Effects of Silybinin on the Pharmacokinetics of Tamoxifen and Its Active Metabolite, 4-Hydroxytamoxifen in Rats
The effects of silybinin, an antioxidant, on the pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. A single dose of tamoxifen was administered intravenously (2 mg/kg) and orally (10 mg/kg) without or with silybinin (0.5, 2.5 and 10 mg/kg) to rats. Silybinin significantly altered the pharmacokinetics of orally administered tamoxifen. Compared to those in the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of tamoxifen were significantly (p<0.05 for 2.5 mg/kg, p<0.01 for 10 mg/kg) increased by 40.2-71.3% and 45.2-78.6%, respectively, with silybinin. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of silybinin (2.5 and 10 mg/kg) was 31.1-38.1%, which was significantly enhanced (p<0.05) compared to that in the oral control group (22.2%). Moreover, the relative bioavailability (RB) of tamoxifen was 1.40- to 1.72-fold greater than that in the control group. Silybinin (10 mg/kg) significantly increased the AUC0-∞ (p<0.05, 40.0%) of 4-hydroxytamoxifen, but the metabolite-parent ratio (MR) of 4-hydroxytamoxifen was significantly altered (p<0.05 for 10 mg/kg), implying that the formation of 4-hydroxytamoxifen was considerably affected by silybinin. The enhanced bioavailability of tamoxifen by silybinin might be due to the promotion of intestinal absorption in the small intestine and the reduction of first-pass metabolism of tamoxifen in the small intestine and in the liver. If these results are confirmed in clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with silybinin or silybinin-containing dietary supplements.
Kim C-S, Choi S-J, Park C-Y, et al. Anticancer Research January 2010 vol. 30 no. 1 79-85
Lymph Node Study Shakes Pillar of Breast Cancer Care
By DENISE GRADY
New York Times. Published: February 8, 2011
The discovery turns standard medical practice on its head. Surgeons have been removing lymph nodes from under the arms of breast cancer patients for 100 years, believing it would prolong women’s lives by keeping the cancer from spreading or coming back.
Now, researchers report that for women who meet certain criteria — about 20 percent of patients, or 40,000 women a year in the United States — taking out cancerous nodes has no advantage. It does not change the treatment plan, improve survival or make the cancer less likely to recur. And it can cause complications like infection and lymphedema, a chronic swelling in the arm that ranges from mild to disabling.
Removing the cancerous lymph nodes proved unnecessary because the women in the study had chemotherapy and radiation, which probably wiped out any disease in the nodes, the researchers said. Those treatments are now standard for women with breast cancer in the lymph nodes, based on the realization that once the disease reaches the nodes, it has the potential to spread to vital organs and cannot be eliminated by surgery alone.
Experts say that the new findings, combined with similar ones from earlier studies, should change medical practice for many patients. Some centers have already acted on the new information. Memorial Sloan-Kettering Cancer Center in Manhattan changed its practice in September, because doctors knew the study results before they were published. But more widespread change may take time, experts say, because the belief in removing nodes is so deeply ingrained.
“This is such a radical change in thought that it’s been hard for many people to get their heads around it,” said Dr. Monica Morrow, chief of the breast service at Sloan-Kettering and an author of the study, which is being published Wednesday in The Journal of the American Medical Association. The National Cancer Institute paid for the study.
Doctors and patients alike find it easy to accept more cancer treatment on the basis of a study, Dr. Morrow said, but get scared when the data favor less treatment.
The new findings are part of a trend to move away from radical surgery for breast cancer. Rates of mastectomy, removal of the whole breast, began declining in the 1980s after studies found that for many patients, survival rates after lumpectomy and radiation were just as good as those after mastectomy.
The trend reflects an evolving understanding of breast cancer. In decades past, there was a belief that surgery could “get it all” — eradicate the cancer before it could spread to organs and bones. But research has found that breast cancer can begin to spread early, even when tumors are small, leaving microscopic traces of the disease after surgery.
The modern approach is to cut out obvious tumors — because lumps big enough to detect may be too dense for drugs and radiation to destroy — and to use radiation and chemotherapy to wipe out microscopic disease in other places.
But doctors have continued to think that even microscopic disease in the lymph nodes should be cut out to improve the odds of survival. And until recently, they counted cancerous lymph nodes to gauge the severity of the disease and choose chemotherapy. But now the number is not so often used to determine drug treatment, doctors say. What matters more is whether the disease has reached any nodes at all. If any are positive, the disease could become deadly. Chemotherapy is recommended, and the drugs are the same, no matter how many nodes are involved.
The new results do not apply to all patients, only to women whose disease and treatment meet the criteria in the study.
The tumors were early, at clinical stage T1 or T2, meaning less than two inches across. Biopsies of one or two armpit nodes had found cancer, but the nodes were not enlarged enough to be felt during an exam, and the cancer had not spread anywhere else. The women had lumpectomies, and most also had radiation to the entire breast, and chemotherapy or hormone-blocking drugs, or both.
The study, at 115 medical centers, included 891 patients. Their median age was in the mid-50s, and they were followed for a median of 6.3 years.
After the initial node biopsy, the women were assigned at random to have 10 or more additional nodes removed, or to leave the nodes alone. In 27 percent of the women who had additional nodes removed, those nodes were cancerous. But over time, the two groups had no difference in survival: more than 90 percent survived at least five years. Recurrence rates in the armpit were also similar, less than 1 percent. If breast cancer is going to recur under the arm, it tends to do so early, so the follow-up period was long enough, the researchers said.
One potential weakness in the study is that there was not complete follow-up information on 166 women, about equal numbers from each group. The researchers said that did not affect the results. A statistician who was not part of the study said the missing information should have been discussed further, but probably did not have an important impact.
It is not known whether the findings also apply to women who do not have radiation and chemotherapy, or to those who have only part of the breast irradiated. Nor is it known whether the findings could be applied to other types of cancer.
The results mean that women like those in the study will still have to have at least one lymph node removed, to look for cancer and decide whether they will need more treatment. But taking out just one or a few nodes should be enough.
Dr. Armando E. Giuliano, the lead author of the study and the chief of surgical oncology at the John Wayne Cancer Institute at St. John’s Health Center in Santa Monica, Calif., said: “It shouldn’t come as a big surprise, but it will. It’s hard for us as surgeons and medical oncologists and radiation oncologists to accept that you don’t have to remove the nodes in the armpit.”
Dr. Grant W. Carlson, a professor of surgery at the Winship Cancer Institute at Emory University, and the author of an editorial accompanying the study, said that by routinely taking out many nodes, “I have a feeling we’ve been doing a lot of harm.”
Indeed, women in the study who had the nodes taken out were far more likely (70 percent versus 25 percent) to have complications like infections, abnormal sensations and fluid collecting in the armpit. They were also more likely to have lymphedema.
But Dr. Carlson said that some of his colleagues, even after hearing the new study results, still thought the nodes should be removed.
“The dogma is strong,” he said. “It’s a little frustrating.”
Eventually, he said, genetic testing of breast tumors might be enough to determine the need for treatment, and eliminate the need for many node biopsies.
Two other breast surgeons not involved with the study said they would take it seriously.
Dr. Elisa R. Port, the chief of breast surgery at Mount Sinai Medical Center in Manhattan, said: “It’s a big deal in the world of breast cancer. It’s definitely practice-changing.”
Dr. Alison Estabrook, the chief of the comprehensive breast center at St. Luke’s-Roosevelt hospital in New York said surgeons had long been awaiting the results.
“In the past, surgeons thought our role was to get out all the cancer,” Dr. Estabrook said. “Now he’s saying we don’t really have to do that.”
But both Dr. Estabrook and Dr. Port said they would still have to make judgment calls during surgery and remove lymph nodes that looked or felt suspicious.
The new research grew out of efforts in the 1990s to minimize lymph node surgery in the armpit, called axillary dissection. Surgeons developed a technique called sentinel node biopsy, in which they injected a dye into the breast and then removed just one or a few nodes that the dye reached first, on the theory that if the tumor was spreading, cancer cells would show up in those nodes. If there was no cancer, no more nodes were taken. But if there were cancer cells, the surgeon would cut out more nodes.
Although the technique spared many women, many others with positive nodes still had extensive cutting in the armpit, and suffered from side effects.
“Women really dread the axillary dissection,” Dr. Giuliano said. “They fear lymphedema. There’s numbness, shoulder pain, and some have limitation of motion. There are a fair number of serious complications. Women know it.”
After armpit surgery, 20 percent to 30 percent of women develop lymphedema, Dr. Port said, and radiation may increase the rate to 40 percent to 50 percent. Physical therapy can help, but there is no cure.
The complications — and the fact that there was no proof that removing the nodes prolonged survival — inspired Dr. Giuliano to compare women with and without axillary dissection. Some doctors objected. They were so sure cancerous nodes had to come out that they said the study was unethical and would endanger women.
“Some prominent institutions wouldn’t even take part in it,” Dr. Giuliano said, though he declined to name them. “They’re very supportive now. We don’t want to hurt their feelings. They’ve seen the light.”
The role of bone microenvironment, vitamin d and calcium.
Starting first from Paget’s “seed and soil” to the latest hypothesis about metastatic process involving the concept of a premetastatic niche, a large amount of data suggested the idea that metastatization is a multistep coordinated process with a high degree of efficiency. A specific subpopulation of cells with tumor-initiating and migratory capacity can selectively migrate toward sites that are able to promote survival, and/or proliferation of metastatic tumor cells through a microenvironment modification. Bone plays a pivotal role in this process, acting not only as a preferential site for cancer cells’ homing and proliferation, due to a complex interplay between different cellular phenotypes such as osteoblasts and osteoclasts, but also as a source of bone marrow precursors that are able to facilitate the metastatic process in extra-skeletal disease. Moreover, bone microenvironment has the unique capacity to retain cancer stem cells in a quiescent status, acting as a reservoir that is able to cause a metastatic spread also many years after the resection of the primary tumor. To add a further level of complexity, these mechanisms are strictly regulated through the signalling through several soluble factors including PTH, vitamin D or calcium concentration. Understanding this complexity represents a major challenge in anti-cancer research and a mandatory step towards the development of new drugs potentially able not only to reduce the consequences of bone lesions but also to target the metastatization process from the “bone pre-neoplastic niche” to “visceral pre-neoplastic niches”.
Santini D, Pantano F, Vincenzi B, Tonini G, Bertoldo F. Recent Results Cancer Res. 2012;192:33-64.
Cancer Stem Cells
Nuclear structure in A: normal cell and B: cancer cell
Tumour sample from different patients and even cells within the same tumour shows significant discrepancy in morphology, proliferative potential, ability for metastasis and invasion as a reflection of variation in genetic and epigenetic aberrations (Curr Biol No.20. 2010 doi:10.1016/j.cub.2010.07.007). The ability to form a tumour has been found to be limited within very small proportion of cancer cells. Experiment with neuroblastoma, ovarian and lung cancer had shown that only 1 out of 1–5,000 cancer cells could form colony in soft agar (Oncogenes. No.23, 2004). Malignant cervical epithelial cells express proteins such as nanog, nucleostemin, and musashi1 which are also highly expressed in embryonic stem cells (BMC Cancer Vol.8 2008). Widespread potential for proliferation is characteristic of both normal stem cells and tumourigenic cells which make them capable of forming normal and abnormal organs, respectively (Nature. No.414 2001).
From this point of view, we can say cancer is an abnormal organ that exhibits false impression of normal tissue development, where growth is driven by the stem cell apex (Annu Rev Biochem. No.74, 2005). Stem cells escape the therapeutic effects of chemo or radiotherapy and may form tumours anew (Semin Cancer Biol. No.17, Issue 3 2007; Neoplasia. No.12, Issue 7 2010)
Cancer might act as unprecedented and abnormal ‘whole’ (like organs) in the complex hierarchy of ‘wholeness’ that works in our body system (cell>organ>organism). This very complex cancer phenomenon, involving so many genes and molecules in the progression of a single tumour, seems to be stochastic by nature, and requires thinking in a way that the alterations are not local, rather the manifestation of the alterations seems to be local and it might be the fact. So, cancer initiation should be viewed from a new holistic paradigm underlying the process of origin and function of life (Oncol Rev. No. 5. 2011 DOI 10.1007/s12156-011-0091-2).
The chemokine system and cancer
Frances R Balkwill. The Journal of Pathology. Special Issue: The Cell Biology of Disease. Volume 226, Issue 2, pages 148–157, January 2012. DOI: 10.1002/path.3029
Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body. Cancer cells acquire the ability to subvert the chemokine system, such that these molecules and their receptors become important regulators of cell movement into and out of the tumour microenvironment and major players in cancer biology.
Chemokines and their receptors are involved in all stages of cancer development, influencing the cellular composition of the tumour microenvironment, malignant cell survival and metastatic spread. From their earliest stages, cancers harness this intricate and tightly regulated network to generate a corrupt version of a system that, in healthy vertebrates, is necessary for embryonic development, tissue homeostasis and successful immune responses. A greater understanding of the chemokine system in malignancy can not only give us important new insights into cancer biology but also suggest new treatment approaches. If drugs that target the chemokine system show success in chronic inflammatory disease over the next few years, we have enough preclinical data to warrant trialling them in cancers.
Figure 1. The chemokine wheel. This cartoon shows major constituents of the chemokine systems, the G-protein-coupled cell-surface receptors and the chemokine ligands. The ‘inflammatory’ chemokines are inducible and involved in all aspects of the immune response. The ‘homeostatic’ chemokines are involved in development and normal physiology. Atypical chemokine receptors are generally ‘silent’ and act as negative regulators of the systems, ‘decoys’ that reduce chemokine levels. Viral chemokines and receptors allow the pathogens to modulate immune responses to infection. Inflammatory, homeostatic and atypical chemokine receptors are all found in the tumour microenvironment. Another chemokine receptor, CXCR7, which also binds to CXCL12 and CXCL11, is shown in the homeostatic group, but there is some evidence that it is an atypical chemokine receptor
Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body 1
The chemokine system evolved with the vertebrates and there are nearly 50 human genes that encode chemokine ligands, with more than 20 corresponding human chemokine receptor genes, the latter being seven-transmembrane G-protein-coupled receptors, GPCRs. Chemokines are divided into four different groups, CXC, CC, CX3C or C, depending on the position of the conserved cysteine residue, and receptor nomenclature essentially follows that of the chemokines, ie CC chemokines bind to CC chemokine receptors, CXC ligands bind to CXC receptors
Prevalence of Vitamin D Insufficiency Among Breast Cancer Survivors
Background: Recent research has linked inadequate vitamin D levels with risk of breast cancer, but there are less data regarding the actual concentrations of vitamin D in women who have survived breast cancer. The objective of this study was to determine if vitamin D insufficiency is a prevalent problem for female breast cancer survivors who have completed treatment for breast cancer.
Methods: Ninety-nine breast cancer survivors and a control population of 54 women with no history of breast cancer participated in this study. Serum 25-hydroxy vitamin D concentrations were measured throughout 2007. Dietary and supplemental intake of vitamin D was assessed by a food frequency questionnaire. Zip code of residence was used to evaluate potential for skin production of vitamin D.
Results: Vitamin D insufficiency (<32 ng/mL) was observed in 76 of 99 (77%) of breast cancer survivors and 51 of 54 (94%) of controls. Women taking vitamin D supplements >1000 IU/d were less likely to exhibit vitamin D insufficiency, but supplementation did not guarantee sufficiency. Conclusion: Vitamin D insufficiency appears to be prevalent among both controls and breast cancer survivors. Vitamin D status should be routinely evaluated for all women as part of regular preventive care if supplemental vitamin D intake is <1000 IU daily.
Source:
Trukova KP, et al. Nutr Clin Pract February 2012 vol. 27 no. 1, Pp.122-8. doi: 10.1177/0884533611431461