JPH01501862A - Cancer treatment with interferon and radiotherapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Treatment of cancer with interferon and radiotherapy 11 Interferons are a group of biologically active members with antiviral and antitumor properties. It is a ring protein. Some subtypes of interferons are antigenic and Defined based on differences in biological characteristics. interferon subtypes α-interferon, β-interferon and γ-interferon It is.

Advances in genetic engineering research over the past decade have led to the development of highly purified recombinant DNA interfaces. Brought Ron's production.

When used as a single drug, interferon can be used to treat cancers such as renal cell carcinoma, melanoma, and Inactive forms of Zykin's lymphoma, Kabosi's sarcoma, and hairy cell leukemia Clinical studies have shown that it has anticancer activity. All subtypes of interferon It is not active against all of the cancers listed by Pu.

Radiotherapy is the mainstay of modern cancer treatment, with proven efficacy for many human cancers. Ru. However, continuous improvements are needed to make these treatments effective. be. Attempts to improve the effectiveness of radiation therapy include methods that can enhance radiation's ability to destroy cancer. radiosensitizers or potentiators such as There are efforts to develop stor). Despite numerous laboratory and clinical studies To date, no single drug has been discovered as the optimal radiation aggravating agent.

Research has been done in several laboratories including interferon and radiation therapy. However, the results were not yet available.

Dritsehilo et al. (Am, J., Ctinie, O. Ne, 579 (1982)) investigated the radiation response of mice 373 in tissue culture. discloses the effects of interferon (IFN) on.

Radiation of irradiated 3T3 cells in the presence of mouse L-cell interferon Species-specific enhancement of cell death was observed as a decrease in the shoulder region of the cell survival curve. . Fractionation designed to test for changes in recovery from sublethal radiation damage Dose (spli to ose) experiments showed no IFN suppressive effect. Doricechiro They found that interferon suppresses the ability of cultured cells to accumulate sublethal radiation damage. We hypothesized that this would probably enhance radiation injury.

Namba et al. (Cancer 5th Sat. 2262 (1984)) In research on the combined use of interferon and radiotherapy with eLa cells. Observations confirmed what Doricechiro et al. said.

Goulc Rira (J, Interferon Re5earch i, 123 (1984>), 1 in vitro treatment of β-interferon-induced Observation of radiosensitization of bronchial carcinoma However, this was not observed with α-interferon. Gould et al. Terferon's radiation field sensitivity is anti-proliferative when used alone on bronchogenic cell lines. reported that it corresponds to Nevertheless, Gould et al. The anticancer effect of the combination with radiation is more than additive5, and if radiation aggravation is shown. I concluded.

Nederman et al. (Acta Radiologica O ncology.

21.23H1982) used interferon or radiation alone Compared to cases, human neural M111fil follicle cultures were significantly reduced after their combination therapy. We observed that growth retardation was enhanced. Needelman et al. released their results. Although it has been attributed to additive anticancer effects of radiation and interferon, there is no evidence of radiosensitization. I couldn't. Primarily due to the species specificity of interferon, radiation and Combination studies with Terferon have not been reported even in animal model systems; Key (Lvovsky) et al. (Int, J.

Rad, One, Bio, Phys, 1, 1721 (1985)) Interferon inducer, poly ICLC and radiation in Lewis mouse lung cancer model and observed that cancer control was enhanced using radiation. inducing agent or release Cancer regrowth was delayed in animals treated with inducing agents and radiation compared to radiation alone. Prolonged survival was observed.

Mabaley et al., J.Bio.Res.Modify rs, 3°19 (1984), conducted an clinical trial in nine patients with anaplastic glioma after partial resection. Report on research on P hase I using combination of terferon and radiotherapy are doing. Patient survival in the corresponding group treated with BCNU combined with radiotherapy This study shows that toxicity is greater than expected when treated with comparable 0 combinations. There are also reports of.

Real et al., J, Bio, Res, Modifiers, Lord, 141 (1985), two patients with Kaboji's sarcoma who required discontinuation of radiotherapy. reported severe oral mucocytes in patients.

Mattson et al., J. Biol. Re5p. Modi. fiers.

4.18 (1985), the simultaneous use of interferon and radiation therapy It has been reported that it is associated with an increased incidence of radiation pneumonitis in cancer patients.

ordinary people The present invention is carried out in combination with radiation irradiation using an interferon radiation aggravating agent. used in the treatment of radiosensitive human cancers such as epithelial cancers and sarcomas.

The method involves administering a sufficient amount of interferon radiosensitizer to radiosensitive pE recipients. sensitize the cancer sufficiently to radiation, and then irradiate it with a standard dose of radiation. It becomes more.

As used herein, "interferon" refers to natural and recombinant alpha-(leukocyte) ) and β-(fibroblast) interferon, but α-interferon is suitable. "α-interferon" as used herein refers to human leukemia Natural or recombinant interferons that exhibit similar biological properties to globular interferons. means Ron. Several alpha types are known, and they have Greek letter names. All types are indicated by the number after The types of α-interferon used in the present invention are α-1 and α-2. Interferon is preferred. Particularly preferred is α-2 interferon. The most suitable one is α-2 interferon, which is produced by the recombinant DNA method. It is so-called recombinant DNA α-2 interferon.

Recombinant DNA α-2 interferon was developed by NaBata et al. ature, 284.316 (1980) and European Patent No. 32,134 It can be manufactured by the method disclosed in No.

Biran rI 哩 The present invention utilizes the radiation enhancer interferon with a prescription that requires a shorter radiation treatment time. and provide a way to treat radiosensitive cancers such as epithelial cancers and sarcomas with standard radiation. , thereby ameliorating the side effects normally associated with radiation therapy.

The present invention further provides for a suitable recombinant DNA α-2 interferon (IFN). Let us explain using (c) as a metaphor.

IFN2-106-5X10JU per cancer square meter for patients with radiosensitive cancers is well tolerated when given 3 times/week followed by standard doses of radiation. It was found that the cancer shrinks and disappears.

The preferred method of administering IFN is injection, which is administered subcutaneously approximately 2 hours before radiation. It is preferable to

The radiation was delivered using a standard megavoltage (mBavoltage) device (e.g. AEC L T heratron 80, Varian C1inae 4 or Va Irradiation is performed according to the present invention by standard techniques using a Cl1nac).

Radiation portal (maximum size of pota is 300c+a2 or less. Suitable The dose is between approximately 15 Gy and 35 Gy, depending on the area of the body irradiated. Therefore, the marrow The dose is approximately 35 Gy, the dose for both kidneys is approximately 15 Gy, and the dose for the whole liver is 20 Gy. It is. Interruption of treatment is at the discretion of the clinician, taking into account the patient's tolerance to radiotherapy. done in quantity.

IFN injectable compositions are prepared by conventional means. It may contain e.g. preservatives. It can be prepared using sterile distilled water or a buffer solution.

A clinical study to demonstrate the invention was conducted as follows: (Methods and Materials) 11 milk Combination of alpha-2 interferon and radiation therapy performed at Georgetown University Hospital Sixteen patients were enrolled in the study. Patients with late-stage unresectable or metastatic epithelial If you have histologically confirmed sexual cancer or sarcoma and have 3 months to live, you are eligible to participate in the study. It was declared appropriate to add.

Of the 16 patients, 8 were male.The age ranged from 43 to 76 years old, with an average age of 61 years. He is talented. 15 of the 16 patients had primary epithelium from the lung, esophagus, pancreas, neck, and kidney. Histological diagnosis was cancer. One patient had bone metastasis and soft tissue implantation was secondary. He had numerous melanomas. Of the 16 students, 14 can use the test.

Two patients were unable to complete the radiotherapy course and were therefore not evaluable. declared. All patients received hormonal therapy or chemotherapy 2-4 weeks before starting the protocol. Original annotations have been discontinued.

1λ, ttJL Before enrollment, all patients were examined symptomatically and the clinical status of their disease was determined by chest X-ray, Pewter tomography, EKG, hematology and blood chemistry were examined. total Blood containing fibrinogen levels, PTT, PT, TT, and fibrin-degrading substances A rice cake test was also conducted. Afterwards, the patients were divided into groups of six, and each They were divided into two subgroups of 3 people (subgroups A and B). 6 patients Each group received the same amount of alpha-2 interferon. stop The dose was increased in each subsequent group. The dose studied was 2.0X10'I U/cIm2 and 5. OX 10'IU/cm'. 5. Ox Amounts greater than 10'IU/cm' were toxic and were not used. covered Among the treatment groups, one subgroup (subgroup A) received treatment in combination with radiotherapy. The combined interferon doses were administered subcutaneously 5 times per week. rest (Subgroup B) received the same FN dose three times per week (M , W, F) Administered subcutaneously. The daily dose of interferon is appropriate at the time of radiation. It was administered 2 hours before radiotherapy to ensure appropriate serum levels. interferon The combination of radiation therapy and radiation may result in significant treatment failure or patient withdrawal from the protocol. It continued until interrupted.

If granulocytopenia occurs to 1500/m2 cells, interferon The Ron dose was adjusted down by 15-25% based on platelet count. Inter -Administration of Feron is effective if the granulocyte count decreases to less than 1000 or the platelet count decreases to so or oo. Treatment was temporarily discontinued in all cases below 0. Interferon administration is Treatment was resumed if the patient demonstrated hematologic recovery. Radiation therapy is standard Radiation technology and megavolt equipment (AECLT heratron 80, Vari Performed using an Clinac 4 or Varian Clinac 18) Ta. All fields where it is possible to follow established radiotherapy principles We conducted a mock experiment using the ``Shrinking field technology''. using 0 individually manufactured blocks using The maximum size of the radiation portal is 300 cm by appropriately shielding the surrounding normal ifl [ The dose to the spinal cord was 35 Gy, the dose to the whole liver was 20 GF, and the dose to both kidneys was 35 Gy. For the internal organs, the dose was limited to 15 Gy. Interruption of radiation therapy that has continued for more than one week may The treatment will be resumed at the discretion of the radiotherapist after making an overall judgment as to whether the patient can tolerate the treatment.

8・′ and #”collarゝ Each patient has the same clinical response as shown on radiographs during and after treatment. Early signs of toxicity were also closely monitored.

Evaluation methods include the frequency of doctor's diagnosis, the regular implementation of laboratory methods (hematology, serum chemistry, etc.). blood clot tests).

Radiographic examinations may include chest x-rays and CT scans, as appropriate. poison World Health Organization (World Health Organization) for classification of acute and subacute toxicity. The evaluation was carried out according to the recommendations of the Alth Organization. State starts from 0 The condition was divided into 4 stages, with 4 being a state of complete disability. ! Tumor response is determined by a series of radiographs. Judgment was made by means of true testing. The area of the irradiated tumor is the longest diameter x the vertical maximum I decided on the diameter. A complete response means that no new obstacles appear within the range of the radiation portal and that there are few Disappearance of all measurable disease as determined by observation for at least 4 weeks. Defined as loss. Partial response is a 50% reduction in the size of the irradiated tumor and remains stable. Disease status was defined as <50% decrease in tumor size or <25% increase in tumor size. . Tumor growth of 25% or more was declared disease progression.

At IFN doses of 2 x 10' and 5 x 10' ItJ/am, there was no apparent No significant differences were observed. The 3-day treatment regimen per week eliminates any harmful side effects associated with treatment. as determined by the patient's ability to complete the planned radiation course. I was able to withstand it. Treatment regimen 5 days per week is associated with adverse side effects for patients Some treatments, both IFN and radiotherapy, are poorly tolerated by patients. It was concluded that

Patients treated with the three-times-weekly regimen received 100% of the planned IFN dose and It was possible to withstand 86% of the planned radiation dose. However, per week Patients treated with the 5-day regimen received 22% of the originally planned IFN dose and total It was able to withstand only 44% of the prescribed radiation dose.

Tumor response was determined 1 month after the end of treatment. Complete or partial response was determined in 6 patients. There were no changes in 8 patients. No patients had tumor progression .

As described above, clinical evidence shows that the combination of IFN and radiotherapy is feasible. This was suggested by the test results. Maximum tolerated dose and combined with daily radiation The amount of recombinant DNA α-2 interferon administered subcutaneously is 3 times per week. It was 5.0×10'TU/am'. This is combined with daily radiation This is superior to administering IFN daily.

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Claims (10)

[Claims] 1. Administration of radiosensitizing interferon and radiation to radiosensitive human cancer patients A method for treating radiation-sensitive human cancer, which comprises combining radiation irradiation. 2. Interferon administration dose is 2.0 x 106 IU/cm2 to 5.0 x 10 The treatment method according to claim 1, wherein the dose is 6 IU/cm2. 3. Interferon may be given subcutaneously 3 days per week before radiation therapy. The treatment method according to claim 2, comprising: 4.5 days per week (including the days on which interferon is administered) doses 15-35 4. The treatment method according to claim 3, wherein radiation of Gy is irradiated. 5. The interferon is α-2 interferon, preferably recombinant DNA α- 2 interferon according to any one of claims 1 to 4. Method of treatment. 6. Radiosensitizing interferon administration and radiation irradiation can reduce radiosensitivity. Use of radiosensitized interferon for the manufacture of drugs for the effective combination treatment of cancer. for. 7. Each interferon dose is 2.0 x 106 IU/cm2 to 5.0 x 1 7. Use according to claim 6, characterized in that the concentration is 0.06 IU/cm2. 8. Interferon may be given subcutaneously 3 days per week before radiation therapy. The use according to claim 7, characterized in that: 9. 5 days per week (including the days on which interferon is administered) doses 15-35 9. The use according to claim 8, characterized in that radiation of Gy is irradiated. 10. The interferon is α-2 interferon, preferably recombinant DNA α -2 interferon according to claims 6 to 9; Use as described in any one of the above.