Bezielle (BZ101) oral botanical

[Rich66]

Bezielle (BZL101) http://www.bzl101.com/


Bezielle is an oral botanical drug designed for the treatment of breast cancer that targets only cancer cells but leaves normal cells intact and functioning.


“There is great patient demand for an oral drug with minimal toxicity among women diagnosed with late stage breast cancer. Bezielle is the exact type of drug that our patients are seeking and the favorable clinical results in 2 different trials among a heavily pretreated patient population are extremely encouraging.”

–Debu Tripathy, M.D.
Industry Opinion Leader, National PI on the Herceptin Trial, Breast Oncologist, University of Texas Southwestern, Dallas, Texas


“In the age of sequential monotherapy as the treatment approach for the treatment of women with metastatic breast cancer, Bezielle is one of the most exciting new therapies under investigation today.”
–Banu Arun, M.D.
Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas




Mechanism of Action
Bezielle is an oral drug designed for the treatment of advanced breast cancer with a novel mechanism of action. Bezielle targets diseased cells while leaving normal cells healthy and intact. Normal cells depend primarily on the citric acid cycle (>85%) and very little on glycolysis (<7%) for energy production. In contrast, cancer cells depend largely on glycolysis (>85%) for energy production. Bezielle induces strong oxidative stress in cancer cells leading to severe DNA damage, but in normal cells the effect is blunted due to their different metabolic profile. Cancer cells attempt but ultimately fail to repair DNA damage that results in the inhibition of glycolysis and cancer cell death while normal cells remain unharmed.

Selective Cytotoxic Activity
Bezielle is selectively cytotoxic to most of twelve breast cancer cell lines examined, as well as to a number of cancer cell lines of different tissue origins such as prostate, lung, colon and pancreatic cancers. At the same dose, Bezielle does not induce appreciable cell death in normal cells such as fibroblasts and normal mammary epithelial cells and lines. Bezielle was also orally active in preventing tumor formation in a mouse xenograph model.
Phase 1 Clinical Results
Bionovo’s lead cancer candidate has been evaluated in two Phase 1 clinical trials and a total of 47 women with advanced breast cancer have been treated with Bezielle. Data from the Phase 1 clinical trials of Bezielle show promising signs of efficacy and indicate the drug is well tolerated and safe for clinical use.

Next Steps: Phase 2 Clinical Trial
A multi-center, Phase 2, open-label, non-randomized clinical trial to assess ongoing safety and preliminary efficacy of Bezielle for the treatment of metastatic breast cancer is being conducted under the co-directorship of Dr. Banu Arun of the M.D. Anderson Cancer Center and Alejandra Perez of the Memorial Cancer Institute. A total of 80 women with histologically confirmed breast cancer and measurable stage IV disease will be enrolled to the Phase 2 trial. Of the 80 women, 40 will have hormone receptor-positive disease and 40 will have hormone receptor-negative disease. The primary outcome measure will be response to therapy evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary measures of efficacy will include: duration of overall objective response, progression-free survival, overall survival, and patient reported quality of life measures. Recruitment for the clinical trial will take place at 15 clinical sites throughout the United States. Click here to visit Bionovo's Bezielle clinical trial website.

Full Bionovo patent application with additional info.

Abstract:
Process of making purified extract of scutellaria barbata d. don

USPTO Application #: 20090130237
Title: Process of making purified extract of scutellaria barbata d. don
Abstract: An extract of Scutellaria barbata D. Don is effective in the arrest of cancer cell growth in the G1 phase, the induction of apoptosis in cancer cells and the shrinking of solid cancers. The extract may be prepared as a pharmaceutical composition for administration to mammals for the treatment of solid cancers, such as epithelial cancers. Such epithelial cancers include breast cancer and ovarian cancers. The extract is obtained from Scutellaria barbata D. Don by contacting aerial portions of a plant from the species Scutellaria barbata D. Don with an aqueous or alcoholic solvent. (end of abstract)

FULL Phase 1 trial TEXT (with "recipe") for purchase HERE




In Chinese medicine, known as Ban Zhi Lian.
Powder extract HERE

http://www.cancermonthly.com/iNP/vie...ter.asp?ID=214
Breast Cancer and Chinese Herb
5/16/2008

The challenge in treating cancer has been to selectively target cancer cells without harming normal cells. Researchers have found a new drug that appears to do just that—they have discovered that an herbal drug called BZL101 significantly damages cancer cells while sparing healthy cells, and now they think they know how it works.
BZL 101 is an extract from the Chinese medicinal herb, Scutellaria barbata.
In a phase 1 trial, the drug showed promise in treating advanced breast cancer, but researchers wanted to find out exactly how the drug kills cancer cells, and why it spares healthy cells. “I think it’s very important to know the mechanism of action, because it’s difficult to give patients drugs when you have no idea how they work,” explains lead author Emma Shtivelman, PhD, Director of Cancer Research at BioNovo, Inc in Emeryville, California. “If you know the mechanisms you can target the drug more precisely and predict potential side effects, which are clear goals of research and development.”
Many cancer therapies that kill cancer cells do so by a process of programmed cell death, called apoptosis. But this didn’t seem to be the case with BZL101, which had the researchers wondering as to the real mechanism.
“The buzzword in cancer research for years was apoptosis—and we saw that BZL101 induces a lot of cell death, but we couldn’t describe it as apoptopic cell death,” says Dr. Shtivelman. In a culture of breast cancer cells, only 10 to 15 percent of the cancer cells were killed by apoptosis. For the remainder, there was obviously a different cause at work.
What the researchers found after treating cancer cell lines with BZL101 was that the drug triggers high levels of reactive oxygen species (ROS)—highly unstable molecules that can damage DNA. “Normal cells are well equipped to cope with highly reactive oxygen species because they’re harmful,” according to Dr. Shtivelman. Tumor cells, though, already have high levels of ROS, and the additional ROS induced by BZL101, “takes them overboard and they die,” she says. Also, because the drug inhibits glycolysis—the method cancer cells use to produce energy—it can force them to deplete their energy stores and essentially starve to death, Dr. Shtivelman and her colleagues reported in Cancer Biology & Therapy.
Because it spares healthy cells, BZL101 appears to be very safe overall. The only side effects noted so far have been mild, including constipation, nausea, and diarrhea.
The next phase of the research, which will look at the drug’s effectiveness, is slated to be completed in September 2009. If the results are favorable, the researchers will move on to phase 3 trials with larger groups of patients. (NOTE: economics delayed this)
The study authors believe BZL offers great promise over many current cancer therapies because of its low toxicity and limited risk of side effects. “Conventional chemotherapeutic drugs hit all proliferating cells in the body,” says Dr. Shtivelman. “That’s why cancer patients who are on chemotherapy lose their hair, have intestinal problems, and are frequently anemic. If that can be avoided you can increase the dose, if necessary. And with BZL101 that seems to be the case—tumor cells are ready to die when they see the drug and normal cells remain healthy.”

Source:
Fong S, Shoemaker M, Cadaoas J, Lo A, Liao W, Tagliaferri M, Cohen I, Shtivelman E. Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells. Cancer Biology & Therapy. 2008;7:7(4).


Cancer Biol Ther. 2008 Apr;7(4):577-86. Epub 2008 Jan 7.
Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells.

Fong S, Shoemaker M, Cadaoas J, Lo A, Liao W, Tagliaferri M, Cohen I, Shtivelman E.
BioNovo, Inc., Emeryville, California 94608, USA.
We studied the mechanism of the cytotoxic activity of BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, which is currently in phase II clinical trial in patients with advanced breast cancer. The phase I trial showed favorable toxicity profile and promising efficacy. We report here that BZL101 induces cell death in breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by BZL101 of reactive oxygen species (ROS) in tumor cells. As a consequence, BZL101 treated cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with BZL101 are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes. In breast cancer cells oxidative damage induced by BZL101 leads to the hyperactivation of poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of NAD and depletion of ATP, neither of which are observed in non-transformed cells. The hyperactivation of PARP is instrumental in the necrotic death program induced by BZL101, because inhibition of PARP results in suppression of necrosis and activation of the apoptotic death program. BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production. Because tumor cells frequently rely on glycolysis for energy production, the observed inhibition of glycolysis is likely a key factor in the energetic collapse and necrotic death that occurs selectively in breast cancer cells. The promising selectivity of BZL101 towards cancer cells is based on metabolic differences between highly glycolytic tumor cells and normal cells.





Breast Cancer Res Treat. 2007 Sep;105(1):17-28. Epub 2006 Nov 17.
Phase I trial and antitumor effects of BZL101 for patients with advanced breast cancer.

FULL TEXT (with "recipe") for purchase HERE



Rugo H, Shtivelman E, Perez A, Vogel C, Franco S, Tan Chiu E, Melisko M, Tagliaferri M, Cohen I, Shoemaker M, Tran Z, Tripathy D.
University of California, San Francisco Carol Franc Buck Breast Care Center, San Francisco, USA.
BACKGROUND: Botanical therapies are often used by breast cancer patients yet few clinical trials have evaluated their safety and efficacy. We studied mechanisms of activity and performed a phase I clinical trial in patients with advanced breast cancer to evaluate BZL101, an aqueous extract from Scutellaria barbata. METHODS: Preclinical studies were conducted in vitro to characterize cell death induced by BZL101. In a phase I trial, eligible patients had histologically confirmed, measurable metastatic breast cancer. Treatment consisted of 350 ml per day of oral BZL101, administered as sole cancer therapy until disease progression, toxicity or personal preference to discontinue. Primary endpoints were safety, toxicity and tumor response. RESULTS: BZL101 extract induced strong growth inhibition and apoptosis of breast cancer cell lines. In the phase I trial, 21 patients received BZL101. Mean age was 54 years (30-77) and mean number of prior treatments for metastatic disease was 3.9 (0-10). There were no grade III or IV adverse events (AEs). The most frequently reported BZL101-related grade I and II AEs included: nausea (38%), diarrhea (24%), headache (19%) flatulence (14%), vomiting (10%), constipation (10%), and fatigue (10%). Sixteen patients were evaluable for response. Four patients had stable disease (SD) for >90 days (25%) and 3/16 had SD for >180 days (19%). Five patients had objective tumor regression, one of which was 1 mm short of a PR based on RECIST criteria. CONCLUSIONS: BZL 101 inhibits breast cancer cell lines by inducing apoptosis. In a phase I clinical trial, BZL101 was safe and had a favorable toxicity profile. BZL101 demonstrated encouraging clinical activity in this heavily pretreated population.

PMID: 17111207 [PubMed - indexed for MEDLINE]






Nan Fang Yi Ke Da Xue Xue Bao. 2008 Oct;28(10):1835-7.
[Antitumor and immune-modulating effects of Scutellaria barbata extract in mice bearing hepatocarcinoma H22 cells-derived tumor]

[Article in Chinese]
Dai ZJ, Liu XX, Tang W, Xue Q, Wang XJ, Ji ZZ, Kang HF, Diao Y.
Department of Oncology, Second Hospital of Xi'an Jiaotong University, Xi'an 710004, China. dzj0911@126.com
OBJECTIVE: To investigate the effects of Scutellaria barbata extract (ESB) in suppressing tumor growth and modulating the immune functions in mice bearing tumors derived from hepatocarcinoma H22 cells. METHODS: Fifty mice inoculated subcutaneously with H22 cells were equally divided into the model group, high-, moderate-, and low-dose ESB groups, and 5-Fu group, with corresponding treatments for 10 days. Another 10 mice with only saline injection served as the normal control group. The body weight, tumor mass, thymus index and spleen index of the mice were measured, and the lymphocyte proliferation activity, NK cell activity and interleukin-2 (IL-2) production by the splenocytes were detected. RESULTS: Moderate- and high-dose ESB significantly suppressed the tumor growth with tumor inhibition rate of 28.68% and 36.98%, respectively. ESB treatment at moderate and high doses significantly increased the thymus index and spleen index (P < 0.01), which were decreased significantly in 5-Fu group. The lymphocyte proliferation activity, NK cell activity and IL-2 production by the splenocytes were significantly lower in the model group than in the normal group (P < 0.05). Compared with the model group, ESB at the high dose obviously increased the three indexes above mentioned. The NK cell activity was also significantly improved in moderate-dose ESB group (P < 0.05). CONCLUSION: ESB can suppress the growth of H22 implant tumor and enhance the immune function of the tumor-bearing mice.




Life Sci. 2004 Sep 17;75(18):2233-44.
Anticancer activity and mechanism of Scutellaria barbata extract on human lung cancer cell line A549.

Yin X, Zhou J, Jie C, Xing D, Zhang Y.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Scutellaria barbata (S. barbata), a traditional Chinese herbal medicine native to southern China, is widely used as an anti-inflammatory and a diuretic in China. Several studies have indicated that extracts of S. barbata have growth inhibitory effects on a number of human cancers. Treatment of lung cancer, digestive system cancers, hepatoma, breast cancer, and chorioepithelioma by S. barbata extracts was reported. However, the mechanism underlying the antitumor activity was unclear. In this study, we studied the growth inhibitory effect of S. barbata and determined its mechanism of antitumor activity using human lung cancer cell line A549. Our results showed that ethanol extracts of S. barbata greatly inhibited A549 cell growth, with IC50 of 0.21 mg/ml. The major mechanisms of inhibition included cell apoptosis and cytotoxic effects. cDNA microarray analysis showed that 16 genes, involved in DNA damage, cell cycle control, nucleic acid binding and protein phosphorylation, underwent more than 5-fold change. These data indicated that these processes are involved in S. barbata-mediated killing of cancer cells. A surprising finding is that CD209, related to dendritic cell (DC) function, was dramatically downregulated by 102-fold. Further functional studies are needed to assess the role of the array-identified genes in S. barbata mediated anticancer activity. Copyright 2004 Elsevier Inc.

PMID: 15325848 [PubMed - indexed for MEDLINE]



J Nat Prod. 2009 Oct;72(10):1793-7.
Cytotoxic neo-clerodane diterpenoid alkaloids from Scutellaria barbata.

Dai SJ, Peng WB, Zhang DW, Shen L, Wang WY, Ren Y.
School of Pharmaceutical Science, Yantai University, Yantai 264005, People's Republic of China. daishengjun_9@hotmail.com
Six new neo-clerodane diterpenoid alkaloids, named scutehenanines A-D (1, 4, 5, 6), 6-O-acetylscutehenanine A (2), and 6-O-(2-carbonyl-3-methylbutanoyl)scutehenanine A (3), were isolated from the whole plant of Scutellaria barbata. Their structures were established on the basis of detailed physical data analyses. In vitro, the six new isolated compounds showed cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells) and gave IC50 values in the range 2.8-6.4 microM.

PMID: 19785430 [PubMed - indexed for MEDLINE]


Bioorg Med Chem Lett. 2010 Jan 1;20(1):288-90. Epub 2009 Nov 17.
Two novel neo-clerodane diterpenoids from Scutellaria barbata.

Lee H, Kim Y, Choi I, Min BS, Shim SH.
School of Biotechnology, Yeungnam University, 214-1 Dae-dong, Gyeongsan, Gyeongbuk 712-749, South Korea.
Two novel neo-clerodane diterpenoids, barbatellarines A (1) and B (2), were isolated from the whole plants of Scutellaria barbata, along with the known compound scutebarbatine F (3). The chemical structures and relative stereochemistry of the isolated compounds were established by NMR (1D and 2D) and mass spectroscopic analyses. Compounds 2 and 3 were evaluated for in vitro cytotoxic activity against the HL-60 (human leukemia), MCF7 (human breast cancer), and LLC (Lewis lung carcinoma) cancer cell lines. Compound 2 exhibited weak cytotoxic activity against HL-60 cells, with an IC(50) value of 41.4microM. Copyright 2009 Elsevier Ltd. All rights reserved.

PMID: 19962306 [PubMed - in process]






Fitoterapia. 2010 Jan 15. [Epub ahead of print]
New neo-clerodane diterpenoids from Scutellaria barbata with cytotoxic activities.

Dai SJ, Qu GW, Yu QY, Zhang DW, Li GS.
School of Pharmaceutical Science, Yantai University, Yantai 264005, PR China.
Two new neo-clerodane diterpenoids have been isolated from the whole plant of Scutellaria barbata D. Don, and their structures were established by detailed spectral analyses as scutehenanine H (1) and 6-(2,3-epoxy-2-isopropyl-n-propoxyl)barbatin C (2). In vitro, the isolated two new compounds showed significant cytotoxic activities against three human cancer lines, and gave IC(50) values in the range OF 2.0-4.2muMu. Copyright © 2010 Elsevier B.V. All rights reserved.

PMID: 20079810 [PubMed - as supplied by publisher]

Video regarding 2006 UK research:

Using Scutellaria Barbata to Make AntiCancer Drugs - Celebrity bloopers here

[Rich66]

Awaiting funding for Phase II. Maybe second half of 2010.

[Rich66]

http://www.prnewswire.com/news-relea...-81475132.html

Bionovo Announces Publication of Positive Results From the Phase 1B Clinical Trial of Bezielle (BZL101) for Metastatic Breast Cancer

EMERYVILLE, Calif., Jan. 14 /PRNewswire-FirstCall/ -- Bionovo, Inc. (Nasdaq: BNVI) announced today the publication of their results from its phase 1B clinical trial of Bezielle (BZL101) for metastatic breast cancer. The results of the study are available online in Breast Cancer Research and Treatment and demonstrate that Bezielle continues to be safe and well tolerated with clinical evidence of anticancer activity in a heavily pretreated population of women diagnosed with metastatic breast cancer. Preliminary results from this study were released previously by the Company.
The purpose of the phase 1B clinical trial was to identify the maximum tolerated dose of Bezielle and to determine the safety and feasibility of the company's novel, oral, anticancer treatment. A total of 27 women with late stage breast cancer were enrolled to the phase 1B trial. The 27 enrolled women had failed an average of six prior therapies since diagnosis with metastatic breast disease and expected survival pre-trial was 90–120 days. To date, a total of 48 women with advanced breast cancer have been treated with Bezielle in two early phase clinical trials.
Highlights of the Bezielle phase 1B clinical trial are as follows:

• Independent radiology showed 6 patients had stable disease.
• Independent radiology showed 3 patients had evidence of tumor regression consistent with a minimal tumor response (>0% and <30%).
• Three patients had stable disease for >120 days.
• Four patients discontinued Bezielle with stable disease; one was on Bezielle for 449 days and had evidence of minimal tumor regression and continues to be stable for 700+ days. A second patient remained stable for 836 days and a third patient remained stable for 594 days.
• There were no deaths that were attributed to Bezielle therapy.
• The most common side effects associated with Bezielle therapy were minor and gastrointestinal in nature.
• The maximum tolerated dose was four times the dose evaluated in the phase 1a study.
• Median treatment compliance was 92%.

A link to the full text of the article is available at:
http://bionovo.com/investors/publications
"We are encouraged by the results of the Company's second phase 1 trial in women with advanced breast cancer and feel the oncology community is equally enthusiastic about Bezielle as our manuscript was accepted by the most widely read breast cancer specific peer reviewed journal in two days," said Mary Tagliaferri, President and Chief Medical Officer of Bionovo. "There are currently over 160,000 women in the United States living with advanced breast cancer who are eagerly awaiting an oral anticancer drug that can extend life without profoundly diminishing quality of life. We believe Bezielle will be an important new anticancer agent because its biological selectivity allows the drug to kill cancer cells without affecting normal cells resulting in dramatically fewer side effects."
"In the age of sequential monotherapy as the treatment approach for women with metastatic breast cancer, Bezielle is one of the most exciting new therapies under investigation today," said Banu Arun, M.D., Department of Breast Medical Oncology, Division of Cancer Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas. "At our center, where over 3,000 women are newly diagnosed with breast cancer each year, there is great patient demand for oral drugs with minimal toxicities for the treatment of any stage breast cancer. Bezielle is the exact type of drug our patients are seeking and the favorable clinical results in Bionovo's two early stage clinical trials among a heavily pretreated patient population are extremely encouraging."
"While safety and maximum tolerability were the primary endpoints of this second phase 1 trial, Bezielle demonstrated promising clinical efficacy in both phase 1 trials affording some women with long periods of stable disease without dramatically altering their day to day quality of life, which is a significant advancement," said Alejandra Perez, M.D., Director of the Breast Cancer Center at the Memorial Regional Hospital Cancer Institute, Hollywood, Florida.
A phase 2 trial of Bezielle for metastatic breast cancer under the directorship of Dr. Banu Arun at the University of Texas, M. D. Anderson Cancer Center and Dr. Alejandra Perez at the Memorial Regional Hospital will commence once funding is secured. The phase 2 study will be conducted at 16 clinical centers in the United States and will enroll 80 women with metastatic breast cancer.

Bezielle (BZL101)
Bezielle is an oral drug designed for the treatment of advanced breast cancer with a novel mechanism of action. Bezielle targets diseased cells while leaving normal cells healthy and intact. Normal cells depend primarily on the citric acid cycle (>85%) and very little on glycolysis (<7%) for energy production. Cancer cells depend largely on glycolysis (>85%) for energy production. Bezielle stops the production cycle of energy in cancer cells by inhibiting glycolysis. This leads to DNA damage and cell death in cancer cells while normal cells remain largely unharmed.