Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients.
Cancer Chemother Pharmacol. 2004 Mar;53(3):220-4. Epub 2003 Dec 4
Department of Medicine, School of Medicine, University of Uruguay, Montevideo, Uruguay. email@example.com
PURPOSE: It has been reported that insulin increases the cytotoxic effect in vitro of methotrexate by as much as 10,000-fold. The purpose of this study was to explore the clinical value of insulin as a potentiator of methotrexate. PATIENTS AND METHODS: Included in this prospective, randomized clinical trial were 30 women with metastatic breast cancer resistant to fluorouracil + Adriamycin + cyclophosphamide and also resistant to hormone therapy with measurable lesions. Three groups each of ten patients received two 21-day courses of the following treatments: insulin + methotrexate, methotrexate, and insulin, respectively. In each patient, the size of the target tumor was measured before and after treatment according to the Response Evaluation Criteria In Solid Tumors. The changes in the size of the target tumor in the three groups were compared statistically. RESULTS: Under the trial conditions, the methotrexate-treated group and the insulin-treated group responded most frequently with progressive disease. The group treated with insulin + methotrexate responded most frequently with stable disease. The median increase in tumor size was significantly lower with insulin + methotrexate than with each drug used separately. DISCUSSION: Our results confirmed in vivo the results of previous in vitro studies showing clinical evidence that insulin potentiates methotrexate under conditions where insulin alone does not promote an increase in tumor growth. Therefore, the chemotherapy antitumoral activity must have been enhanced by the biochemical events elicited in tumor cells by insulin. CONCLUSIONS: In multidrug-resistant metastatic breast cancer, methotrexate + insulin produced a significant antitumoral response that was not seen with either methotrexate or insulin used separately.
Study protocol: Insulin and its role in cancer.
ABSTRACT: BACKGROUND: Studies have shown that metabolic syndrome and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis. A part of this carcinogenic effect could be attributed to hyperinsulinism. High levels of insulin decrease the production of IGF-1 binding proteins and hence increase levels of free IGF-1. It is well established that bioactivity of free insulin growth factor 1 (IGF-1) increases tumor turnover rate. The objective is to investigate the role of insulin resistance/sensitivity in carcinogenesis by studying the relation between insulin resistance/sensitivity and IGF-1 levels in cancer patients. We postulate that hyperinsulinaemia which prevails during initial phases of insulin resistance (condition prior to overt diabetes) increases bioactivity of free IGF-1, which may contribute to process of carcinogenesis. Methods / Design: Based on our pilot study results and power analysis of the same, we have designed a two group case-control study. 800 proven untreated cancer patients (solid epithelial cell tumors) under age of 50 shall be recruited with 200 healthy subjects serving as controls. Insulin resistance/sensitivity and free IGF-1 levels shall be determined in all subjects. Association between the two parameters shall be tested using suitable statistical methods.
DISCUSSION: Well controlled studies in humans are essential to study the link between insulin resistance, hyperinsulinaemia, IGF-1 and carcinogenesis. This study could provide insights to the role of insulin, insulin resistance, IGF-1 in carcinogenesis although a precise role and the extent of influence cannot be determined. In future, cancer prevention and treatment strategies could revolve around insulin and insulin resistance.
Ann Surg Oncol. 1998 Mar;5(2):194-201.Links
Altered serum levels of insulin-like growth-factor binding proteins in breast cancer patients.
Department of Surgery, Singapore General Hospital, Republic of Singapore.
BACKGROUND: Insulin-like growth factor 1 (IGF-1) has mitogenic properties for breast cancer cell lines and has been proposed to be an important factor in breast carcinogenesis. We hypothesized that differences in IGF-1 or its binding proteins might increase susceptibility to breast cancer. This case-control study was designed to investigate whether patients with breast cancer have altered levels of either IGF-1 or its intermediary modulatory proteins, the IGF binding proteins (BP). METHODS: Serum was collected from 90 patients (63 with breast cancer and 27 with benign breast disease) after an overnight fast and before surgery. IGF-1, BP1, and BP3 levels were determined by immunoradiometric assays. In a subset of 66 patients, Western ligand blots were also performed for a semiquantitative measurement of functioning BP levels. A forward stepwise logistic regression model to adjust for other confounding variables (age, menopausal status, parity, age at menarche, use of oral contraceptives, history of breast biopsy, family history of breast cancer, hormone replacement therapy, and body-mass index) was used in the multivariate analysis.
RESULTS: Serum IGF-1 levels were similar in cases and controls. However, levels of BP3 (p < 0.001), BP4 (p < 0.01), and BP1 (p < 0.05) were significantly associated with risk of breast cancer. The level of BP3 was the most significant factor predictive of breast cancer. The odds ratio for breast cancer in women with BP3 levels >2066 ng/ml was 0.18 (95% CI, 0.05-0.55). Correspondingly, women with BP1 levels higher than 39 ng/ml had an odds ratio of 0.21 (95% CI, 0.07-0.68) for breast cancer. When considering only cancer patients (n = 63), decreasing levels of BP4 (p < 0.01) and increasing levels of BP1 (p < 0.02) were significantly associated with progesterone receptor positivity (PR+) in the tumor. The odds ratio of PR+ in patients with BP1 levels higher than 34 ng/ml was 7.49 (95% CI, 1.5-37.4). Better grade of tumor (well and moderately differentiated) was observed in patients with higher levels of BP3 (p < 0.03).
CONCLUSIONS: Distinct differences in BP profiles exist among patients with breast cancer and also among those with high-grade, hormonal receptor-negative tumors. These findings suggest that the bioavailability of IGF-1 as mediated by its binding proteins may participate in both breast carcinogenesis and selection of more aggressive breast carcinomas.
Advanced breast cancer: anti-progressive immunotherapy using a thermostable autologous hemoderivative.
Breast Cancer Res Treat. 2006 Nov;100(2):149-60. Epub 2006 Jul 4.
PharmaBlood Inc, Research & Development Department, 2050 NE 163rd Street, # 202, North Miami Beach, Florida 33162, USA. firstname.lastname@example.org
INTRODUCTION: Advanced breast cancer patients, acquired-chemotherapy resistant and in progression, are therapeutically terminal. We tested a recently described medical procedure using a thermostable autohemoderivative purported to inhibit tumor growth possibly through an immunological mechanism of action. PATIENTS AND METHODS: Metastatic breast cancer patients, chemotherapy-resistant, high CEA and CA 15-3 plasma levels of tumor markers, in progression, were 2-group randomized. Group 1 received the test procedure and Group 2 adequate measures to be comparable control. From 121 included patients, 108 could be evaluated. During 8-month follow-up period, tumor growth, number of cases attaining clinical non-progressive status and mortality were monthly assessed. Immunologic effect was assessed by delayed type hypersensitivity test and lymphocyte proliferation assay. Responding-tumors histopathologies were studied. The proteome of the autologous immunogen was characterized by 2-D electrophoresis. RESULTS AND DISCUSSION: In a significant number of cases, the test procedure promoted inhibition of tumor growth, non-progressive disease status, and lower cumulative mortality. These clinical results were associated with polyvalent immunization against several tested antigens: the hemoderivative used for treatment, the blood tumor markers and the derivative obtained from a regulatory lymphocyte population (CD4+CD25+). Interference with this regulatory activity could explain the selective autoimmunity suggested by the histopathology findings in responding tumors. The thermostability could be an essential property of the immunogen hemoderivative. CONCLUSION: The thermostable autohemoderivative tested is antigenically polyvalent and promoted a polytargeted immune response associated to a tumor anti-progressive effect, consequently, acting as an autohemoderivative cancer vaccine.
Advanced colon cancer: antiprogressive immunotherapy using an autologous hemoderivative.
Med Oncol. 2006;23(1):91-104.
Department of Research & Development, PharmaBlood Inc, 2050 NE 163rd Street, # 202, North Miami Beach, Florida 33162, USA. email@example.com
INTRODUCTION: Advanced colon cancer patients, acquired-chemotherapy resistant and in progression, are therapeutically terminal. We tested a recently described medical procedure using a thermostable autologous hemoderivative purported to inhibit tumor growth possibly through an immunological mechanism of action. PATIENTS AND METHODS: Metastatic colon cancer patients chemotherapy-resistant, high CEA plasma levels, in progression, were 2-group randomized. Group 1 received the test procedure and Group 2 adequate control measures. During an 8-mo follow-up period (n = 101), tumor growth, number of cases attaining clinical nonprogressive status, and mortality were assessed monthly. Immunological effect was assessed by delayed-type hypersensitivity test and lymphocyte proliferation assay. Responding-tumors histopathologies were studied. RESULTS AND DISCUSSION: In a significant number of cases, the test procedure promoted inhibition of tumor growth, nonprogressive disease status, and lower cumulative mortality. These clinical results were associated with polyvalent immunization against several tested antigens: the hemoderivative used for treatment, the blood tumor markers, and the regulatory lymphocyte population (CD4+CD25+). Interference with this regulatory activity could explain the selective autoimmunity suggested by the histopathology findings in responding tumors. CONCLUSION: The autologous hemoderivative tested is antigenically polyvalent and promotes a polytargeted immune response associated with a tumor antiprogressive effect, consequently, acting as an autologous hemoderivative cancer vaccine.
Antitumoral effect of a vaccination procedure with an autologous hemoderivative.
Cancer Biol Ther. 2003 Mar-Apr;2(2):155-60.
School of Medicine, University of Uruguay, Uruguay. firstname.lastname@example.org
Lately, the promising results obtained with autologous cancer vaccines are stimulating new research in the old field of cancer immunotherapy. This paper describes the development of a procedure previously reported by us that is used to obtain an autologous hemoderivative with antitumoral properties. The procedure has been tested in a phase I-II, randomized, controlled clinical trial of 28 cancer patients with different primary malignancies in metastatic and chemotherapy-resistant stages. The histology of the lesions that responded to this treatment was consistent with the characteristic histology observed in malignant lesions treated with a similar antitumoral hemoderivative: proliferation of stromal connective tissue, T-lymphocyte infiltration, and a reduction in the amount of tumor cells and blood vessels. We concluded that vaccination had elicited an immune response because a delayed-type hypersensitivity test made with the autologous hemoderivative produced a significantly more intense response in the responding treated patients. We propose that an immune mechanism acting on tumor cells and/or the regulatory system for stromal growth explains the histological results observed. The use of blood to obtain the immunogen allows vaccination to be repeated, so this method could avoid tumor escape responses due to mutations in the antigen library of the tumor. The results of our study justify further research to optimize the antitumoral effect of vaccination.
Serum markers variation consistent with autoschizis induced by ascorbic acid-menadione in patients with prostate cancer.
Med Oncol. 2003;20(1):45-52.
School of Medicine, University of Uraguay, Montevideo, Uriguay. email@example.com
In vitro exposure of malignant prostate cell lines to ascorbic acid-menadione showed that tumor cells were killed through a mechanism named autoschizis. Experimental animal studies showed that autoschizis is also evident when ascorbic acid-menadione is administered to nude mice with implanted human prostate tumors. Prostate-specific antigen (PSA) is a known serum marker of prostate tumor cells specific activity. Recently, total serum homocysteine has been identified as a marker of tumor cell numbers with sensitivity for early detection of tumor cell death induced by treatments. A clinical trial with prostate cancer patients submitted to the association of ascorbic acid-menadione was performed and PSA/homocysteine was assessed in the follow- up. The early response in serum PSA and homocysteine levels was reported. The results showed that ascorbic acid-menadione produced an immediate drop in tumor cell numbers as assessed by homocysteine levels. Serum PSA levels showed an early rise and later dropped. These results suggest that autoschizis can also be induced by this pharmacological association at the clinical level in prostate cancer patients. Further studies are being performed in order to research if these results can be found with other primary tumors as it was shown in in vitro and experimental models. Ascorbic acid-menadione could be emerging as a new antitumoral chemotherapy.