TWI335229B - - Google Patents

Description

1335229 (1) Field of the Invention The present invention relates to an arsenic-containing pharmaceutical composition for use in combination with radiation therapy for treating tumors/cancer, and more particularly to the use of combined radiation therapy for the treatment of metastatic cancer of the skin. An arsenic pharmaceutical composition selected from the group consisting of As2〇3, AS2S3, As2S2, and combinations thereof. [Prior Art] Tumor/cancer has always been a threat to human health. For many years, the medical community has worked to develop effective drugs for the treatment of cancer/cancer. However, at present, there is still no drug that can effectively treat tumors/cancers. For example, in the treatment of metastatic breast cancer, the most common sources of skin metastatic cancer are breast cancer, colon cancer, ovarian cancer, Cancers such as lung cancer, head and neck cancer, and oral cancer [Cheng CF] et al., Taiwan Internal Medicine, 2003; 14: 31-36]. In the early 20th century, arsenic compounds were used to treat chronic myeloid leukemia and malignant lymphoma. In recent years, arsenic trioxide (As203) has been used in the treatment of patients with primary and refractory acute promyelocytic leukemia (APL), achieving high response rates and high blood/molecular remission rates [Soignet SL et al. N Engl J Med 1998; 339: 1341-1348]. Clinical response has also been obtained in patients with type 1 human tau lymphocytic virus associated with adult T cell leukemia/lymphoma [Bazarbachi A & Hermine 〇·, Virus Res 200 1 ; 78 : 79-92] . Since 1990, arsenic-containing compounds ((2) (2) 1335229 arsenicals) have provided another direction for the development of tumors/cancers. Furthermore, As203 inhibits cell growth and initiates apoptosis in certain types of cancer, including APL [Shoo W et al, J Natl Cancer I 1998; 90: 124-133], hepatocytes Cancer C Siu KP et al, Life Sci. 2002; 71: 275-2 85], and pancreatic cancer [Li X et al, Anticancer Res 2002; 22: 2205-22 1 3] and gastric cancer [Jiang XH et al, Int J Cancer 200 1 ;91 ··〗 73-1 79]. According to reports, in addition to arsenic trioxide, for example, "Composite Indigo Naturalis Tablets" arsenic-containing substances, including arsenic disulfide (As2S2) and pure tetra-arsenide tetrasulfide (As4S4), can reach 98% and 84.9% complete response rate [Wang ZY, Cancer Chemother Pharmacol (2001), 48 (suppl 1): S72-S76] 0 In 2001, the National Institutes of Health (NIH) conducted arsenic trioxide in the United States. Clinical trials of cancer cells of hematological tumors and solid tumors, and reported in the report that arsenic trioxide can inhibit the growth of various cancer cell lines and promote apoptosis of cancer cell lines. In clinical trials of hematological malignancies, in addition to acute promyelocytic leukemia, sputum includes acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia , CML), non-Hodgkin's lymphoma 'Hodgkin's lymphoma' 'chronic lymphocytic (3) (3) 1335229 leukemia ), myeloablative syndrome (myelodysplastic syndrome) and multiple myeloma (multiple myeloma). In the clinical trials of solid tumors, including prostate cancer, cervical cancer, bladder cancer, etc. [Murgo AJ, The Oncologist (200 1 ), 6 ( suppl 2 ) : 22-28〕 ° The US Food and Drug Administration (FDA) approved arsenic trioxide as an orphan drug in September 2000 for the treatment of acute promyelocytic leukemia. In January 2002, the Republic of China Department of Health approved a pharmaceutical preparation for arsenic trioxide in Taiwan's Toyo Pharmaceutical Co., Ltd. (DHH No. 000005, the Chinese name is "arsenic injection", the English name is "ASADIN Injection"). In the treatment of tumors/cancers, in addition to chemotherapy, since the discovery of radioactive radium (2 2 6 Ra) by the Curie couples in 1898, radiation began to be used in the medical field for the diagnosis and treatment of diseases, especially cancer. (eg skin cancer 'nasopharyngeal cancer, etc.) treatment. After the end of the Second World War, due to the progress of nuclear science research, scientists have become more aware of the effects of radiation on living organisms, improved the methods and techniques of radiation therapy, and improved the survival rate and survival time of cancer patients. Reduce the side effects of radiation on normal tissues.

Chun et al. have demonstrated that As2〇3 is sensitive to ionizing radiation in human cervical cancer cells both in vitro and in vivo [Chun YJ et al., FEBS Lett. 2002; 5 1 9: 1 95-200]. When combined with ionizing radiation, pre-treatment of As203 has synergistic effect on the survival and remission of proliferating cells of the implanted human cervical tumor xenograft (4) (4) 1335229 (Chun YJ et al., FEBS) Lett 2002 ; 5 1 9 : 1 95-200]. However, at the time of writing this report, the effect of the combination of As203 and radiation on clinical cancer patients has not been reported. Furthermore, in the published literature of Chun et al., it is not disclosed whether the treatment of cervical cancer can be extended to skin metastatic cancer. In the previous study of skin metastatic breast cancer, it has been confirmed that local A s203 can be significantly Improvement of local tumor control and reduction of wound secretion under systemic or local negative effects [Cheng CF et al., Taiwan Internal Medicine, 2003; 14 : 3]-36]« However, radiotherapy or chemotherapy alone Treatment of skin metastatic cancer has shown generally disappointing results. SUMMARY OF THE INVENTION In the present invention, the inventors tested the efficiency and safety of a combination of radiation and As203 pretreatment to alleviate superficial malignant lesions in breast cancer patients. For the effectiveness assessment, record the diameter of the skin metastasis area included, the pain assessment index, and the daily changing dressing (CD) frequency. For safety reasons, the skin, gastrointestinal, blood, kidney and liver toxicity of the treatment methods are also monitored. All documents and patents mentioned above, as well as the references cited therein, are hereby incorporated by reference in their entirety. The present invention provides a pharmaceutical composition and a method thereof for treating cancer by combining radiation. -8 - (5) (5) 1335229 Further, the present invention provides a method for treating a human patient suffering from metastatic carcinoma of the skin, which comprises the steps of: (a) locally administering a arsenic-containing pharmaceutical composition; The arsenic-containing pharmaceutical composition comprises a therapeutically effective amount of an arsenic-containing compound and a pharmaceutically acceptable carrier at a site of skin metastatic cancer in a human patient; and (b) applying an electron beam to the site via the skin 'so that the arsenic-containing pharmaceutical composition is allowed to be delivered to cells that penetrate the skin metastatic cancer. The present invention provides an arsenic-containing pharmaceutical composition for treating skin metastatic cancer in combination with radiation therapy, which comprises an effective amount of an arsenic-containing compound selected from the group consisting of As203, As2S3, As2S2, and combinations thereof. Component. These and other aspects and features of the present invention will become more fully apparent from the <RTIgt; DETAILED DESCRIPTION OF THE INVENTION In the present invention, the term "effective amount" means an amount sufficient to provide an effect of sufficiently inhibiting the growth of tumor cells in vitro and in vivo. In the present invention, the term "carrier" or "pharmaceutically acceptable carrier" means a diluent, an excipient, a receptor, etc. for preparing a pharmaceutical composition. It is known to use an electron beam for a biofilm. Known "Electrochemotherapy" involves the application of an electron beam to a target cell, resulting in increased permeability of the cell membrane, known as "electroporation" and allowing for a greater amount of anticancer drug. The molecule enters the cell membrane of the target cell. Therefore, a lower concentration of the drug can be utilized without sacrificing effectiveness and at the same time to reduce or eliminate side effects in the prior art.

In the present invention, three patients with a skin infiltrating lesion of the chest wall and a patient exemplified in the drawing achieve complete remission. The cumulative radiation doses for the relief of these invasive skin lesions on the chest wall were 20, 22 and 28 Gy, respectively. Partial remission was achieved for the other three patients with thoracic axillary umbrella tumors (see Table 1). A patient with a thoracic wall umbrella type ulcer tumor confirmed resistance to this combination therapy and was classified as a stable disease. The doses of radiation administered to each patient are listed in Table 2. After 1 month of treatment, the wound secretions of all superficial and sputum-type ulcer wounds were significantly reduced as the daily average dressing change (CD) frequency was changed from 4.4 to 0.9'. All patients were able to achieve chest wall pain relief by visual analog scaie (VAS) (Table 1).

-10- (7) I335229 Table 1: Response to treatment Radiation dose (Gy)a of a patient's disease Tumor response Change of wounds required per wound (CD) Reduction of skin pain in VAS (mm) _ 1 50 Complete 6-&gt;0 75 _ 2 50 Complete 4^0 65 One 3 50 Complete 4-^0 80 One 4 50 Part 5-» 1 70 _ 5 50 Part 3-^1 65 _ 6 30 Part 5-&gt ;2 75 one.7 50 stable 4^2 55

The dose of 50 Gy was divided into 25 deliveries; the dose of 30 Gy was divided into 10 deliveries.

Table 2 shows the most negative effects that occur during combination therapy and after combination therapy. The most severe acute cutaneous dermatitis was observed in this experiment as Grade 3 dermatitis in two patients. However, this dermatitis has healed satisfactorily after 2 to 3 weeks of completion of radiation therapy, but no patient occurred. Grade 3 chronic radiation dermatitis. During the combination therapy, no granulocytosis or leukopenia of grade 2 -4 was found. Other negative reactions included head-lightedness during radiotherapy and moderate fatigue after radiation therapy; however, there was no significant change in performance status. Furthermore, there was no change in skin pigmentation or renal or hepatic function during combination therapy. No significant ECG Q-τ interval extension was found. _ Table 2: Negative effects and toxicity 0 CTC level 1 2 3 4 granulocytosis 6 1 0 0 0 leukopenia 7 0 0 0 0 thrombocytopenia (Thrombocytopenia) 7 0 0 0 0 chewing heart (Nausea 4 2 1 0 - Anorexia 4 2 1 0 0 Vomit 6 1 0 0 0 Acute radiation dermatitis 1 1 3 2 0 Chronic radiation dermatitis 4 2 1 0 0 Fatigue 3 2 2 0 0 Pigment Hyperpigmentation 7 0 0 • • The numbers shown below in levels 0-4 in the above table are the numbers of patients with negative effects. In the preliminary study of topical As2〇3 treatment for skin metastatic breast cancer, 'significant systemic absorption of As203 was not determined by pharmacokinetic studies [Cheng CF et al., Taiwan Internal Medicine 2〇03 ;14: 31-36]. Thus, in addition to reducing wound secretion and improving local tumor control, other advantages including dry skin lesions and reduced odors can be found. -12- (9) 1335229 About 10% of patients with metastatic cancer have skin metastases. Treatment of such metastatic skin lesions with radiotherapy or chemotherapy is generally unsatisfactory. In the study of superficial malignant lesions of breast cancer, the inventors found that combining local As2〇3 and radiation therapy not only achieved a satisfactory tumor response, but also achieved a good mitigation effect.

As2〇3 can stop the tumor cell cycle in the G2/M phase. [Bazarbachi A et al., Blood 1999; 93: 278-283], here

At the cycle stage, tumor cells are most sensitive to radiation [Chakravarthy A et al., Clin Breast Cancer 2000; 1: 68-71]. This produces sensitization of solid tumor cells to radiation [Lew YS et al., Cancer Res 2 002; 62: 4202-4205]. However, these prior documents do not suggest that a combination of As203 and radiation can be used to treat cutaneous metastatic cancer.

In this preliminary study, the combination of topical As203 and radiation therapy can achieve a higher clinical response rate (42.9% complete response rate and 42.9% partial response) compared with local As203 treatment alone [Cheng CF] ) et al., Taiwan Science Journal 2003; 14:31-36]. Based on these favorable results, regional control of local As2〇3 and radiation to achieve better superficial malignant lesions is recommended and further clinical investigation is recommended. Because As203 also has the activity of inducing apoptosis and differentiation, the development of granulocytosis is a common feature of As203 clinically used in the systemic treatment of leukemia [Soignet SL et al, N Engl J Med 1998; 339: 1341-1348]. However, in the study of the inventors, no significant changes in the blood system were observed. The possible solution to this finding -13- 1335229 do) is to remove the gel prior to radiation therapy, limiting the penetration of the circulation. Furthermore, although it has been confirmed that topical As203 treatment has skin toxicity such as skin rash [Rust DM and Soignet SL., Onco 丨ogist 200 1 ; 6 (suppl): 32-3 7], the inventors of the present invention have studied No such toxicity was found in this type, perhaps because of the optimal period of daily administration (less than 1 hour) and treatment (not more than 5 weeks).

Regarding quality of life, the combination of As203 and radiation therapy shows palliative care for breast cancer patients with superficial malignant lesions, providing an effective, tolerable and safe treatment model. [Embodiment] Examples The preparation methods, characteristics and uses of the compositions of the present invention are illustrated by the following examples. The embodiments are not intended to limit the invention in any way.

Example 1 Patient and clinical work procedures Between December 2001 and March 2003, 7 breast cancer patients with superficial umbilical ulcer tumors or skin invasive tumors who had undergone standard treatment Receive local As203 and radiation therapy at Ma Rong Memorial Hospital (Table 3). The eligibility criteria for this study included confirmation of the diagnosis of breast cancer by pathology. In addition, patients must relapse after standard treatments such as surgery, radiation therapy, or chemotherapy. Six patients had received postoperative radiotherapy for the chest wall and the underarm area. Patients are required to sign a written informed consent form, and the project is reviewed and approved by the Review Committee of the Research Institute at the Ma Rong Memorial Hospital. Table 3: Patient characteristics Patient: Early stage of malignant lesion type Pre-radiation treatment of tumors in the fine-grained WHO cell form potency: State 1 Female 53 IDC Skin invasive lesions 1 2 Women 46 IDC Skin invasive lesions 2 3 Female 62 LIC Skin Invasive Lesion 2 4 Female 33 IDC Umbrella Ulcer Tumor 2 5 Female 4 1 LIC Umbrella Ulcer Tumor 2 6 Female 57 IDC Umbrella Ulcer Tumor 3 7 Female 71 IDC Umbrella Ulcer 3 IDC : Skin invasive ductal carcinoma; LIC: breast leaf invasive cancer. Example 2 Preparation of As2〇3 Gel Pharmaceutical Composition The pharmaceutical composition per unit dose in the gel consisted of the following components: Ingredient content (mg) Percent (%) AS 2 〇3 0.5 0.05 Polymer gel 940 95 0.95 PEG400 90 9 propyl paraben 100 10 pure water 800 80 total 1000 100 -15- (12) 1335229 Example 3 Treatment schedule

The As203 gel prepared by Example 2 was administered to a patient in a daily dose ranging from 〇·〇1 to 0.5 mg/cm2/day, preferably 〇.〇5-0-15 mg/cm2/day. . The gel was administered before daily radiation therapy and then removed 5 minutes before exposure to radiation. Electron beam radiation therapy was delivered using a linear accelerator (9-12 1^乂, dose rate 2.4〇7/min; (:11113〇1800; ¥31^11 Associate' Pal〇Alto, CA). Radiation was irradiated for 5 days per week ( Total dose: 50 Gy divided into 25 deliveries or 30 Gy divided into 10 deliveries.) Example 4 Evaluation of the reaction

The tumor response and skin reaction were observed daily and photographed weekly. The complete response was defined as the disappearance of all known skin lesions in the area of radiation exposure, which was confirmed by subsequent observations at least 4 weeks apart. The partial response is defined as the sum of the maximum vertical diameters of the skin area contained in the radiation-irradiated area, which is reduced by more than 50%, which is confirmed by at least four weeks after the observation. The progressive disease is defined as the sum of the maximum vertical diameter of the skin area contained in the radiation-irradiated area, increased by at least 25%, or a new lesion appears in the radioactive area. All other tumor outcomes were classified as stable disease. For the efficiency of pain control, chest wall pain was assessed using a visual analog scale (VAS). The pre-treatment VAS score was set as the baseline for each patient, and the change between subsequent data and baseline after treatment was compared. When the difference is greater than 50 mm on a 100-mm scale, the patient is defined as -16- (13) 1335229 Reactive. The number of dressings (CDs) required for each day of the wound is also recorded by the nurse responsible for each patient. The results are shown in Table 1 above. Example 5 Monitoring of negative effects

Regarding drug absorption through the skin, a possible systemic negative effect was assessed. Perform continuous blood counts and plot blood chemistry profiles. The blood sputum chemical distribution includes the measurement of aianine aminotransferase, aspartate aminotransferase, blood urea nitrogen and creatinine using a Synchron LX20 spectrophotometer (Beckman Coulter, San Diego' CA). (creatinine). Electrocardiograms were recorded before and after radiation therapy in each patient. Negative effects and toxicity were assessed according to the 2.0th edition of the Common Toxicity Criteria (CTC) published by DCTD' NCI, NIH and DHHS in 1999. The results are shown in Table 2 above.

Although the present invention has been described with reference to the specific embodiments thereof, it is obvious that those skilled in the art can make various changes and modifications without departing from the technical scope of the present invention. The scope of the invention is limited by the scope of the appended claims. [Simplified illustration] Figure 1 (A) shows the skin invasive tumor of breast cancer patient (patient 1) before combination therapy; and Figure 1 (B) shows breast cancer patient (patient 1) The condition of skin invasive tumors after 3 weeks of combination therapy. -17- (14) 1335229 References 1. Soignet SL, Maslak P, Wang ZG 5 et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339: 1341 -1 3 4 8. 2. B azarbachi A, Hermine 0. Treatment of adult T-cell leukaemia/lymphoma : current strategy and future

Perspectives. Virus Res 2 0 0 1; 7 8 : 7 9 — 92. 3 . Shao W5 Fane 11 i M, Ferrara FF, et a 1. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute Promethocytic leukemia cells. J Natl Cancer I 1 99 8; 90 : 1 24-1 3 3. 4. Siu KP, Chan JY, Fung KP, Effect of arsenic trioxide on human hepatocellular carcinoma HepG2 cells : inhibition of proliferation and induction .

Life Sci 2002; 71 : 275-285. 5. Li X, Ding X, Adrian TE. Arsenic trioxide inhibits proliferation and induces apoptosis in pancreatic cancer cells. Anticancer Res 2 0 0 2; 22 : 2205-22 1 3. 6. Jiang XH5 Wong BC5 Yuen ST, et al. Arsenic trioxide induces apoptosis in human gastric cancer cells through υρ-regulation of p 5 3 and activation of caspase-3. Int J Cancer 200 1; 91 : 1 73-1 79.

Wang ZY, Arsenic compounds as anticancer -18- (15) 1335229 agents. Cancer Chemother Pharmacol (200 1 ), 48 (suppl 1) : S72-S76 8 . Murgo A . J . 5 Clinical trials of arsenic trioxide in hematologic and solid Tumors ·· overview of the National

Cancer Institute Cooperative Research and Development Studies. The Oncologist (2001),6 (suppl 2) : 22-28

9. Chun YJ, Park IC, Park MJ, et a 1. Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (A s 2 O 3). FEBS Lett 2002; 519: 195-200. 10. Cheng CF, Hsu HH, Huang ML, Huang MJ. Study on the systemic absorption of topically applied As203 lotion in patients with cutaneous metastatic breast cancer — report of 2 cases. J Intern Med Taiwan 2003 ; 1 4 : 3 1-36 .

1 1 . Bazarbachi A, El Sabban ME, Nasr R, et a 1. Arsenic trioxide and interferon alpha synergize to induce cell cycle arrest and apoptosis in human T - ce 11 lymphotropic virus type I-transformed cells. Blood 1 999; 93 : 278 -283. 12, Chakravarthy A. Nicholson B 3 Kel ley M, et al. A pilot study of neoadjuvant paclitaxel and radiation with correlative molecular studies in stage II/III breast cancer. Clin Breast Cancer 2000: 1 : 68-7 1 . -19- (16) 1335229 13. Lew YS5 Kolozsvary A, Brown SL, Kim Synergistic interaction with arsenic trioxide fractionated radiation in locally advanced murine tun Cancer Res 2002; 62 : 4202-4205. 1 4. Rust DM, Soignet SL. Risk /benefit profile arsenic trioxide. Oncologist 2 0 0 1; 6(suppl) : 3 2-3 7. JH. and lo r. of -20·

Claims (1)

1335229 Ο) Picking up, applying for patent scope No. 93 1 121 No. 12 Patent application Chinese patent application Fan Zheng t. • · ·» .:;....· Republic of China 96: Year I; 6:4 repair: 正1·— An arsenic-containing pharmaceutical composition for use in combination with a method for treating skin metastatic cancer, characterized in that the arsenic-containing pharmaceutical composition is an arsenic-containing gel formulation and comprises an effective amount of an arsenic-containing compound and a medicine. An acceptable carrier, the arsenic-containing pharmaceutical composition is administered in an amount ranging from 0.01 to 0.5 mg/cm2/day. 2. The arsenic-containing pharmaceutical composition according to claim 1, wherein the arsenic-containing compound is selected from the group consisting of As203, As2S3, As2S2, and combinations thereof. 3. The arsenic-containing pharmaceutical composition according to claim 1, wherein the arsenic-containing compound is A S 2 Ο 3. 4. The arsenic-containing pharmaceutical composition according to claim 1, wherein the skin metastatic cancer is selected from the group consisting of breast cancer, colon cancer, ovarian cancer, lung cancer, head and neck cancer, and cancer of oral cancer. 5. The arsenic-containing pharmaceutical composition according to item 4 of the patent application, wherein the skin metastatic cancer is breast cancer. 6. The arsenic-containing pharmaceutical composition according to claim 1, wherein the arsenic-containing pharmaceutical composition is administered in an amount ranging from 0.05 to 0.15 mg/cm2/day. 7. The arsenic-containing pharmaceutical composition of claim 1, wherein the arsenic-containing pharmaceutical composition is administered locally to (2) (2) 1335229 patients with skin metastatic cancer before performing radiotherapy. The skin metastatic cancer site. 8. The arsenic-containing pharmaceutical composition according to claim 7, wherein the arsenic-containing arsenic pharmaceutical composition is locally administered to the skin metastatic cancer site of the patient suffering from skin metastatic cancer, and It is removed from the site of metastatic cancer of the skin before radiotherapy. 9. For example, the arsenic-containing pharmaceutical composition of claim 1 wherein the total radiation dose of the radiation therapy range is 30 to 50 Gy / 5 days. -2-