Platinum and Blue Light Combine to Combat Cancer...

Research led by the University of Warwick, along with researchers from Ninewells Hospital Dundee, and the University of Edinburgh, have found a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use “light activation” to kill cancer cells in a much more targeted way than similar treatments. 

The University of Warwick team had already found a platinum-based compound that they could activate with ultra-violet light but that narrow wave length of light would have limited its use. Their latest breakthrough has discovered a new platinum based compound known as trans,trans,trans-[Pt(N₃)₂(OH)₂(py)₂] (see structure)  that can be activated by normal visible blue, or even green, light. It is also stable and easy to work with, and it is water soluble so it can simply dissolve and be flushed out of the body after use. Tests show that once activated by blue light the compound was highly effective requiring a concentration of just 8.4 micro moles per litre to kill 50% of the cancer cells. The researchers are also beginning to examine the compound’s effectiveness against ovarian and liver cancer cells. Early results there are also excellent but that testing work is not yet complete.

“This compound could have a significant impact on the effectiveness of future cancer treatments. Light activation provides this compound’s massive toxic power and also allows treatment to be targeted much more accurately against cancer cells...claims Prof.  Peter Sadler...

Ref : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980786/

Cancer drug target is promising lead for new TB treatments

Cancer drug target is promising lead for new TB treatments

PARP inhibitor, MK-4827, shows anti-tumour activity in first trial in humans....

MK-4827 , (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride.

A recent study claim that the new drug MK-4827 (see structure), that targets proteins responsible for helping cancer cells to repair damage to their DNA has shown promising anti-tumor activity in its first trial in humans. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year.

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2  (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. As per the claim by the researchers, drug act by inhibiting the action of PARP, double-strand breaks occur, leading to cell death. Researchers add that tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells don't replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

The researchers saw anti-tumor responses in both sporadic and BRCA1/2 mutation-associated cancers. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

More...

Anti-Cancer Effects of Broccoli Ingredient Explained......

In continuation of my update on the dietary benefits of broccoli and how it helps to reduce the cancer risk....

Researchers writing in BioMed Central's open access journal Molecular Cancer have found that sulforaphane, a chemical found in broccoli, interacts with cells lacking a gene called PTEN to reduce the chances of prostate cancer developing.

Richard Mithen, from the Institute of Food Research, an institute of BBSRC, worked with a team of researchers on Norwich Research Park, UK, to carry out a series of experiments in human prostate tissue and mouse models of prostate cancer to investigate the interactions between expression of the PTEN gene and the anti cancer activity of sulforaphane.

"PTEN is a tumour suppressor gene, the deletion or inactivation of which can initiate prostate carcinogenesis, and enhance the probability of cancer progression. We've shown here that sulforaphane has different effects depending on whether the PTEN gene is present."

The research team found that in cells which express PTEN, dietary intervention with SF has no effect on the development of cancer. In cells that don't express the gene, however, sulforaphane causes them to become less competitive, providing an explanation of how consuming broccoli can reduce the risk of prostate cancer incidence and progression.

Ref :  http://www.molecular-cancer.com/content/pdf/1476-4598-9-189.pdf

How Dietary Supplement (Broccoli, Cabbage) May Block Cancer Cells....

In continuation of  how dietary supplement may block cancer cells... In my earlier blogs,  I have mentioned that, natural compound formed during the autolytic breakdown of glucobrassicin present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts, cauliflower and kale) are responsible for the anticancer activity associated with broccoli and other Brassica genus.

Now researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) have discovered how a substance  (see below structure) that is produced when eating broccoli and Brussels sprouts can block the proliferation of cancer cells.

Compelling evidence indicates that the substance, indole-3-carbinol [(above structure, I3C) : Glucobrassicin (right structure) is a type of glucosinolate that can be found in almost all cruciferous plants, such as cabbages  and broccoli, degradation by the enzyme myrosinase is expected to produce an isothiocyanate, indol-3-ylmethylisothiocyanate- which is unstable and hydrlyses to give, I3C, as most dominant degradation product], may have anticancer effects and other health benefits, the researchers say. These findings show how I3C affects cancer cells and normal cells.

The laboratory and animal study discovered a connection between I3C and a molecule called Cdc25A, which is essential for cell division and proliferation. The research showed that I3C causes the destruction of that molecule and thereby blocks the growth of breast cancer cells.

"Cdc25A is present at abnormally high levels in about half of breast cancer cases, and it is associated with a poor prognosis," says study leader Xianghong Zou, assistant professor of pathology at the Ohio State University Medical Center.

For this study, Zou and his colleagues exposed three breast cancer cell lines to I3C. These experiments revealed that the substance caused the destruction of Cdc25A. They also pinpointed a specific location on that molecule that made it susceptible to I3C, showing that if that location is altered (because of a gene mutation), I3C no longer causes the molecule's destruction.

Last, the investigators tested the effectiveness of I3C in breast tumors in a mouse model. When the substance was given orally to the mice, it reduced tumor size by up to 65 percent. They also showed that I3C had no affect on breast-cell tumors in which the Cdc25A molecule had a mutation in that key location.

Ref :  American Association for Cancer Research : Cancer Prevention Research, Xianghong Zou et al.,

Crizotinib Shows Dramatic Results for Shrinking Tumors (lung cancer)....

Patients with a specific kind of lung cancer may benefit from a Phase III clinical trial offered by the Moores UCSD Cancer Center. The new drug, crizotinib (structure), under development by Pfizer, showed dramatic results in reducing lung cancer tumors in some patients during Phase I and II clinical trials.

"The results of the first two trials have been very encouraging," said Lyudmila Bazhenova, MD, assistant clinical professor at UC San Diego School of Medicine and a member of the Moores UCSD Cancer Center...

According to a preliminary study,  57% of patients had their tumors reduced and at eight weeks of the treatment, 87% showed disease stabilization.

The Phase III clinical trial will compare crizotinib with standard-of-care chemotherapy in the treatment of ALK-positive recurrent NSCLC. Through a randomized selection process, patients will either be treated with chemotherapy or crizotinib. If the patients who are given the chemotherapy do not respond to treatment, they will be given crizotinib at the end of the trial....

Ref : http://ucsdnews.ucsd.edu/newsrel/health/06-22ShrinkingTumors.asp

Sulindac inhibits tumor growth !...

We know that, Sulindac(structure), is useful in the treatment of acute or  chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAID's except for drugs of the COX-2 inhibitor class. The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

Now researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham) and their colleagues have figured out how  Sulindac, inhibits tumor growth. The study reveals that Sulindac shuts down cancer cell growth and initiates cell death by binding to nuclear receptor RXRα, a protein that receives a signal and carries it into the nucleus to turn genes on or off. 

As per the claim by the researchers, RXRα normally suppresses tumors, but many types of cancer cells produce a truncated form of this nuclear receptor that does just the opposite. This study showed that shortened RXRα enhances tumor growth by stimulating other proteins that help cancer cells survive. Luckily, the researchers also found that Sulindac can be used to combat this deviant RXRα by switching off its pro-survival function and turning on apoptosis, a process that tells cells to self-destruct.  The interesting part of their research lies in the fact that, they were able to overcome the limitation (cardiovascular side effects associated with Sulindac and other NSAIDs), the researchers tweaked Sulindac, creating a new version of the drug now called K-80003 that both decreases negative consequences and increases binding to truncated RXRα..

"Depending on the conditions, the same protein, such as RXRα, can either kill cancer cells or promote their growth," Dr. Zhang said. "The addition of K-80003 shifts that balance by blocking survival pathways and sensitizing cancer cells to triggers of apoptosis."

Ref :  http://www.cell.com/cancer-cell/retrieve/pii/S1535610810001595

Two-drug phase I trial shows promise in treating late-stage ovarian cancer

In continuation of my update on carboplatin .....

Researchers from Indiana University School of Medicine, have come up  with interesting finding from a two-Drug Phase I Trial Show, i.e.,  the combination of decitabine (see structure) and carboplatin appears to improve the outcome of women who have late-stage ovarian cancer. Researchers report four of 10 patients who participated in a phase I clinical trial had no disease progression after six months of treatment. One patient experienced complete resolution of tumor tissue for a period of time.

"Carboplatin is the most efficient drug therapy for ovarian cancer,"  unfortunately, patients with recurrent disease become resistant to the drug after one or two rounds claims the lead researcher.."

Decitabine was first used to treat the study patients intravenously daily for five days followed on the eighth day with carboplatin. After a month, the regimen begins again.

Encouraged by the results of the phase I trial, which determined the safety of two different dosing regimens, a phase II trial is now under way with 17 patients already enrolled. Phase II trials are primarily focused on assessing the effectiveness of a drug or treatment protocol.

As per the claim by the researcher, decitabine  (a known methylation inhibitor) can help return tumor suppression genes to an active state, and also improve cells' susceptibility to anti-cancer drugs like carboplatin. Researchers adds that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments. 

Researchers conclude that, by keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages.

Ref : http://www3.interscience.wiley.com/journal/123500856/abstract?CRETRY=1&SRETRY=0

ACT Biotech's Telatinib receives orphan drug designation from FDA for treatment of gastric cancer

ACT Biotech's Telatinib receives orphan drug designation from FDA for treatment of gastric cancer..

Telatinib (see structure,  source : ChemBlink) :
(17-Demethoxy-17-allylaminogeldanamycin; Tanespimycin; 17-Allylaminogeldanamycin)

RADIANT-3 study results show everolimus significantly extends progression-free survival in patients with advanced pancreatic neuroendocrine tumors...

We know that Everolimus (RAD-001, marketed by Novartis under the  tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology) is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now Novartis Pharmaceuticals Corporation announced that the  Phase III study of Afinitor® (everolimus, see structure) tablets plus best supportive care met its primary endpoint, showing the drug significantly extended progression-free survival, or time without tumor growth, in patients with advanced pancreatic neuroendocrine tumors (NET). The study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), is part of the largest clinical trial program of its kind. 

Everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.  

As  per the claim by   Herve Hoppenot, President, Novartis Oncology, Everolimus was developed to inhibit the mTOR protein, which is a critical target in treating various cancers, including NET. Results from RADIANT-3 demonstrate that everolimus has the potential to become an important treatment option for patients with advanced pancreatic NET, where there is a major unmet need.

"These study results will serve as the basis of worldwide regulatory filings for everolimus and bring us one step closer to our goal of offering these patients a new therapy."...says Herve Hoppenot...

Ref : http://www.novartis.com/newsroom/media-releases/en/2010/1421290.shtml

Bafetinib demonstrates significant inhibition of glioblastoma multiforme cell lines (preclinical trials)..

The treatment of chronic myeloid leukemia (CML)  changed  dramatically with the emergence of the ABL tyrosine kinase inhibitor (TKI) imatinib mesilate. However, primary and secondary imatinib resistance has been frequently reported, particularly in patients with advanced-stage disease. To override imatinib resistance, three second-generation ABL TKIs, i.e., dasatinib, nilotinib and bosutinib, were developed. Bafetinib (see structure source : Chemblink :INNO-406, NS-187) is a dual ABL/Lyn inhibitor developed by the team at Kyoto University Hospital in collaboration with Nippon Shinyaku. 

Bafetinib was 25-55 times more potent than imatinib in blocking BCR/ABL autophosphorylation, while otherwise retaining specificity for ABL and Lyn. Bafetinib had antiproliferative effects against cells bearing wild-type or most mutated BCR/ABL proteins, except T315I, and also inhibited BCR/ABL-positive leukemic cell growth in the central nervous system. A phase I study on bafetinib was completed and the agent was well tolerated and demonstrated clinical activity across a range of doses. Responses occurred even in the setting of a heavily pretreated population, thus making bafetinib a viable option for CML therapy.

Recently  CytRx Corporation, announced that its drug candidate bafetinib (formerly known as INNO-406) demonstrated statistically significant inhibition of glioblastoma multiforme cell lines in a preclinical trial. The company believe that bafetinib could be efficacious in several hematological cancers and  it is  preparing to begin evaluating bafetinib in a Phase 2 proof-of-concept clinical trial in high-risk B-cell chronic lymphocytic leukemia (B-CLL) this quarter, as well as a Phase 2 clinical trial in advanced prostate cancer next quarter.... 

Ref : http://www.cytrx.com/inno_406.html

Flaxseed-fed chickens shed light on ovarian cancer.....

In continuation of my update on the benefits of  flax seeds,  I found this info interesting to share with. Researchers from College of Agricultural, Consumer and Environmental Sciences, lead by Prof. Janice Bahr, have come up with interesting info about flax seeds, i.e., hens fed a flaxseed-enriched diet for one year experienced a significant reduction in late-stage ovarian tumors.

The interesting part of the research lies in that fact that, chicken is the only animal that spontaneously develops ovarian cancer on the surface of the ovaries like humans and researchers  evaluated how a flaxseed-enriched diet affected 2-year-old laying hens (hens that have ovulated as many times as a woman entering menopause). As we know flaxseed is the richest plant source of alpha-linolenic acid, (omega-3 fatty acid). Several studies have already shown that flaxseed inhibits the formation of colon, breast, skin and lung tumors.

As per the claim by the researchers, hens fed the control diet had significantly more late-stage tumors that presented with fluid and metastases as compared to the hens fed a flaxseed diet. Though hens fed the flaxseed diet did not have a decreased incidence of ovarian cancer, they did experience fewer late-stage tumors and higher survival rates.

In addition, researchers found that hens fed the flaxseed diet had better weight control which is important because obesity increases cancer risk. Both diets had equal caloric content, however the flaxseed-fed hens weighed less at six months than the control-fed hens. But at 12 months, the flaxseed-fed hens were the same weight and the control-fed hens had loss significant weight, which was indicative of their failing health. Ultimately, the flaxseed-enriched diet helped the birds maintain a healthy weight and resulted in less sickness and death.

"Through this research, we have proven that flaxseed supplementation for one year is able to reduce the severity of ovarian cancer in hens," she said. "These findings may provide the basis for a clinical trial that evaluates the efficacy of flaxseed as a chemosuppressant of ovarian cancer in women."

Bahr believes this hypothesis is valid and is currently in the middle of a four-year study to determine if long-term dietary intervention with flaxseed will reduce the incidence of ovarian cancer development....

Ref : http://www.aces.uiuc.edu/news/stories/news5165.html

HAMLET (found in breast milk) may target molecules in specific membrane regions.....

We know that HAMLET (human α-lactalbumin made lethal to tumor cells) is a molecular complex of α-lactalbumin and oleic acid (see structure courtesy : Lunds Univ). It induces apoptosis in tumor cells, but normal differentiated cells are resistant to its effect . The activity of HAMLET was discovered by serendipity, while using human milk fractions to investigate bacteria adherence to lung carcinoma cell lines. In addition to blocking adherence, one milk fraction actually killed the cells by inducing apoptosis. Cell death was accompanied by changes in morphology, nuclear condensation, cytoplasmic blebbing, and formation of apoptotic bodies, similar to cells that undergo classical apoptosis.

Further studies showed that HAMLET comprises a protein and a fatty acid that are both found naturally in breast milk. So far, however, it has not been proven that the HAMLET complex is spontaneously formed in the milk. It is speculated, however, that HAMLET can form in the acidic environment of the babies´ stomachs. Laboratory experiments have shown that HAMLET kills 40 different types of cancer, and the researchers are studying  its effect on skin cancer, tumours in the mucous membranes and brain tumours. Importantly, HAMLET kills only cancer cells and does not affect healthy cells.

Although the substance was found several years ago, it is only now that it has been possible to test it on humans. Patients with cancer of the bladder who were treated with the substance excreted dead cancer cells in their urine after each treatment, which has given rise to hopes that it can be developed into medication for cancer care in the future.

Researchers at the University of Gothenburg are focussed on how HAMLET can be taken up into tumour cells. Researchers  lead by,  Roger Karlsson attempting to gain an in-depth understanding of how the substance interacts with cell membranes. 

In their study, researchers examined the interactions of HAMLET with in vitro generated membranes of known composition, and compared HAMLET to the native or partially unfolded, fatty acid free proteins. They also examined the effect of HAMLET on plasma membrane vesicles (PMVs) obtained from tumor cells. Researchers could show that HAMLET interacts with membranes and disturbs their integrity under physiological conditions. Binding to intact tumor cell membranes showed a patchy distribution, indicating that HAMLET may target molecules in specific membrane regions.

Researchers conclude that, HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death...

Ref : Roger Karlsson et.al.,  PLoS One., February 23, 2010

Anti-cancer agent stops metastasis in its tracks....

Like microscopic inchworms, cancer cells slink away from tumors to travel and settle elsewhere in the body. Now, researchers at Weill Cornell Medical College, have found  that new anti-cancer agent, i.e., macroketone (see structure) break down the loping gait these cells use to migrate, stopping them in their tracks.

As per the claim by the lead researcher, Dr. Xin-Yun Huang, a professor in the Department of Physiology and Biophysics at Weill Cornell Medical College, mice implanted with cancer cells and treated with the small molecule macroketone lived a full life without any cancer spread, compared with control animals, which all died of metastasis. When macroketone was given a week after cancer cells were introduced, it still blocked greater than 80 percent of cancer metastasis in mice. He further adds that, these findings provide a very encouraging direction for development of a new class of anti-cancer agents, the first to specifically stop cancer metastasis. 

Dr. Huang and his research team have been working on macroketone since 2003. Their work started after researchers in Japan isolated a natural substance, dubbed migrastatin, secreted by Streptomyces bacteria, that is the basis of many antibiotic drugs. The Japanese researchers noted that migrastatin had a weak inhibitory effect on tumor cell migration. After a lot of modifications, researchers made several versions that were a thousand-fold more potent than the original. In 2005, they published a study showing that several of the new versions, including macroketone, stopped cancer cell metastasis in laboratory animals, but they didn't know how the agent worked. 

Interestingly, in the current study, the researchers revealed the mechanism. As per the claim  macroketone targets an actin cytoskeletal protein known as fascin that is critical to cell movement. In order for a cancer cell to leave a primary tumor, fascin bundles actin filaments together like a thick finger. The front edge of this finger creeps forward and pulls along the rear of the cell. Cells crawl away in the same way that an inchworm moves. Macroketone latches on to individual fascin, preventing the actin fibers from adhering to each other and forming the pushing leading edge Because individual actin fibers are too soft when they are not bundled together, the cell cannot move.

Researchers conclude that, the new animal experiments detailed in the study confirmed the power of macroketone. The agent did not stop the cancer cells implanted into the animals from forming tumors or from growing.

"This suggests to us that an agent like macroketone could be used to both prevent cancer spread and to treat it as well," Dr. Huang says. "Of course, because it has no effect on the growth of a primary tumor, such a drug would have to be combined with other anti-cancer therapies acting on tumor cell growth."

 Ref : http://weill.cornell.edu/news/releases/wcmc/wcmc_2010/04_14_10.shtml

Two-drug combination destroys precancerous colon polyps....

A team of scientists at The University of Texas M. D. Anderson Cancer Center lead by Dr. Xiangwei Wu have come up with interesting finding i.e.,  a two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer. 

The regimen, tested so far in mouse models and on human colon cancer tissue in the lab, appears to address a problem with chemopreventive drugs - they must be taken continuously long term to be effective, exposing patients to possible side effects. 

The team found that a combination of Vitamin A acetate (RAc see  structure; source: Wikipedia) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancer.  

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism.

Interestingly, early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps called adenomas.

RAc and TRAIL together killed adenoma cells, causing programmed cell suicide know as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL.

The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL.

APC-deficient mice were treated with 15 cycles of the RAc/TRAIL combination over six weeks. Others received either RAc or TRAIL and a control group received nothing. One month later, control mice and those treated with one of the drugs averaged between 35 and 42 polyps, while those receiving the combination averaged 10.

To test the combination’s potential as short-term therapy, APC-deficient mice were treated with two cycles of the combination in one week, causing a 69 percent polyp reduction two weeks later. A 10-fold increase in dose left treated mice with only 10 percent of the polyps found in controls.

A longer term test of relative survival using five treatments over four months improved survival from 186 days for controls to beyond 213 days for treated mice, with five of seven treated mice living more than eight months. Next, the researchers treated biopsy samples of normal tissue and tumor regions from patients with familial adenomatous polyposis – an inherited condition that inevitably leads to colon cancer if the colon is not removed. Treatment of normal tissue caused little cell death, while 57 percent of polyp cells were killed via apoptosis.

Targeted therapies today aim at blocking some aspect of the tumor that drives its growth, Wu said, whereas RAc and TRAIL together kill precancerous polyps outright. Since APC is deficient or mutated in other types of cancer, the combination therapy could become a more general drug.

Before human clinical trials can be considered, the team will conduct additional research to understand potential side effects and also will try to develop an injectable version of the combination, which is administered intravenously now..

Ref : http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08871.html

Gemcitabine and cisplatin a promising combination for endometrial cancer...

In continuation of my update on cis-platin and its importance, I find this  info interesting to share with...

Gemcitabine (see structure) and cisplatin in combination have been investigated extensively in other disease sites, and synergism of the two agents has been confirmed in cell lines of human endometrial, ovarian, colon, lung and squamous cell head and neck carcinoma

Now researchers from The University of Texas M. D. Anderson Cancer Center , lead by Dr.Jubilee Brown, report from a small study of women with advanced or recurrent endometrial cancer, that gemcitabine and cisplatin, when used in combination, produced a response rate in fifty percent of patients.

The Phase II study of 20 patients found that the combination of gemcitabine and cisplatin, two drugs currently used to treat other types of cancer, limited the disease's progression, increasing progression-free survival while maintaining tolerable toxicity levels. It is believed that when administered together, gemcitabine helps overcome cell resistance to cisplatin, throwing tumor cells a potent one-two punch.


Findings demonstrated a 50 percent overall response rate, or improvement in disease. Additionally, the clinical benefit of the two-drug combination was 80 percent, as 16 of the 20 women experienced either an improvement or stabilization of disease. All side effects resulting from the therapy were manageable. Lead researcher, Dr. Brown concluded  that results from the study warrant investigation of the chemotherapy combination in a larger, definitive trial at multiple institutions.....

Ref :  Dr. Jubilee Brown, http://www.mdanderson.org/

Cabazitaxel improves survival in patients with metastatic hormone-refractory prostate cancer....

Cabazitaxel (see structure), is an orally bioavailable semi-synthetic  derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB).

Sanofi-aventis recently announced results from a Phase 3 trial which demonstrated cabazitaxel plus prednisone/prednisolone significantly improved overall survival and progression-free survival in patients with metastatic (advanced) hormone-refractory prostate cancer whose disease progressed following treatment with docetaxel-based chemotherapy. 

TROPIC (trial) was designed to assess patients with metastatic hormone-refractory prostate cancer whose disease had progressed following treatment with docetaxel-based chemotherapy. Results showed that the combination of cabazitaxel and prednisone/prednisolone significantly reduced the risk of death by 30%.

Researchers are  happy with these compelling results  and  hope that these results will provide new options and hope for patients with serious diseases, such as metastatic hormone-refractory prostate cancer.....

Ref : http://en.sanofi-aventis.com/binaries/20100304_Asco_GU_en_tcm28-27547.pdf

Baked rhubarb may help fight cancer....

Rhubarb (herbaceous perennial plants growing from short, thick rhizomes) is a  group of plants that belong to the genus Rheum in the family Polygonaceae.  They have large leaves that are somewhat triangular shaped with long fleshy petioles and small flowers. While the leaves are toxic, the plants have medicinal uses, but most commonly the plant's stalks (see picture, source : Wikipedia) are cooked and used in pies and other foods for their tart flavour.  A number of varieties have been domesticated for human consumption, most of which are recognised as Rheum x hybridum by the Royal Horticultural Society.

Rhubarb (stem & roots) has been used as a strong laxative (the two  - anthraquinones emodin and rhein are responsible). Rubarb has been used in traditional Chinese medicine & medieval Arabic and European prescriptions. The rhizomes ('roots') contain stilbene compounds (including rhaponticin) which seem to lower blood glucose levels in diabetic mice.

Now,  researchers from Biomedical Research Center at Sheffield Hallam University, lead by Dr. Nikki Jordan-Mahy, have come up with new findings. Researchers found that baking British garden rhubarb for 20 minutes dramatically boosted levels of anti-cancer chemicals called polyphenols. Previous research has shown that polyphenols selectively kill or prevent the growth of cancer cells.

This is the first study to examine the benefits of British rhubarb, specifically a variety grown in South Yorkshire. Earlier research has studied Oriental medicinal rhubarb, which has been used in traditional Chinese medicine for thousands of years. 

Baking and slow stewing offered the best maintenance of colour through preservation of anthocyanin and the highest antioxidant capacity. Baking for 20 min provided well-cooked rhubarb with the highest antioxidant capacity and the highest anthocyanin content, which is important for the aesthetic quality of the dish.  

As per the claim by the researchers, LC–MS analysis putatively identified over 40 polyphenol components in raw rhubarb (including anthraquinone, stilbene, anthocyanin and flavonol derivatives.) Baking caused selective effects on the stability of the different polyphenol components. Initially, the yield of all components increased but there was a drastic decline in the relative stability of anthraquinone aglycones with increasing cooking time and initial evidence for the turnover of other anthraquinone derivatives was obtained. Researchers now plan to study the effect of rhubarb's polyphenols on leukemia.....

Ref : Dr. Nikki Jordan-Mahy, et. al., Food Chemistry, Vol. 119, Issue 2, 15 March 2010, Pages 758-764

Bitter melon (gourd) extract inhibits breast cancer cell proliferation.....

Momordica charantia (picture, source : wikipedia) is a tropical  and subtropical vine of the family Cucurbitaceae, widely grown for edible fruit, which is among the most bitter of all vegetables. English names for the plant and its fruit include bitter melon or bitter gourd.  Extract of this vegetable is being popularized as a dietary supplement in Western Countries, since it is known to contain additional glycosides such as mormordin, vitamin C, carotenoids, flavanoids and polyphenols.

Momordica charantia has a non-nitrogenous neutral principle charantin (see structure  an insulin-like chemical that can lower blood sugar and cholesterol), and on hydrolysis gives glucose and a sterol.

Now researchers from Saint Louis University, have come up with an in interesting finding, i.e., bitter melon extract, a common dietary supplement, exerts a significant effect against breast cancer cell growth and may eventually become a chemopreventive agent against this form of cancer.

Previous research has shown Momordica charantia, to have hypoglycemic and hypolipidemic effects. Because of these effects, the extract is commonly used in folk medicines as a remedy for diabetes in locales such as India, China and Central America, as per  the claim by  researchers.

Using human breast cancer cells and primary human mammary epithelial cells in vitro, Dr. Ratna  Ray (Professor in the Department of Pathology at Saint Louis University) and colleagues found the bitter melon extract significantly decreased proliferation, of cell growth and division, and induced death in breast cancer cells. These early results offer an encouraging path for research into breast cancer. Researchers claim that, "this study may provide us with one more agent as an extract that could be used against breast cancer if additional studies hold true". 

Ray and colleagues are currently conducting follow-up studies using a number of cancer cell lines to examine the anti proliferative effect of the extract. They are also planning a preclinical trial to evaluate its chemopreventive efficacy by oral administration. Hope they come up with positive results.......

Ref : Dr. Ratna Ray et.al., Cancer Research, 10.1158/0008-5472, February 23, 2010.

Researchers able to predict and reverse resistance to Sunitinib treatment....

Van Andel Research Institute (VARI) researchers have found a way to  reverse resistance to Sunitinib (see structure), a treatment that is currently the first line of defense against clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Most patients who show a positive response to Sunitinib develop a resistance to the drug after one year of treatment.

Researchers lead by Dr. Teh, Bin Tean found that ccRCC tumor cells that had developed a resistance to Sunitinib had increased secretion of the protein interleukin-8 (IL-8). Administering Sunitinib and IL-8 neutralizing antibodies re-sensitized tumors to sunitinib treatment. Researchers also found that IL-8 may serve as a useful biomarker to predict patients' response to sunitinib treatment.

Interestingly,  another  study from same  group  of  Teh’s laboratory, looked into exactly how sunitinib works.  The study found that the treatment does not target tumor cells, but rather the tumor’s blood supply.

Researchers conclude that “it is now of critical importance to validate these findings in the clinical setting" and they hope that these insights will help to build upon recent advances to extend clinical benefits to more patients with metastatic kidney cancer....

Ref : 1.  Cancer Research 70, 1053, February 1, 2010. 

        2.  Cancer Research 70, 1063, February 1, 2010