[Rich66]

J Clin Oncol. 2009 Nov 30. [Epub ahead of print]
Metformin, B12 and Enhanced Breast Cancer Response to Chemotherapy.

1 page PDF suggests Metformin (and chemo) induced B12 reduction is part of benefit.

...it is entirely reasonable to assume that some patients in the metformin treated group may have had occult, active B12 insufficiency.
In addition, our most recent work revealed that 18 of 21 patients undergoing a variety of chemotherapy protocols experienced large decreases in the active component of B12, holotranscobalamin.12

Interesting mention of Nitrous oxide anaesthesia rapidly reduces B12 and can kill tumor cells:

Work by others demonstrated that rapid inactivation of B12 by nitrous oxide anesthesia induced tumor-cell kill in vitro and increased tissue toxicity in patients receiving adjuvant chemotherapy with methotrexate. This was assumed to be due to acute, N2Oinduced B12 deficiency.13 Rapid N2O-induced B12 deficiency decreased leukemia cell proliferation in patients with leukemia14 and suppressed bone marrow cell proliferation in tetanus patients.15

Garcia A, Tisman G.
Department of Medical Oncology, The Whittier Cancer Research Building, Whittier, CA.
PMID: 19949002 [PubMed - as supplied by publisher]


Int J Radiat Biol. 2009 Nov;85(11):963-71.
The anti-oxidant capacity of tumour glycolysis.

Sattler UG, Mueller-Klieser W.
Institute of Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
PURPOSE: In this mini-review data are summarised which provide evidence for the biological and clinical significance of tumour glycolysis and of its relationship to the redox state of cancer cells. RESULTS: Malignant transformation is associated with an overexpression of numerous glycolysis-related genes in the vast majority of human cancers. At the same time, glycolytic activity and glycolysis-linked metabolic milieu are often variable between individual tumours which induces large variations in treatment response and aggressiveness. Currently, there is no genetic or proteomic marker for the prediction of the therapeutic response for individual tumours, but the prognostic value of tumour lactate accumulation for the emergence of metastasis, for patient survival and for radioresistance has been documented in a number of studies. CONCLUSIONS: Transactivation of tumour glycolyis appears to generate a chemically reduced milieu associated with an inhibition of ROS (reactive oxygen species) -mediated fixation of DNA damage and induction of radioresistance. Furthermore, highly glycolytic cells enhance the antioxidant defense via glutathione, and pyruvate can be decarboxylated non-enzymatically upon reducing hydrogen peroxide. The summary of data given here emphasises the importance of further research efforts on the link between carbohydrate metabolism and redox state of cancer cells.

PMID: 19895273 [PubMed - in process]


LINK to full text
LINK to PDF

Abstract
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great
promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent,
doxorubicin, kills both cancer stem cells and non–stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2months after combinatorial therapy with metformin and doxorubicin is
ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):7507–11]

To our knowledge, the ability of metformin to selectively kill cancer stem cells and to function synergistically with doxorubicin to block both cancer stem cells and non–stem-transformed cells is unique. In the case of breast cancer, herceptin and tamoxifen are useful drugs for cancer types that, respectively, express the HER2 and ERs, but some forms of breast cancer lack these receptors and resist these treatments. For all of these types of
breast cancer, metformin selectively inhibits cancer stem cell growth and, hence, is likely to function synergistically with chemotherapeutic drugs. In addition, as metformin inhibits transformation of MCF10A-ER-Src cells, it might have a potential use in preventing the development of cancer, as opposed to treating cancer that has already occurred.

...the concentration of metformin needed for the anticancer effects observed here is considerably below that used for the treatment of diabetes. Lastly, the selectivity of metformin and doxorubicin for distinct types of cells in the tumor can explain the striking combinatorial effects on reducing tumor mass and prolonging remission in nude mice, and it provides the rationale for combining metformin with chemotherapy as a new treatment for breast (and possibly other) cancers.





SABC 2009
[1054] Deleterious Effect of Chemotherapy on Measures of Insulin Resistance in Patients with Newly-Diagnosed Invasive Breast Cancer.

Makari-Judson G, Katz D, Barham R, Mertens WC Comprehensive Breast Center/Baystate Regional Cancer Program and Tufts University School of Medicine, Springfield, MA

Background: Women treated with early stage breast cancer often gain weight in the two years following diagnosis, with adjuvant chemotherapy, younger age, lower body mass index (BMI) and pretreatment menopausal status being associated factors (Breast J 2007; 13:258). The effect of insulin resistance on treatment-related weight gain, and of treatment on measures of insulin resistance, are unclear.
Purpose: To prospectively study weight gain in women receiving adjuvant therapy for early stage breast cancer and assess changes in body mass index, body composition, and explore the relationship between markers of insulin resistance, cancer therapy, exercise and weight gain.
Methods: Prospective, observational study of non-diabetic women with early-stage breast cancer receiving adjuvant chemotherapy and/or hormonal therapy. Fasting insulin, glucose, and triglycerides, weight, BMI, waist and hip circumference were obtained at baseline before adjuvant therapy, and at 6, and 12 months. Patients completed nutrition and exercise logs using the Nutritionist-Pro program. Insulin resistance was calculated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Waist/hip ratio (WHR) was used as a surrogate for percent body fat.
Results: Complete data available for 95 patients are reported regarding weight change at 6 months (mean 0.4 kg, 95%CI -0.3, 1.0; p=.23 compared to baseline) and 12 months (0.9 kg, 95%CI 0.4, 1.8, p=.04 compared with baseline). Mean baseline HOMA-IR was 2.3 (95%CI 1.9, 2.7); mean baseline WHR was 0.82 (95%CI 0.81, 0.84). Six-month HOMA-IR tended to increase (by mean 0.34, p=.06) as did glucose/insulin ratio (p=.05). Waist measurement (p=.96) and WHR (p=.52) were unchanged. Chemotherapy-treated patients exhibited adverse changes compared with others (mean change for chemotherapy-treated and no chemotherapy for HOMA-IR: 0.53 vs. -0.64, p=.005; glucose/insulin: -2.1 vs. 2.7, p=.003; waist: 0.37 vs. -1.94 cm, p=.08; WHR: 0.001 vs. -0.024, p=.06). Age, BMI, hormonal therapy, or types of breast surgery were not associated with significant changes. Exercising patients demonstrated lower HOMA-IR and WHR, and greater glucose/insulin ratios at baseline, but exercise (aerobic, strength, or any exercise) was not associated with significant change at 6 and 12 months for any of these variables. While differences disappeared at 12 months despite further weight gain repeated measures analysis of variance confirmed the effect of chemotherapy over time for HOMA-IR (p=.048), glucose/insulin (p=.038) and WHR (p=.050).
Conclusions: These preliminary data suggest that patients completing chemotherapy within 6 months of baseline appear to experience at least short-term changes in metabolism suggestive of insulin resistance. These adverse changes may help explain weight gain associated with adjuvant chemotherapy, and merit further prospective study.

Thursday, December 10, 2009 5:30 PM

Poster Session 1: Social, Behavior, Economic, and Outreach Studies: Survivorship Research (5:30 PM-7:

Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy Journal Breast Cancer Research and Treatment Publisher Springer Netherlands ISSN 0167-6806 (Print) 1573-7217 (Online) Category Preclinical study DOI 10.1007/s10549-009-0647-z Subject Collection Medicine SpringerLink Date Monday, November 23, 2009	Add to marked items Add to saved items Permissions & Reprints Recommend this article

PDF (598.0 KB)HTMLSupplemental Material

Preclinical study

Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy
Kathryn N. Phoenix¹, Frank Vumbaca¹, Melissa M. Fox¹, Rebecca Evans¹ and Kevin P. Claffey¹

(1)	Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-3501, USA

Received: 9 September 2009 Accepted: 11 November 2009 Published online: 22 November 2009
Abstract
Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.
Electronic supplementary material The online version of this article (doi:10.1007/s10549-009-0647-z) contains supplementary material, which is available to authorized users.


11/16/09
Targets 09 Episode 3: Listen to David Sabatini, M.D., Ph.D., a member of the Whitehead Institute and associate professor of biology at MIT, speak about his work on dietary restriction and tumor response.
http://media.libsyn.com/media/aacr/A...odcastsEp3.mp3

Some notes:

History of dietary/caloric restriction theory: restriction by 30% thought to reduce incidence and growth amongst all cancers.

Current research found disparities in response

divided cancers into responsive/unresponsive

Resistant cancers, when cell analyzed didn't care about insulin growth factors. Responsive cancers followed insulin levels tightly which implicated PI3 kinase pathway, one of the major systems of response to insulin levels.
Looked at the two types of cells and found Pi3 kinase pathways differed, resistant cells had mutated PI3 kinase pathways. Manipulation of pathway could induce resistance or responsiveness showing causation and identified PI3K as pivotal.
Mimetics (metformin?) of caloric restriction could prove helpful. However findings suggest need to identify which tumors will respond.

Despite prevalent thinking that restriction worked on all tumors, closer look at data from the 30's actually does show disparities.

Identification of main pathway/response determination is biggest finding. Simplifies what was thought to be a complex process. Insulin levels drop when you calorically restrict. But here's a (mutated) pathway that lets the cells think there's always insulin.

If caloric restriction important the reverse is implicated. Obesity may be biggest driver of increased cancer. Need to find out role of mutated pathway in obese patients.

Suggests organism/metabolism focus is warranted.

Study demonstrated advancement in mouse models that showed same results of human xenograft models.