chirurgicale, ce qui permet de prévenir des métastases d'un cancer solide et sa récurrence dans des organes normaux. Les agents selon l'invention comprennent un agent anticancéreux lié à un composé polymère. L'invention concerne également une méthode de prévention de métastases et de la récurrence de cancer grâce à ces agents. Les agents selon l'invention peuvent être retenus dans un tissu organique dans une partie normale où des cellules tumorales récurrentes ou disséminées sont susceptibles de prendre, et peuvent donc avoir pour effet de tuer des cellules tumorales infiltrées ou disséminées ou des cellules tumorales restant après l'opération. Comme agents de type polymères destinés à la prévention d'une métastase de cancer, des dérivés de néocarcinostatine liés à des groupes copolymères styrène-acide maléique sont particulièrement efficaces.
PCT/JP2000/004307 1999-07-07 2000-06-29 Agents de type polymeres destines a la prevention de metastases et de la recurrence du cancer et methode de prevention de metastases et de la recurrence du cancer WO2001003738A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT413487B (de) * 2002-08-12 2006-03-15 Igeneon Krebs Immuntherapie Verwendung von antikörpern gegen ein tumor-assoziiertes antigen
CN107812180A (zh) * 2017-10-31 2018-03-20 华仁药业股份有限公司 一种胃印戒细胞癌手术切口冲洗液及制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT413487B (de) * 2002-08-12 2006-03-15 Igeneon Krebs Immuntherapie Verwendung von antikörpern gegen ein tumor-assoziiertes antigen
CN107812180A (zh) * 2017-10-31 2018-03-20 华仁药业股份有限公司 一种胃印戒细胞癌手术切口冲洗液及制备方法

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