WO1999058148A1 - The method of treatment of locally propagated mammary gland cancer - Google Patents

The method of treatment of locally propagated mammary gland cancer Download PDF

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Publication number
WO1999058148A1
WO1999058148A1 PCT/KZ1999/000007 KZ9900007W WO9958148A1 WO 1999058148 A1 WO1999058148 A1 WO 1999058148A1 KZ 9900007 W KZ9900007 W KZ 9900007W WO 9958148 A1 WO9958148 A1 WO 9958148A1
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Prior art keywords
gamma
tumor
mammary gland
gland cancer
arglabin
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PCT/KZ1999/000007
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French (fr)
Inventor
Kani Jumkenovich Musulmanbekov
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Tovarischestvo S Ogranichennoi Otvetstvennostju Tabifarm
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Publication of WO1999058148A1 publication Critical patent/WO1999058148A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy

Definitions

  • Chemotherapy is known as the method of cancer treatment.
  • a single (monochemotherapy) or several (polychemotherapy) drugs are usually applied.
  • all known and widely applied drugs are of low antitumoral activity and have numerous negative after-effects (leucopenia, anemia, thrombopenia, immunity depression, etc).
  • Just a minimal increase in human longevity is identified in case of chemotherapy in the treatment of locally propagated mammary gland cancer (Blokhin N.N., Perevodchikova N.I. Chemotherapy of Tumor Diseases. M., Medicine Publ., 1984).
  • the method of locally propagated mammary gland cancer treatment consisting of pre-surgery gamma-ray therapy and following radical surgery is the most similar to the invention presented.
  • the former one's drawback is low efficiency of gamma-ray therapy in case of locally propagated mammary gland cancer when the risk of tumor process generalization as sub-clinical metastases appearance is very high (Bazhenova A.P., Ostrovtzev L.D., Khakhanashvili G.M. Mammary Gland Cancer. M., Medicine Publ., 1985; Dimarsky L.Ju., Mammary Gland Cancer. M. Medicine Publ., 1980).
  • the technical outcome of the present invention will be enhanced treatment efficiency due to the improvement of tumor regression dynamics.
  • the gamma-ray therapy is one of the most widely spread methods in the combined treatment of mammary gland cancer. According to the WHO (World Health Organization) experts, the effect of gamma-ray therapy strongly depends upon the tumor radio-sensitivity (approximately 50%). At the present level of tumor gamma-ray therapy development the radio-sensibilization is the most preferable method to increase the efficiency of gamma-ray therapy. However, all available radio-sensibilizing agents are insufficiently effective (oxygenation), highly toxic in effective concentrations (imidazoles), or very aggressive for the organism (high level hyperthermia, hyperglycemia).
  • Arglabin is a biologically active sesquiterpene lactone produced from aerial part of the Sagebrush (Artemisia glabell ⁇ ) growing in Ukraine. Arglabin is of antitumoral effect. Its radio-sensibilizing characteristics were found during its use in complex treatment of mammary gland cancer.
  • the intratumoral Arglabin injections have promoted the gamma-ray therapy efficiency 30%, which resulted in 5.5 times reduction of tumor volume (in a number of cases the tumor 3 regression reached 100%), and post gamma-ray therapy III-IV grades pathomorphosis was observed in 64%.
  • Arglabin solution (2mg/cm 3 tumor volume) is injected intratumorally twice a week 10-15 min before gamma-ray therapy and under ultrasonic topometry control (UST). Course duration is 4-5 weeks. Total number of Arglabin injections is 8-10. Accumulated dose of Arglabin solution injected depends upon the tumor size and varies from 80mg to 1280mg. Case Study 1. The patient M., 50 y.o., was hospitalized with the diagnosis: left- hand mammary gland cancer, stage Illb (T 3 N ⁇ M 0 ), nodal type, upper lateral quadrant.
  • the treatment consisted of gamma-ray therapy with single focal dose of 2Gr and intratumoral Arglabin injection (single dose of 60 mg) 10-15 min before gamma-ray therapy twice a week. Accumulated dose was 480 mg. Neither local nor general adverse reactions to Arglabin were detected.
  • Pre-surgery size of tumor (US tomography) was 1.5x1.0x1.2 cm, tumor volume - 0.9 cm 3 .
  • the radical Peity mastectomy has been done on the left-hand side; the post-surgery period being quiet; the initial course of adjuvant polychemotherapy is carried out according to CFM scheme - (cyclophosphan, ftoruracyl, metatryxate). 4
  • fibrotic tissue focuses in the mamma, focal- diffused lymphoid-macrophage infiltration with the presence of giant cells, vast necrotic areas.
  • the diagnosis is verified cytologically as adenocarcinoma. Under US tomography pretreatment tumor size before the treatment was 2.2x2.0x2.2 cm, tumor volume - 5.0 cm .
  • the complex treatment was conducted with pre-surgery distant gamma-ray therapy at normal fractions and 4 weeks intratumoral Arglabin injection (2mg/cm 3 tumor volume) twice a week at 10-15 min before gamma-ray therapy.
  • Total dose of Arglabin was 80mg.
  • the complex treatment was conducted with pre-surgery distant gamma-ray therapy at normal fractions and 4 weeks intratumoral 5
  • Arglabin injection (2mg/cm tumor volume) twice a week at 10-15 min before the gamma-ray therapy.
  • Total Arglabin dose was 160 mg.
  • the tumor volume after gamma-ray therapy is reduced to 1.4 cm and tumor regress is 86%.
  • Histological study area of fibrotic and hyalinous tissues with focuses of edema and mixomatosis, cancer cells are absent.
  • pathomorphosis of mammary tissue expresses as fibrosis and hyalinosis.
  • the proposed method was applied to 30 patients with II-III grades locally propagated mammary gland cancer (T 2-3 N 0- ⁇ Mo).
  • the control group of 30 patients was treated with the distant gamma-ray therapy only.
  • the volume of the latter decreased 29 times, in control group - 1.4 times; with tumor volume of 4.1 - 8.0 cm - 8.3 times in the test group and 2.1 times in the control group; with tumor volume of 8.1 - 16.0 cm 3 - 4.1 times in the test group and 1.9 times in the control group; with tumor volume more than 16.0 cm 3 - 5.5 times in the test group and 3.4 times in the control group.
  • Presented results of the tumor regression dynamics confirm the marked radiosensibilizing activity of Arglabin.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Locally propagated mammary gland cancer Treatment Method. The invention is referred to oncology as a method of locally propagated mammary gland cancer treatment. The method consists of the pre-surgery gamma-ray therapy with the preceding intratumoral Arglabin injection, 2 mg/cm3 tumor volume twice a week within 4-5 weeks. Arglabin injections lead to the enhanced treatment efficiency.

Description

The Method of Treatment of Locally Propagated
Mammary Gland Cancer
The invention presented is referred to oncology, namely to the possible ways to treat patients with locally propagated mammary gland cancer. Chemotherapy is known as the method of cancer treatment. For the chemotherapy as an independent medical course a single (monochemotherapy) or several (polychemotherapy) drugs are usually applied. However, all known and widely applied drugs are of low antitumoral activity and have numerous negative after-effects (leucopenia, anemia, thrombopenia, immunity depression, etc). Just a minimal increase in human longevity is identified in case of chemotherapy in the treatment of locally propagated mammary gland cancer (Blokhin N.N., Perevodchikova N.I. Chemotherapy of Tumor Diseases. M., Medicine Publ., 1984). The method of locally propagated mammary gland cancer treatment consisting of pre-surgery gamma-ray therapy and following radical surgery is the most similar to the invention presented. The former one's drawback is low efficiency of gamma-ray therapy in case of locally propagated mammary gland cancer when the risk of tumor process generalization as sub-clinical metastases appearance is very high (Bazhenova A.P., Ostrovtzev L.D., Khakhanashvili G.M. Mammary Gland Cancer. M., Medicine Publ., 1985; Dimarsky L.Ju., Mammary Gland Cancer. M. Medicine Publ., 1980). The technical outcome of the present invention will be enhanced treatment efficiency due to the improvement of tumor regression dynamics.
The above mentioned technical outcome is achieved in the method of locally propagated mammary gland cancer treatment including the combination of gamma-ray therapy and preliminary Arglabin intratumoral injection, 2mg/cm3 tumor volume twice a week within 4-5 weeks.
An essence of the invention is as follows. The gamma-ray therapy is one of the most widely spread methods in the combined treatment of mammary gland cancer. According to the WHO (World Health Organization) experts, the effect of gamma-ray therapy strongly depends upon the tumor radio-sensitivity (approximately 50%). At the present level of tumor gamma-ray therapy development the radio-sensibilization is the most preferable method to increase the efficiency of gamma-ray therapy. However, all available radio-sensibilizing agents are insufficiently effective (oxygenation), highly toxic in effective concentrations (imidazoles), or very aggressive for the organism (high level hyperthermia, hyperglycemia). The proposed method supposes the use of a new radio- sensibilizing agent called «ARGLABIN» in combination with gamma- ray therapy. Arglabin is a biologically active sesquiterpene lactone produced from aerial part of the Sagebrush (Artemisia glabellά) growing in Kazakhstan. Arglabin is of antitumoral effect. Its radio-sensibilizing characteristics were found during its use in complex treatment of mammary gland cancer. The intratumoral Arglabin injections have promoted the gamma-ray therapy efficiency 30%, which resulted in 5.5 times reduction of tumor volume (in a number of cases the tumor 3 regression reached 100%), and post gamma-ray therapy III-IV grades pathomorphosis was observed in 64%.
The method works as follows. During distant gamma-ray therapy 2% Arglabin solution (2mg/cm3 tumor volume) is injected intratumorally twice a week 10-15 min before gamma-ray therapy and under ultrasonic topometry control (UST). Course duration is 4-5 weeks. Total number of Arglabin injections is 8-10. Accumulated dose of Arglabin solution injected depends upon the tumor size and varies from 80mg to 1280mg. Case Study 1. The patient M., 50 y.o., was hospitalized with the diagnosis: left- hand mammary gland cancer, stage Illb (T3NιM0), nodal type, upper lateral quadrant. Under clinical observation a symptom of «skin involvement ., is detected in the upper lateral quadrant zone. In the same area there was palpated a tumor up to 8 cm in diameter, and painless and mobile dense lymph node up to 1.5 cm in the left subaxillary area. The diagnosis was cytologically verified as adenocarcinoma. Ultrasonic tomography showed the pretreatment tumor size as 5.0x3.3x3.6 cm, tumor volume 30.9 cm3.
The treatment consisted of gamma-ray therapy with single focal dose of 2Gr and intratumoral Arglabin injection (single dose of 60 mg) 10-15 min before gamma-ray therapy twice a week. Accumulated dose was 480 mg. Neither local nor general adverse reactions to Arglabin were detected. Pre-surgery size of tumor (US tomography) was 1.5x1.0x1.2 cm, tumor volume - 0.9 cm3. The radical Peity mastectomy has been done on the left-hand side; the post-surgery period being quiet; the initial course of adjuvant polychemotherapy is carried out according to CFM scheme - (cyclophosphan, ftoruracyl, metatryxate). 4
Histological study: fibrotic tissue focuses in the mamma, focal- diffused lymphoid-macrophage infiltration with the presence of giant cells, vast necrotic areas.
Conclusion: IV grade mammary gland cancer in the state of tumor pathomorphosis.
Case Study 2.
The patient L., 41 y. o., was hospitalized with diagnosis: right- hand mammary gland cancer, stage III (T3N]M0), nodal type, upper lateral quadrant. The diagnosis is verified cytologically as adenocarcinoma. Under US tomography pretreatment tumor size before the treatment was 2.2x2.0x2.2 cm, tumor volume - 5.0 cm .
The complex treatment was conducted with pre-surgery distant gamma-ray therapy at normal fractions and 4 weeks intratumoral Arglabin injection (2mg/cm3 tumor volume) twice a week at 10-15 min before gamma-ray therapy. Total dose of Arglabin was 80mg.
The tumor volume after gamma-ray therapy - 0, tumor regression - 100%.
Histological conclusion: mammary gland tissue with fibrotic area, cancer cells are absent. Case Study 3.
The patient N., 69 y. o., was hospitalized with diagnosis: left-hand mammary gland cancer, stage II (T2NιM0), nodal type, upper lateral quadrant. The diagnosis is verified cytologically as adenocarcinoma. Attendant pathology: hypertension of 2nd degree, atherosclerosis of aorta, cardiosclerosis. Menopause - 17 years. Under US tomography the pretreatment tumor was 2.7x2.6x2.5cm, tumor volume 10.0 cm3.
The complex treatment was conducted with pre-surgery distant gamma-ray therapy at normal fractions and 4 weeks intratumoral 5
Arglabin injection (2mg/cm tumor volume) twice a week at 10-15 min before the gamma-ray therapy. Total Arglabin dose was 160 mg.
The tumor volume after gamma-ray therapy is reduced to 1.4 cm and tumor regress is 86%. Histological study: area of fibrotic and hyalinous tissues with focuses of edema and mixomatosis, cancer cells are absent.
Conclusion: pathomorphosis of mammary tissue expresses as fibrosis and hyalinosis.
The proposed method was applied to 30 patients with II-III grades locally propagated mammary gland cancer (T2-3N0-ιMo). The control group of 30 patients was treated with the distant gamma-ray therapy only.
The direct clinical effects, peculiarities of tumor regression dynamics and pathomorphological changes of tumor have been studied. Assessment of the direct clinical effects was conducted according to WHO (World Health Organization) recommendations. ..Complete reply» means complete tumor disappearance, ..Partial reply» means reduction of tumor and regional metastases up to 50% and more, «No reply» means tumor reduction less than 50%.
The analysis of clinical effects of gamma-ray therapy in the treated groups showed that treatment efficiency in the test-group is higher than in the control one. Of 30 patients in the test group «Complete reply» was registered in 16 patients (53.3 ±9.1%), partial cancer regression (less than 50%) was registered in 11 patients (36.7 ± 8.8%) and three patients (10.0 ± 5.5%o) process stabilization was noted, none of them having growth of tumor node.
In the control group treated only by gamma-ray therapy complete regression was noted in 3 patients of 30 (10.0 ± 5.5%). Partial regression of the mammary gland tumor was noted in 15 patients (50.0 ± 9.1%), 6 regression of tumor less than 50% - in 10 patients (33.3 ± 8.6%), 2 patients (6.7 ± 4.6) showed further progressive development of the tumor with the gamma-ray therapy. The positive clinical effect of gamma-ray therapy ((.Complete reply»+ «Partial reply») in the test group was 90% while in control group - only 60%o, i.e. the efficiency of gamma-ray therapy combined with Arglabin intratumoral injections was 30% higher than that in patients of the test group.
The tumor volume widely varied (2.0 - 90.4 cm' ) and an average index (according to UST) was 15.5±0,35 cm in the control group and 16.6±0.36 cm3 in the test one, respectively. It is important that the rate of tumor reduction was different in the groups compared. Thus, in patients treated with complex gamma-ray therapy with intratumoral Arglabin injection an average 5.5 times tumor reduction was registered and in the control one this meaning was 2.8 in average. During all stages of the treatment the tumor regression was relatively even, although the rate of tumor regression was markedly higher in those patients who got gamma-ray therapy in combination with intratumoral Arglabin injection. Thus, in patients of the test group with tumor volume up to 4.0 cm , the volume of the latter decreased 29 times, in control group - 1.4 times; with tumor volume of 4.1 - 8.0 cm - 8.3 times in the test group and 2.1 times in the control group; with tumor volume of 8.1 - 16.0 cm3 - 4.1 times in the test group and 1.9 times in the control group; with tumor volume more than 16.0 cm3- 5.5 times in the test group and 3.4 times in the control group. Presented results of the tumor regression dynamics confirm the marked radiosensibilizing activity of Arglabin.
Moreover, during Arglabin treatment much more frequent is a marked tumor III-IV grade radiopathomorphosis in the test group - 64± 7
9.8%) (including 36±4.9% IVth grade) compared to the control one - 37± 9.5 % (including 14.8±6.9 IV grade), that promotes more profound damage and more earlier destruction of cancer cells in comparison with gamma-ray therapy only.
Thus, high efficiency of the locally propagated mammary gland cancer treatment is reached due to the application of the presented method of gamma-ray therapy combined with the intratumoral Arglabin injection.

Claims

Locally propagated mammary gland cancer treatment method of gamma-ray therapy distinguished from the previously known ones by the intratumoral Arglabin injection preceding every gamma-ray treatment, 2mg/cm3 tumor volume twice a week within 4-5 weeks.
PCT/KZ1999/000007 1998-05-14 1999-05-13 The method of treatment of locally propagated mammary gland cancer WO1999058148A1 (en)

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KZ980499.1 1998-05-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242481B1 (en) 1997-03-18 2001-06-05 The Children's Medical Center Corp. Methods for the inhibition of angiogenesis with arglabin
RU2805915C1 (en) * 2023-02-22 2023-10-24 федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) Arglabin derivatives with selective cytotoxic effects

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERNHARD, ERIC J. ET AL: "The farnesyl transferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts", CANCER RES. (1996), 56(8), 1727-30, XP002114695 *
BOTTEX-GAUTHIER C. ET AL.: "IN VITRO BIOLOGICAL ACTIVITIES OF ARGLABIN, A SESQUITERPENE LACTONE FROM THE CHINESE HERB Artemisi myriantha WALL. (ASTERACEAE)", BIOTECHNOLOGY THERAPEUTICS, vol. 4, no. 1,2, 1993, pages 77 - 98, XP002114696 *
CHEMICAL ABSTRACTS, vol. 131, Columbus, Ohio, US; abstract no. 67730, SHAIKENOV, T. E. ET AL: "Arglabine as a novel inhibitor of the farnesylation of Ras proteins" XP002114697 *
DOKL. MINIST. NAUKI--AKAD. NAUK RESP. KAZ. (1998), (5), 64-75 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242481B1 (en) 1997-03-18 2001-06-05 The Children's Medical Center Corp. Methods for the inhibition of angiogenesis with arglabin
RU2805915C1 (en) * 2023-02-22 2023-10-24 федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) Arglabin derivatives with selective cytotoxic effects
RU2814259C1 (en) * 2023-09-01 2024-02-28 федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) Agent based on arglabin derivative, having selective cytotoxic action
RU2814738C1 (en) * 2023-09-01 2024-03-04 федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) Agent based on arglabin derivative, having selective cytotoxic action

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