WO2004087163A2 - Chimiotherapie de modification de pharmacocinetique - Google Patents

Chimiotherapie de modification de pharmacocinetique Download PDF

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Publication number
WO2004087163A2
WO2004087163A2 PCT/JP1998/005424 JP9805424W WO2004087163A2 WO 2004087163 A2 WO2004087163 A2 WO 2004087163A2 JP 9805424 W JP9805424 W JP 9805424W WO 2004087163 A2 WO2004087163 A2 WO 2004087163A2
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WO
WIPO (PCT)
Prior art keywords
cancer
uft
week
hours
treatment
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Application number
PCT/JP1998/005424
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English (en)
Japanese (ja)
Inventor
Masato Kusunoki
Original Assignee
Masato Kusunoki
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Masato Kusunoki filed Critical Masato Kusunoki
Priority to US09/381,287 priority Critical patent/US6303583B1/en
Priority to PCT/JP1998/005424 priority patent/WO2004087163A2/fr
Publication of WO2004087163A2 publication Critical patent/WO2004087163A2/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a novel adjuvant therapy after surgical resection of intestinal cancer such as colorectal cancer and small intestine cancer.
  • Adjuvant therapy is adjuvant therapy.
  • the curative treatment of colorectal cancer is surgical resection, endoscopic polytomy for early rectal cancer, and abdominal perineal and sacral abdominal rectoctomy for advanced cancer. Examples include penetrating, low anterior resection, pelvic exenteration, Hartmann's surgery, and colostomy.
  • the 5-year survival rate of patients undergoing radical surgery was 50 to 60% .
  • the rate of postoperative recurrence was higher when the lesion was closer to the anus, and local recurrence was at the site of recurrence.
  • the most common metastases are liver metastasis and lung metastasis.
  • the rate of recurrence and metastasis is about 40% for rectal cancer and about 20% for colon cancer.
  • Fujii and colleagues inject 5 FU at a low concentration (2 Omg / kgZday) for a long period of time into rats transplanted with Yoshida sarcoma for 6 consecutive days, and simultaneously give UFT (UFT, described later) at 20 mg / kg, 1 day It was shown that a single oral dose suppresses leukemia and exhibits an excellent tumor shrinking effect (Jpn. J. Cancer Res .. 80, 509-5 12, 1989). Disclosure of the invention The present inventors have intensively studied the dosage and administration schedule so that the basic experiments of Fujii et al. Can be used practically in the clinic with the aim of improving the treatment results of postoperative intestinal cancer. Have been found and the present invention has been completed.
  • the present invention relates to a novel adjuvant therapy after surgical resection of intestinal cancer. More specifically, the present invention relates to a method for treating intestinal cancer, which comprises performing adjuvant therapy combining continuous injection of 5FU and oral administration of UFT after surgical resection of human intestinal cancer.
  • UFT is an antineoplastic agent obtained by mixing 1- (2-tetrahydrofuryl) -1-5-fluorouracinole (trade name: Futraful, generic name: Tegaful) and perasinole in a molar ratio of 1: 4. .
  • Tegafur is a 5FU derivative in which the tetrahydrofuryl group is bonded to the 1-position of 5-fluoroperasinole to reduce the side effect of 5FU, and is administered orally, suppository, parenteral such as injection. This drug is metabolized in the liver to release 5FU and exerts an antitumor effect.
  • UFT is an oral 5FT-type antitumor obtained by mixing terafur with peracil in a ratio of 1: 4 and further improving it, and is widely used in the field of cancer treatment in the United States and Japan.
  • the treatment method of the present invention can be applied to intestinal cancer that has undergone various surgical operations.
  • Intestinal cancer includes, for example, colon cancer that occurs in the cecum, appendix, ascending colon, transverse colon, descending colon, sigmoid colon, rectum, anal canal, etc., and small intestine cancer that occurs in the duodenum, jejunum, ileum, etc. it can.
  • the treatment method of the present invention relates to a novel adjuvant treatment for patients who have surgically resected bowel cancer, and the treatment can remarkably improve recurrence or metastasis.
  • the novel adjuvant therapy of the present invention is to obtain good therapeutic results by administering 5FU and UFT to a patient who has undergone surgical resection based on the treatment schedule of the present invention.
  • the present inventor has named this treatment method Pharmacokinetic Modulating Chemotherapy (PMC) therapy.
  • PMC therapy of the present invention is a treatment in which 5FU is continuously infused from the artery or vein after surgical resection of cancer, and UFT is orally administered. This will cause metastases and stations The number of recurrences has been significantly reduced, and long-term survival has been achieved.
  • the intestinal cancer patient targeted by the treatment method of the present invention is a patient whose primary tumor is the large intestine and small intestine and whose primary cancer tissue has been removed by surgical operation. Therefore, it includes cases where cancer tissue is completely removed and cases where liver metastasis is involved.
  • the continuous infusion may be performed by a means capable of injecting a certain amount of drug, and may be performed by ordinary infusion. However, it is preferable to use an extracorporeal pump capable of adjusting the infusion amount and time.
  • a catheter to be used for the surgical area is inserted into the blood vessel, and 5FU is continuously injected at a constant rate by a drug solution injection device attached to the end of the catheter. As the catheter, those commonly used in the field of surgery may be used.
  • Examples thereof include a Teflon catheter and a polyethylene catheter, and a 5Fr Anthrone Pu catheter (manufactured by Toray Medical Co., Ltd.) is preferred.
  • An implantable port system, an intravenous pump and an arterial pump are used as the liquid injector.
  • An implantable port system may be used as long as it can continuously inject a certain amount of drug into a vein or artery.
  • MI port ard Access Systems, nc, .S
  • MI port (Bard Access Systems, nc, .S) alt L ke City, UT, USA) 1 Watkins' chronofusor continuous infusion pump, Sharp continuous infusion pump MP-22, Intemiate (registered trademark Baxter3 ⁇ 4), and IV injection pump
  • Singleday Infusor (Baxter: h3 ⁇ 4) or the like is preferable.
  • Fill the implantable port system with 5 FU and insert the needle into the vessel as in a drip. If these liquid injectors cannot be used for various reasons, they may be injected by infusion.
  • the blood vessel to be injected is appropriately selected depending on the condition of the patient, the site of the cancer, and the like, but is generally a vein or an artery.
  • Examples of the vein include the right subclavian vein and the elbow vein, and examples of the artery include the hepatic artery, gastric and duodenal artery, and the subclavian artery.
  • Radiation therapy is given in the usual manner used to treat bowel cancer.
  • the timing may be before, during, or after surgical resection. Preoperative irradiation is preferred especially for the purpose of expanding surgical indications, suppressing metastasis, and suppressing local recurrence.
  • the irradiation method may be a method usually employed in radiation therapy, and examples thereof include extracorporeal irradiation and rectal cavity irradiation (Brachytherapy).
  • the radiation dose is not constant depending on the patient's condition and disease state, but is usually 5 to 70 Gy, preferably 20 to 50 Gy, and irradiation can be performed once or in multiple times.
  • adjuvant therapy using a combination of continuous injection of 5FU and oral administration of UFT is performed. Specifically, 5FU is continuously injected for a certain period of time, and UFT is orally administered before, during, and after the continuous injection.
  • 5FU is preferably used by dissolving it in, for example, a saline solution, a replacement fluid for infusion of heparin, glucose, fructose, etc., and particularly preferably mixed with 45 ml of saline and 2,000 units of heparin, and then used.
  • the drug is administered by a liquid injector.
  • one week is taken as one dosage unit, and one dosage unit is a continuous injection of 5 FU into the artery or vein for 3 to 48 hours, preferably 6 to 36 hours, more preferably 12 to 24 hours, and UFT Should be administered orally 1 to 4 times a day for 3 to 7 days, and this dosage unit should be continued for 2 months to 3 years.
  • the therapeutic method of the present invention aims to maintain the blood concentration of 5FU at a constant level over a long period of time by continuous infusion of 5FU and oral administration of UFT. , But generally between 50 ng and 400 ng.
  • the present invention has obtained significant improvements in relapse rate and prognosis.
  • the PMC of the present invention significantly improved the prognosis of patients because metastasis at other sites was significantly reduced. Improving prognosis includes improving survival, prolonging survival, preventing recurrence, and preventing metastasis to other sites.
  • the treatment method of the present invention was well tolerated by patients and showed that enhancing 5FU by pharmacokinetic modification was effective in treating tumors.
  • the dosage of 5FU is usually 100 ⁇ : L 00 Omg m 2 / day, especially 200 ⁇ 60 Omg / m 2 / day is preferred.
  • the dose of UFT is within 300 Omg per week, preferably about 1000-280 Omg.
  • Per day is Shi usually 200 ⁇ 60 Omg / m 2 / day, preferred is particularly 200 ⁇ 300 mg / m 2 / day about Rere.
  • intravenous injection and / or oral administration can be performed by using other drugs in combination with the oral administration of UFT.
  • other drugs include leucovorin (LV), cisplatin (CDDP), irinotecan hydrochloride (CPT-11), mitomycin (MMC), methotrexet (MTX) and the like.
  • the treatment method of the present invention can be treated at home or outpatient without hospitalization by being applied to a patient who has surgically removed a cancer lesion, and is inexpensive in terms of medical costs compared to conventional treatment. It is also very effective in terms of the medical economy.
  • Figure 1 shows the local reproduction curves of both the chemotherapy (CT) and non-chemotherapy (NCT) groups.
  • FIG. 2 shows distant metastatic recurrence curves of both the CT group and the NCT group.
  • FIG. 3 shows the survival curves of both the CT group and the NCT group.
  • IBT rectal ⁇ plaque therapy
  • a catheter was inserted into the subclavian vein (5F r anthrone p- u force catheter, Toray Medical Co.), and this force catheter was transferred to the MR I port (Bard Access Systems inc., ⁇ ). alt j ⁇ ake City, U ⁇ , USA ', the port was placed subcutaneously 5 FU (600 mg) mixed with 45 ml of saline and heparin (2000 units) / mV 24 h) was injected continuously once a week UFT was administered orally daily This protocol was started 2 weeks after surgery and performed for 1 year.
  • P53 staining was performed on three sections of each tumor. Tissue sections of 5 ⁇ m thickness were cut from formalin-fixed paraffin-embedded archival specimens and examined for p53 protein expression by standard avidin-protin conjugated peroxidase-conjugated streptavidin immunohistochemical staining technique. The details of the staining method are as described above. Mutation p53 with an increased half-life was recognized by the antibody (RSp53, Nichirei). (Winoredo type!) 5 The concentration of 3 was low and the half-life was short.
  • Table 1 shows the characteristics of both groups.
  • the total radiation dose in the CT group was significantly lower than in the NCT group.
  • the percentage of severe malignancies in the CT group was significantly higher than in the NCT group.
  • the median follow-up period in the CT group was 30.8 months, and patients in the CT group received at least 6 months of chemotherapy. No significant chemotherapy-related toxicities (more than 3 degrees) were noted. Nausea or diarrhea occurred in 2 out of 14 patients.
  • the UFT dose was changed from 40 Omg / day to 30 OmgZ, and administration was continued 5 days a week.
  • Figures 3 to 3 show the cumulative recurrence curves of both groups. In this figure, it can be seen that there is a significant difference between the two groups.
  • Tumor site Stage Preoperative radiation Postoperative radiation Patient 3 ⁇ 4 3 years 3 years
  • A 5 FU once weekly 24 hours intravenous continuous injection, UFT, twice daily oral administration
  • B 5FU weekly 24 hours continuous intravenous injection, UFT, twice daily 5 days a week
  • the dose of 5 FU is 60 OingZm 2/7 days
  • the dose of UF T was adjusted to 2 'from 000 to 280 Omg per week.
  • the prognosis after a cancer treatment, the prognosis can be improved, such as improving the survival rate, prolonging the survival time, preventing recurrence, and preventing metastasis to other sites.
  • the treatment method of the present invention can be treated at home or outpatient without hospitalization by being applied to a patient who has surgically removed a cancer lesion, and is inexpensive in terms of medical costs compared to conventional treatment. It is also very effective in terms of the medical economy.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

art. 17.2
PCT/JP1998/005424 1997-10-09 1998-12-02 Chimiotherapie de modification de pharmacocinetique WO2004087163A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/381,287 US6303583B1 (en) 1997-10-09 1998-12-02 Pharmacokinetic modulating chemotherapy
PCT/JP1998/005424 WO2004087163A2 (fr) 1998-12-02 1998-12-02 Chimiotherapie de modification de pharmacocinetique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1998/005424 WO2004087163A2 (fr) 1998-12-02 1998-12-02 Chimiotherapie de modification de pharmacocinetique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016033135A (ja) * 2005-05-09 2016-03-10 小野薬品工業株式会社 ＰｒｏｇｒａｍｍｅｄＤｅａｔｈ１（ＰＤ−１）に対するヒトモノクローナル抗体および抗ＰＤ−１抗体単独または他の免疫療法と併用した癌治療方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016033135A (ja) * 2005-05-09 2016-03-10 小野薬品工業株式会社 ＰｒｏｇｒａｍｍｅｄＤｅａｔｈ１（ＰＤ−１）に対するヒトモノクローナル抗体および抗ＰＤ−１抗体単独または他の免疫療法と併用した癌治療方法

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