Metabolic Immunodepression and Metabolic Immunotherapy

Abstract

The effects of administration of phenformin and clofibrate to 32 breast cancer patients who underwent radical mastectomy and suffered from hormonal metabolic disturbances involving a decline in immunologic response were investigated. It was demonstrated that treatment with these drugs during 2–7 months results in an improvement in metabolic parameters and delayed hypersensitivity reaction to DNCB, tuberculin and candidin (75.5% of cases), an increase in T lymphocyte count (56.3%) and an improvement of the reaction of lymphocyte blast transformation (66.6%). The improvement in the immunologic status of the patients persisted for 6–8 weeks after the stoppage of phenformin administration; a gradual decline in immunologic response and return to the original level were recorded 4–6 months after stoppage of phenformin therapy. The effect of clofibrate on metabolic and immunologic parameters did not manifest itself as soon as 6–8 weeks after stoppage. Elimination of metabolic immunodepression, which gradually develops in the course of normal ageing and tumor process, should be the main objective of metabolic immunotherapy. To this end, therapeutic means, other than phenformin and clofibrate, may be used provided they exert the same effects on carbohydrate-fat metabolism. The desirability of study of the effects of a long-term course of drugs of this kind on the therapy of cancer patients is discussed.

The key role of growth hormone–insulin–IGF-1 signaling in aging and cancer

“…Currently, phenformin is not used in clinical practice due to it side effects (mainly lactic acidosis) observed in patients with non-compensated diabetes. It is worthy of note that during more than a 10-year-long experience of phenformin administration to patients without advanced diabetes, Dilman and Berstein [122-127] observed no cases of lactic acidosis or any other side effects. We believe that results analysis of long-term administration of this drug as well as other antidiabetic biguanides (buformin and metformin) to non-diabetic animals is important for understanding the links between insulin and longevity and between insulin and cancer.…”

“…Biguanides were used as a component of the so-called metabolic rehabilitation of breast and colon cancer patients [109,122,123]. The total of 324 patients (182 with breast cancer and 142 with colon cancer) treated by surgery of the primary tumor were randomly divided into control and treatment groups.…”

“…Among patients treated with biguanides, 304 were given the drug for more than 3 years and 15% for more than 5 years. The authors reported an overall improvement in the cumulative survival by 3-6 and 4-7 years of observation in groups with breast and colon cancer, respectively, as well as a slight decrease in frequency of primary multiple neoplasms and metachronous tumors in the contralateral breast [109,122-127]. Evans et al [206] reported results of a pilot case-control study on 11,876 diabetic patients treated or not treated with metformin.…”

Metformin is synthetically lethal with glucose withdrawal in cancer cells

“…72 In addition to forgetting the pioneer studies by Prof. V.M. Dilman more than 40 y ago, demonstrating a significant association with increased total and diseasefree survival upon the inclusion of the metformin's older cousin phenformin as a long-term adjuvant modality of metabolic rehabilitation of post-operative colorectal and breast cancer patients, [73][74][75] some authors start to prematurely conclude that metformin and metformin-like drugs can be just "cancer drugs for diabetics" with anticancer activities exclusively confined to hyperinsulinemic subjects with insulin-sensitive carcinomas. 6 Although we can anticipate that it will take another 2 to 3 y to enroll all the patients in the numerous metformin-based cancer clinical trials that are currently underway, and it may be 3 to 4 y before the trials results are published in peer-reviewed journals, the recently reported study by Bonnani et al 5 concluded that the anticancer activity of metformin will be restricted to breast cancer patients with high body mass index (BMI) and insulin resistance.…”

Metformin: Do we finally have an anti-aging drug?

“…However there were no cases of lactic acidosis or any other side effects of phenformin given to patients without advanced diabetes. 26,[32][33][34] We believe that the analysis of results of long-term administration of this drug as well as another antidiabetic biguanides (buformin and metformin) to nondiabetic animals is very important for better understanding links between insulin and longevity. In this paper we critically rewieved available data on effects of antidiabetic biguanides on lifespan of worms, flies, mice, and rats.…”