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Old 11-18-2009, 05:47 PM   #21
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

Cancers' sweet tooth may be weakness

http://www.physorg.com/news177769436.html
November 18th, 2009 in Medicine & Health / Cancer
The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered.
Scientists who study cancer have known for decades that cancer cells tend to consume more glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931 Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose.
The results were published this week in the journal Science Signaling.
Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough.
Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells.
"Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly."
Working with Chen, postdoctoral researcher Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in tumor cells.
In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into cancer cells forces them to grow slower and be more dependent on oxygen, they found.
Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others.
"People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism."
PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says.
More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
Source: Emory University (news : web) http://www.physorg.com/news177769436.html


[1133] Metformin Enhances Trastuzumab Efficacy and Overcomes Resistance in HER2 Type Breast Cancer Cells.

Thor AD, Fan Z, Yang X-H, Esteva FJ, Jones FE, Edgerton SM, Lind SE, Liu B University of Colorado Denver, Aurora, CO; University of Oklahoma Health Sciences Center, Oklahoma City, OK; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Tulane University, New Orleans, LA

Background: HER2 alterations occur in one-fourth of breast cancers and are associated with an aggressive tumor phenotype. The anti-HER2 agent trastuzumab reduces cell proliferation, angiogenesis, DNA repair and induces antibody-dependent cellular cytotoxicity. Objective response rates and median duration of response for eligible patients given trastuzumab alone is low (12-34% and 9 months respectively), hence, it is administered in combination with other agents. Mechanisms of trastuzumab resistance include: altered receptor antibody interactions, increased signaling through other EGFR type I growth factor receptors, modulation of p27 kip1 and increased insulin-like growth factor 1 receptor (IGF-1) signaling. We have reported that metformin inhibits HER2 expression, tyrosine kinase activity (phosphorylated HER2 at both auto- and Src- phosphorylation sites), AKT/mTOR signaling, Cyclin D1 and E2F1 with G1 arrest in HER2 overexpressing breast cancer cells. We sought to determine if metformin would enhance trastuzumab associated cytotoxicity and modulate acquired resistance in vitro.
Methods: We used trastuzumab sensitive (SKBR3, BT474) and resistant cell lines (BT-474/HR20, SKBR3/P2, MCF-7/713 and MCF-7/HER2Δ16) to study the effects of metformin, metformin + trastuzumab and trastuzumab alone. Assays included MTS for proliferation, clonogenicity studies, Western blots, and pull down experiments with Western blots.
Results: Trastuzumab sensitive breast cancer cells were less sensitive to metformin alone, compared to trastuzumab resistant HER2 subtype breast cancer cell lines. Trastuzumab sensitive cells showed enhanced growth and clonogenicity inhibition when treated by both metformin and trastuzumab. At the molecular level, these bi-treated cells showed decreases in HER2/pHER2, erbB3/perbB3, and inactivation of AKT and MAPk signaling. Metformin as low as 20mM increased the efficacy of trastuzumab. All HER2 resistant cell lines showed higher levels of IGF1R and HER2/IGF1R complexes, as compared to sensitive parental lines. In these resistant lines Metformin decreased cell proliferation and clonogenicity, HER2/IGF1R complexes (identified through pull down experiments) and protein expression of HER2/pHER2, erbB3/perbB3, IGF1R/pIGF1R as well as downstream signaling via Akt and IGF1 pathways. Metformin overcame trastuzumab resistance as demonstrated by growth and clonogenicity assays.
Conclusions: HER2 amplified trastuzumab resistant breast cancer cells showed greater sensitivity to metformin than sensitive parental lines. Metformin reversed trastuzumab resistance and decreased HER2:IGF1R complexes, HER2/pHER2 and IGF1R expression, whereas sensitive parental lines showed no complex formation. These preclinical data suggest a combination of metformin and trastuzumab may have clinical benefit, improving the efficacy and reducing the emergence of or reversing trastuzumab resistance in HER2 positive breast cancer patients.
Herceptin graciously provided by Genentech

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Old 11-22-2009, 06:32 PM   #22
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

http://genesdev.cshlp.org/content/23/5/537.full#sec-1

http://genesdev.cshlp.org/content/23....full.pdf+html

Tumor suppressors and cell metabolism: a recipe for cancer growth.

Abstract

Growing tumors face two major metabolic challenges—how to meet the bioenergetic and biosynthetic demands of increased cell proliferation, and how to survive environmental fluctuations in external nutrient and oxygen availability when tumor growth outpaces the delivery capabilities of the existing vasculature. Cancer cells display dramatically altered metabolic circuitry that appears to directly result from the oncogenic mutations selected during the tumorigenic process. An emerging theme in cancer biology is that many of the genes that can initiate tumorigenesis are intricately linked to metabolic regulation. In turn, it appears that a number of well-established tumor suppressors play critical roles in suppressing growth and/or proliferation when intracellular supplies of essential metabolites become reduced. In this review, we consider the potential role of tumor suppressors as metabolic regulators.


Quote:
Cancer therapy is increasingly shifting toward individualized therapeutic approaches based on the genetic abnormalities exhibited by transformed cells. In cancer cells, a given transformation event (i.e., oncogene activation) may play a qualitatively different or essential role in a given pathway compared with its role in normal cells, such that cancer cells become dependent on the activity of a specific oncogene for function and survival, a concept known as oncogene addiction. From this logic, oncogene-driven signal transduction may promote greater dependence on specific metabolic pathways such as glycolysis to maintain tumor growth. When combined with the loss of tumor suppressors that promote metabolic adaptation, cancer cells risk developing greater sensitivity to bioenergetic stress. The LKB1-AMPK-p53 pathway best illustrates exposure of such a metabolic “Achilles' heel” and its impact on tumor survival.
Quote:
LKB or p53 deficiency, while permissive for unchecked cell growth, renders cells more susceptible to death by metabolic stress. Moreover, the ability of tumor cells to survive metabolic stress in vivo requires AMPK-dependent activation of p53 (Buzzai et al. 2007), which may explain why metformin, an anti-diabetic therapy, can be anti-tumorigenic (Evans et al. 2005; Huang et al. 2008).
Understanding the pathways that regulate cancer cell metabolism may lead to greater understanding of cancer development and progression, and has the potential to open a new vista of metabolic therapy for cancer treatment.
Metformin for Cancer

October 26, 2008 http://cancerx.wordpress.com/2008/10...in-for-cancer/


Metformin’s many physiologic actions include suppressing liver’s own sugar production (”hepatic gluconeogenesis”), increasing insulin sensitivity, enhancing body sugar utilization and decreasing absorption of sugar from the intestines. Overall, we can summarily say that Metformin improves overall sugar metabolism (I have long supported reducing carbohydrate consumption as an adjunct in controlling cancer, perhaps to my colleagues’ consternation if not ridicule. Sugar and cancer is a very important theme, though usually under appreciated by conventional oncologists despite the strength of corollary data. But alas, the topic would be a whole separate blog)
Given so many modern illnesses (eg hyperlipidemia, obesity, diabetes etc) resulting from deranged carbohydrate metabolism, it is not hard to imagine that Metformin may have a role to play in the treatment of conditions resulting from defective insulin signalling (incl. polycystic ovary syndrome [PCOS], infertility, non-alcoholic fatty liver disease (NAFLD) or steato hepatitis, metabolic syndrome X, etc), and these could all be considered “off-label” uses for Metformin as a drug .
A higher incidence of cancer in patients with diabetes has been observed for a century, so much so that Dr Anna Barker, deputy director at the National Cancer Institute estimated that the obesity and diabetes pandemic will cause an additional 30-40% increase in incidence of total solid tumour cancers over the next 10 years – notably in breast, prostate, and colorectal cancer (Financial Times, Oct 1st, 2008). So it makes common sense that an anti-diabetic medicine may somehow inhibit cancer. More recently, despite many mainstream oncologists curiously still denying a role of sugar and diet for cancer control, science has reviewed an emerging key role for insulin and sugar metabolism or insulin signalling in determining cancer risk, tumor growth or cancer progression (See recent review “Insulin, Insulin-like growth factors, Insulin resistance and neoplasia” by Pollack MN of McGill University in Am J Clin Nutri 2007 Sep;86(3):s820-2 for an overview), then it is no surprise that Metformin has off-label application potential in cancer treatment, as do drugs from another class of anti-diabetic agents, the PPAR agonists [discussion to be posted in this blog soon].
And there is a bit of evidence for this:-
a) In Vitro (cellular evidence):
Active against breast cancer (Zakikhani M,Cancer Res. 2006 Nov 1;66(21):10269-73), ovarian cancer (Gotlieb WH et al. Gynecol Oncol. 2008 Aug;110(2):246-50), prostate cancer (Ben Sahra I, et al.Oncogene. 2008 Jun 5;27(25):3576-86), glioma brain cancer (Isakovic A, Cell Mol Life Sci. 2007 May;64(10):1290-302).
Observed mechanisms of action of Metformin against various cancers seems mainly to be related to apoptosis and includes decrease in cyclin D1, AMPK activation leading to inhibition of mTOR and a reduction in translation initiation, selective toxicity to p53-deficient cells, and induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation.
b) In Vivo (animal evidence):
Prevention of pancreas cancer in hamsters (Schneider MB, Gastroenterology. 2001 Apr;120(5):1263-70)
Metformin inhibits development of breast cancer in mice (Anisimov VN, : Bull Exp Biol Med. 2005 Jun;139(6):721-3)
Metformin suppresses intestinal polyp growth in mice (Tomimoto et al. 2008)
Metformin attenuates growth of lung cancer in mice (Algire C. et al, Endocr Relat Cancer. 2008 Sep;15(3):833-9)
Metformin inhibits prostate cancer (Ben Sahra I, et al.Oncogene. 2008 Jun 5;27(25):3576-86)
c) Clinical (human evidence):
Dr. Dario Alessi’s research (U. of Dundee) involving data from patient records over ten years, have shown that patients on metformin showed anywhere between a 30-40% protection against all forms of cancer. While this and lowered instance of breast cancer in women with diabetes treated with Metformin has been known for a while, but recent work presented this year demonstrating Metformin’s role in increasing the response rates of breast cancer patients with diabetes is very exciting:
“Using the M. D. Anderson Breast Medical Oncology database, Drs. Gonzalez-Angulo, Jiralerspong and their team at MD Anderson identified 2,529 women with early-stage breast cancer who received chemotherapy. Of the patients, 68 were diabetic but not taking metaformin and 87 were diabetic and taking the drug. The researchers found that the pathologic complete response rates in the breast cancer patients taking Metformin was 24 percent, three times higher than the rates in patients not taking the drug”
When interviewed, Dr. Gonzalez-Angulo thinks that the result maybe from decreased insulin levels as insulin is a known potent growth factor for cancer. The MD Anderson doctors are planning a trial of Metformin in metastatic breast cancer patients who are obese (and who may thus have insulin resistance and high circulating insulin levels).
My take
Such a benign drug as Metformin can be safely given as an off-label adjunctive treatment in cancer patients, especially breast, ovarian, colorectal, prostate, pancreas and perhaps in glioma patients who have Type 2 diabetes, exhibit metabolic syndrome X, who have elevated circulating insulin levels, or are obese, or even simply those who cannot or do not adhere to a low carb low fat diet.




Future Oncol. 2010 Aug;6(8):1313-23.
Modern approach to metabolic rehabilitation of cancer patients: biguanides (phenformin and metformin) and beyond.

Berstein LM.
N.N.Petrov Research Institute of Oncology, Pesochny-2, Leningradskaja 68, St Petersburg 197758, Russia. levmb@endocrin.spb.ru.


TEXT

Abstract

Comparing the experience accumulated for more than 40 years in the Laboratory of Endocrinology of Petrov Institute of Oncology (St Petersburg, Russia) with similar approaches practiced elsewhere, evidence supports the reasonability of metabolic rehabilitation of patients suffering from breast cancer or other hormone-dependent malignancies. The primary objective of such approaches is to improve treatment results by ameliorating hormonal-metabolic disturbances, including excess body fat, glucose intolerance, insulin resistance and manifestations of endocrine-genotoxic switchings, and modify tissue and cellular targets or mechanisms related or nondirectly related to the aforementioned disturbances. The relevant measures may be categorized as pharmacological (antidiabetic biguanides exemplified with metformin being most popular but not exclusive) and nonpharmacological (rational nutrition, moderate physical activity and so forth) and used separately or in different combinations.

PMID: 20799876 [PubMed - in process]

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Old 12-02-2009, 12:25 AM   #23
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

Is it the time for metformin to take place in adjuvant treatment of Her-2 positive breast cancer? Teaching new tricks to old dogs.

Yurekli BS, Karaca B, Cetinkalp S, Uslu R.
Division of Endocrinology and Metabolism, Ege University School of Medicine, 35100 Izmir, Turkey. bsareryurekli@yahoo.com
Breast cancer is the most common malignancy diagnosed among women. According to the new molecular subclassification, basal like and Her-2 positive breast cancers have the worst outcome and these are the ones in which chemotherapy is a must as a part of adjuvant treatment. New treatment options that could be used as an adjuvant maintenance treatment are still being investigated. Insulin hormone is one of the reasons of breast cancer recurrence and death in breast cancer survivors. Targeting insulin as a therapeutic modality in breast cancer could be an option in the adjuvant treatment of breast cancer. It seems that insulin may signal to activate a cascade of proliferative and anti-apoptotic events in the cancer cell. Metformin, an oral anti-diabetic known for 50 years, may also have direct effects on cancer cells. Metformin causes Her-2 suppression via the inhibition of mTOR in breast cancer cells. Thus, we believe that the time has arrived both to target insulin reduction and to alter Her-2 oncogene based molecular pathogenetic steps in breast cancer by using metformin as an adjuvant therapy in breast cancer patients.



Cell Cycle. 2010 Jan 22;9(1). [Epub ahead of print]
Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo.

Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA.
N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia.
Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. In our animal studies, metformin delayed the onset of mammary adenocarcinoma (MAC) in transgenic HER-2/neu mice but not the onset of spontaneous mammary tumors in female SHR mice. Pineal hormone also inhibits mammary carcinoma development in HER2/neu transgenic mice as well as in female SHR mice. Here we demonstrated that a combination of metformin and melatonin significantly inhibits growth of transplanted tumors in mice. Metformin (0.5 mg/ml in drinking water) increased mean life span by 8% and MAC latency by 13.2% (p < 0.05) in HER2/neu mice. The treatment with melatonin alone (2 mg/L in drinking water during the night time) or combined treatment with metformin (0.5 mg/ ml in drinking water during the day time) + melatonin (2 mg/L in drinking water during the night time) did not influence mammary carcinogenesis in the mice. The treatment metformin alone inhibited the growth of transplantable HER2 mammary carcinoma in FVB/N male mice by 46% at the 45(th) day after transplantation (p < 0.001). The combined treatment with metformin + melatonin significantly suppressed Ehrlich tumor growth (by 40%, p < 0.001). These results suggest that metformin may be useful in prevention and treatment of breast cancer.

PMID: 20016287 [PubMed - as supplied by publisher]




Indian J Cancer. 2009 Oct-Dec;46(4):274-87. Chemotherapy in adult soft tissue sarcoma.

Jain A, Sajeevan KV, Babu KG, Lakshmaiah KC.
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India. ankitjaindm@gmail.com
Soft tissue sarcomas (STSs) are rare and histologically diverse neoplasms. Recent results of various meta-analyses and development of newer drugs have changed the medical management of soft tissue sarcoma. This review gives an outline of chemotherapy and the newer targeted therapies for the same. We have carried out an extensive search in PubMed, Medline for almost all relevant articles concerning chemotherapy of soft tissue sarcoma. The available data from the literature is mainly composed of the most recent reviews, meta-analyses, phase II, and randomized phase III trials published in various peer reviewed journals and various international conferences. The role of neoadjuvant and adjuvant chemotherapy has been found to be controversial. The recent meta-analysis for adjuvant therapy in STSs has shown an increase in the overall survival with combination of ifosfamide and adriamycin. In locally advanced and metastatic STSs, single agent adriamycin remains the basic standard of medication. The combination of ifosfamide and adriamycin may also be used for rapid symptom relief and in patients planned for curative resection for metastases. Newer combinations of docetaxel and gemcitabine appear promising in selected subgroups, especially in leiomyosarcoma and malignant fibrous histiocytoma. Some recent developments include the European Union’s approval of trabectedin for advanced STSs patients who had progressed on adriamycin and ifosfamide therapy. The future of mTOR inhibitors, insulin like growth factor receptor inhibitors and anti-angiogenic drugs appear quite promising. Newer methodologies such as, Bayesian adaptive randomization and inclusion of newer end points like progression-free rate, time of progression rate, and tumor growth rate will improve the results of sarcoma trials. At the end of each section we have also presented recommendations from FNx01European Society of Medical Oncology and FNx08National Comprehensive Cancer Network guidelines v.1.2009 for better correlation with the present literature.





Curr Oncol Rep. 2009 Nov;11(6):446-53.
Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions.

Geryk-Hall M, Hughes DP.
Department of Pediatrics Research, Unit 853, Children’s Cancer Hospital, The University of Texas, M. D. Anderson Cancer Center, PO Box 301402, Houston, TX 77030, USA.
Bone sarcomas cause disproportionate morbidity and mortality and desperately need new therapies as there has been little improvement in outcomes in 20 years. Identification of critical signaling pathways, including type 1 insulin-like growth factor receptor (IGF-1R) for Ewing sarcoma and possibly osteosarcoma, and the ERBB and the Wnt signaling pathways for osteosarcoma, have emerged as receptors mediating vital signals for bone sarcoma. Akt, mammalian target of rapamycin (mTOR), phosphoinositide 3-kinases, mitogen-activated protein kinase kinase, extracellular signal-regulated kinases, and Ras pathway play key roles in at least some tumors, and inhibition of mTOR in particular will likely lead to improved survival, although clinical trials are still underway. The Notch pathway and ezrin are essential for osteosarcoma metastasis, and Fas downregulation is necessary for survival of metastases in lungs. As little is known about chondrosarcoma signaling, more preclinical work is needed. By defining vital signaling pathways in bone sarcomas, small molecule inhibitors can be applied rationally, leading to longer survival and reducing morbidity and late effects from intensive chemotherapy.



3.
Cancer. 2009 Nov 15;115(22):5243-50.
Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma.

Abdeen A, Chou AJ, Healey JH, Khanna C, Osborne TS, Hewitt SM, Kim M, Wang D, Moody K, Gorlick R.
Department of Orthopaedic Surgery, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York.
BACKGROUND:: Multiple cell-signaling ligands and receptors-including vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), endothelial growth factor (EGF), v-akt murine thymoma viral oncogene homolog (AKT), platelet-derived growth factor (PDGF), mitogen-activated protein kinase (MAPK), and 70-kilodalton (kD) protein S6 kinase (p70S6 kinase)-reportedly are variably expressed in osteogenic sarcoma. Expression of these proteins may have future implications for prognostication and targeted therapy. The objective of the current study was to determine the relation between clinical outcome and the expression of these proteins. METHODS:: A paraffin-embedded microarray of 48 human osteogenic sarcoma tissue specimens was stained with the antibodies against VEGF, IGF, EGF, AKT, PDGF, MAPK, and p70S6 kinase. Staining for each protein included the total protein and, when applicable, the phosphorylated version of the protein. Immunohistochemical staining was then correlated with patient survival (overall survival [OS] and event-free survival [EFS]), histologic response to chemotherapy, and serum markers.
RESULTS:: There was a negative correlation between VEGF receptor 3 (VEGF-R3) and both OS and EFS. VEGF-B was correlated with a poor histologic response to chemotherapy. Serum markers were not correlated with any specific proteins. When using a P value of .05, multiple correlations were observed between proteins of various pathways.
CONCLUSIONS: The current results suggested that the VEGF pathway is a critical signaling pathway in osteogenic sarcoma. These data have identified specific proteins within these pathways toward which future investigations should be directed to further clarify their prognostic potential. Cancer 2009. Published 2009 by the American Cancer Society.

Related articles




4.
Curr Drug Targets. 2009 Oct;10(10):923-36.
Clinical development of inhibitors of the insulin-like growth factor receptor in oncology.

Gualberto A, Pollak M.
Pfizer Oncology, 50 Pequot Ave. MS6025-A3266, New London, CT 06320, USA. antonio.gualberto@pfizer.com
The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. Ancillary evidence that targeting the IGF-IR may be useful in the treatment of cancer has been accumulating for almost two decades. Today, more than two dozen compounds have been developed and clinical trials are underway for at least 12 of those. The ability to pharmacologically control the IGF-IR pathway holds not only promising therapeutic implications but also the possibility to gather a better understanding of the role of the IGF axis in tumor initiation and progression. This review focuses on the preclinical rationale for targeting the IGF-IR and other components of the IGF-I system, early clinical results observed to date, biomarker approaches employed and the lessons from these early results for future study design. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence of receptor targeting. Instances of single-agent activity during phase I evaluations have been well documented and a recently reported randomized phase II study indicates that co-administration of an anti-IGF-IR antibody with chemotherapy improves objective response rate and progression-free survival in non-small cell lung cancer patients. These early results support ongoing research across a broad range of cancer indications.

PMID: 19663769 [PubMed - in process]


J Clin Endocrinol Metab. 2009 Oct;94(10):3931-8. Epub 2009 Jul 21.
Growth hormone excess promotes breast cancer chemoresistance.

Zatelli MC, Minoia M, Molè D, Cason V, Tagliati F, Margutti A, Bondanelli M, Ambrosio MR, degli Uberti E.
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy.
CONTEXT: GH and IGF-I are known to promote breast carcinogenesis. Even if breast cancer (BC) incidence is not increased in female acromegalic patients, mortality is greater as compared with general population. OBJECTIVE: The objective of the study was to evaluate whether GH/IGF-I excess might influence BC response to chemotherapy. DESIGN: We evaluated GH and IGF-I effects on cell proliferation of a BC cell line, MCF7 cells, in the presence of doxorubicin (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved.
RESULTS: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I because they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. The expression of the MDR1 gene, involved in resistance to chemotherapeutic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Pegvisomant inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain.
CONCLUSIONS: These data indicate that GH can directly induce resistance to chemotherapeutic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.



Oncogene. 2009 Aug 27;28(34):3009-21. Epub 2009 Jul 6.
Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions.

Gualberto A, Pollak M.
Clinical Department, Pfizer Oncology, New London, CT, USA.
Preclinical evidence that targeting the insulin-like growth factor receptor (IGF-IR) is effective in cancer treatment has been accumulating for almost two decades. Efforts to develop drugs began in the late 1990s, and initial data from clinical trials were reported in 2006. The biological rationale for IGF-IR targeting has potential relevance to many tumor types, and early results have justified expanded programs to evaluate IGF-IR-targeting agents in many areas of clinical need. More than two dozen drug candidates have been developed and clinical trials are underway for at least 12 of these. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence that the receptor can be successfully targeted. It is premature to draw conclusions regarding efficacy, but well-documented instances of single-agent activity were noted during phase I evaluations, and recent evidence from a phase II study suggests that co-administration of an anti-IGF-IR antibody with chemotherapy for non-small-cell lung cancer improves objective response rate and progression-free survival. With more than 70 trials involving a variety of drug candidates underway, the IGF-IR is becoming one of the most intensively investigated molecular targets in oncology. Early results justify the continuation of ongoing research across a broad range of cancer indications.



Med Hypotheses. 2009 Oct;73(4):606-7. Epub 2009 Jun 27.
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Old 12-04-2009, 04:02 PM   #24
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

http://www.oncologystat.com/news-and..._Study_US.html

Metformin Use Protective Against Cancer Mortality in Prospective Study Elsevier Global Medical News.
2009 Nov 25, D Napoli

Metformin may be protective against cancer-related mortality in type 2 diabetes, according to data from a prospective study of over 1,300 patients in the Netherlands. The finding - the first to come from a prospective study - could "further strengthen the position of metformin as preferred initial treatment in patients with type 2 diabetes mellitus," wrote the study authors in an article published online on Nov. 16 ahead of print in Diabetes Care (doi:10.2337/dc09-1380). The authors, led by Dr. Gijs W. Landman of the Isala Clinics in Zwolle, the Netherlands, looked at 1,353 patients who were enrolled in the Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study. That study, begun in 1998, aimed to assess patients under the care of diabetes specialist nurses in addition to general practitioners. A total of 289 patients in the ZODIAC study used metformin at baseline; 1,064 did not. The average age of all patients was about 68 years, and slightly more than half were women. Among metformin users, the average duration of disease was 4.9 years, compared with 7.1 years in the nonuser group, a non-significant difference. The nonuser group did have significantly lower HbA1c levels, lower body mass index levels, and lower estimated glomerular filtration rates (eGFR), as well as significantly higher rates of use of insulin and sulfonylurea. After a mean follow-up of 9.6 years, there were a total of 122 cancer deaths in the entire cohort. According to the authors, the standardized mortality rate for cancer mortality among all patients was 1.47 (95% CI 1.22-1.76). However, adjusted for 13 variables including smoking, age, sex, diabetes duration and pertinent lab values, metformin patients' hazard ratio fell to 0.43, compared with nonusers (95% CI 0.23-0.80). Furthermore, "The hazard [ratio] for cancer mortality decreased by 42% for every one gram increase in the metformin dosage," wrote the authors. The research study had some limitations. According to the authors, "patients with a very short life expectancy (including patients with active cancer) or insufficient cognitive abilities were excluded" from the original ZODIAC study. In addition, there are no data about nonfatal cancer incidence, nor about cancer history. The authors also pointed out that metformin was a relatively new drug at the ZODIAC study's baseline. "Patients who were taking metformin at the beginning of this study (in 1998) might also be different from patients taking metformin at this moment," they wrote. "If there is an association between cancer mortality and metformin use, a long-term follow-up is needed, because cancer takes a long time to develop and it takes time before patients die from cancer," they added. According to Dr. Landman, the study authors - all from the Netherlands - had no personal disclosures to report, nor did the study receive any outside funding or support.


Metformin and Letrozole seem compatible at some level in non-cancer setting:

Hum Reprod. 2006 Jun;21(6):1432-5. Epub 2006 Feb 14.
Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.

Sohrabvand F, Ansari Sh, Bagheri M.
Department of Infertility & IVF, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran. fsohrabvand@yahoo.com
BACKGROUND: Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. METHODS: Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6-8 weeks of metformin, they received either letrozole (2.5 mg) or clomiphene (100 mg) from day 3-7 of their menstrual cycle. Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. RESULTS: Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. CONCLUSION: In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.

PMID: 16478764 [PubMed - indexed for MEDLINE]
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Old 12-06-2009, 12:36 AM   #25
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

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.
Quote:
...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:
Quote:
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:


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.
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Old 12-08-2009, 01:59 AM   #26
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

Am J Ther. 2004 May-Jun;11(3):236-7.
Metformin-associated respiratory alkalosis.

Bryant SM, Cumpston K, Lipsky MS, Patel N, Leikin JB.
Division of Medical Toxicology and Hyperbaric Medicine, Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

PMID: 15133541 [PubMed - indexed for MEDLINE]
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Old 12-28-2009, 03:26 AM   #27
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

Updated with audio clip in beginning of thread: LINK
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Old 01-22-2010, 12:10 AM   #28
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Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea

Oncogene. 2008 Jun 5;27(25):3576-86. Epub 2008 Jan 21.
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F.
INSERM U568, Nice, France.
Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.




Front Biosci. 2008 May 1;13:3273-87.
The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance.

Casa AJ, Dearth RK, Litzenburger BC, Lee AV, Cui X.
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

PMID: 18508432 [PubMed - indexed for MEDLINE]




ACTOPLUS MET combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.


http://www.themoneytimes.com/feature...-10115966.html


A new study suggests that a low-dose combination therapy using [COLOR=#009600 ! important][COLOR=#009600 ! important]GlaxoSmithKline[/COLOR][/COLOR]
(GSK) Avandia and anti-[COLOR=#009600 ! important][COLOR=#009600 ! important]diabetic [COLOR=#009600 ! important]treatment[/COLOR][/COLOR][/COLOR]
metformin may help prevent progression to type 2 diabetes by two-thirds in people at risk of the ailment. According to experts, Avandia, also known as [COLOR=#009600 ! important][COLOR=#009600 ! important]rosiglitazone[/COLOR][/COLOR]
and metformin both lower the development of diabetes in patients with impaired glucose tolerance (IGT).


However, both the drugs work differently. While, Avandia is known to increase insulin sensitivity, metformin reduces liver glucose production.
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