New treatment prevents chemotherapy-induced hearing loss in children with cancer

Investigators from Children's Hospital Los Angeles and 37 other Children's Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

"This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer," said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles, who was lead author and chair of the study. "It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors." Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.

Cancer drug may protect kidneys from damage caused by chemotherapy agent cisplatin

In continuation of my update on cis platin...

A class of drugs used increasingly to help fight cancer may have the additional benefit of protecting the kidneys when packaged with the powerful chemotherapy agent cisplatin.

The nearly 40-year-old cisplatin can be a strong opponent against aggressive cancers, such as head and neck, ovarian and lung cancers.

But in more than 10 percent of patients, the drug, given intravenously for typically a handful of days, can also take a quick and potentially deadly toll on the kidneys, said Dr. Ganesan Ramesh, kidney pathologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University and at the university's Cancer Center.

Ramesh and his colleagues have new laboratory evidence that histone deacetylase inhibitors, or HDAC inhibitors, can eliminate 80-90 percent of that kidney toxicity.

"Cisplatin is a very effective drug, and we don't want to stop using it," said Ramesh, corresponding author of the study in the journal Kidney International. "We want to reduce its toxicity to the normal tissue."

The super-busy kidneys filter the entire blood volume of the body every 20 minutes. A big part of their job is removing toxins for elimination in the urine and pushing back into the body valuables such as glucose and nutrients. The major problem with cisplatin is it can get stuck in the kidneys, where the platinum metal compounds the drug releases to kill a tumor can do serious harm. Inside the kidneys, the malingerer stimulates inflammation, DNA damage, free-radical production and cell death.

When MCG researchers gave HDAC inhibitors to mice receiving cisplatin, it dramatically suppressed the usual inflammation and cell death that follow cisplatin dosing alone.

Histones are the protein spools DNA wraps around, and histone deacetylase enables DNA to be wound tightly and regulates gene expression and protein function. One way HDAC inhibitors help fight cancer is by temporarily loosening DNA, increasing the expression of tumor-suppressing genes and making the tumor more vulnerable. Evidence that HDAC inhibitors also can protect kidneys following injury, led Ramesh to reason it was logical to pair these drugs with cisplatin.

Cancer drug may protect kidneys from damage caused by chemotherapy agent cisplatin

Mitaplatin as a better anticancer agent.......

In continuation of my update on Platinum compounds as anticancer drugs, I find  this one more interesting info to share with. MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

As per the claim by the researchers, glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. With this idea behind researchers have prepared the new compound by combining dichloroacetate, DCA and cisplatin. Mitaplatin, thus obtained has two DCA units which are appended to the axial positions of a six-coordinate Pt (IV) center.

As per the claim by the authors, the negative intracellular redox potential reduces the platinum to release cisplatin, a Pt (II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt (IV) compounds and is comparable to that of cisplatin.

Mitaplatin alters the mitochondrial membrane potential gradient of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance. Further studies like mice transplanted with human tissues are to be substantiated, in my opinion its a good achievement...

Ref : http://www.pnas.org/content/early/2009/12/09/0912276106.abstract?related-urls=yes&legid=pnas;0912276106v1

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

In continuation of my update on cisplatin and 5-fluorouracil derivative S-1v

Research suggests that treatment with cisplatin plus S-1 together with thoracic radiotherapy is relatively efficacious and tolerable in patients with locally advanced non-small-cell lung cancer (NSCLC).

Although cisplatin-based chemotherapy with thoracic radiotherapy is a standard treatment for unresectable, locally advanced NSCLC, the outcomes are not satisfactory, explain Katsuyuki Hotta, from Okayama University Hospital in Japan, and colleagues. They investigated the effect of adding the 5-fluorouracil derivative S-1 to the standard treatment in a phase II trial, the primary endpoint of which was the response rate.

A total of 48 patients with stage III NSCLC received cisplatin plus S-1 (at a dose of 40 mg/m2 twice daily from days 1–14 and 29–42 of treatment) with concurrent thoracic irradiation, of whom 37 had a partial response, giving an overall response rate (ORR) of 77%.

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

Phase III trial: Rolapitant lessens chemotherapy-induced nausea and vomiting

Rolapitant reduces nausea and vomiting in patients receiving cisplatin-based chemotherapy, according to the results of a phase III trial presented for the first time today at the ESMO 2014 Congress in Madrid, Spain.

Dr Martin Chasen, lead author and medical director, Palliative Care, Ottawa Hospital Cancer Centre, Canada, said: "This agent makes a significant difference in the way people tolerate their chemotherapy. Patients experienced no loss in quality of life and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he had just finished 18 holes of golf one week after receiving chemotherapy. This is in sharp contrast to many patients on current standard anti-emetics that are too ill to get out of bed within a week after each cycle of cisplatin."

"We must treat nausea and vomiting, not just the cancer," added Chasen, emphasising that some patients are extremely sensitive to cisplatin effects and recalling that he had one or two patients with curable cancers who refused treatment after one round of cisplatin. "They preferred to die," he said.

The phase III trial investigated rolapitant, a novel antagonist of the NK-1 receptor, for the prevention of severe nausea and vomiting often experienced by patients receiving cisplatin-based chemotherapy, which may cause dose reductions and treatment discontinuation. The multicentre trial randomised 532 patients 1:1 to receive rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to cisplatin-based chemotherapy.

Phase III trial: Rolapitant lessens chemotherapy-induced nausea and vomiting

Cisplatin doubles lung cancer survival time in mice !

When I was studying my M.Sc., (1992), we used to have a question regarding the anticancer activity of cisplatin and after that I could see lots of research in the field of anticancer activity. And so many new drugs have been established and are being used as drugs. Cisplatin works by crosslinking across DNA inter-strands, making it impossible for rapidly dividing cells to duplicate their DNA for cell division (mitosis). The damaged DNA sets off DNA repair mechanisms which fails to work, so in turn activate cell death processes (apoptosis). The trans isomer does not have this pharmacological effect.

After so many years, I could find this something interesting findings about cisplatin, by Patrizia Russo of Lung Cancer Unit of the National Cancer Research Institute in Genoa, Italy and colleagues from San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Catholic University.

In the study, the authors took the research a step further and showed that α-CbT could inhibit non-small cell lung carcinoma (NSCLC) growth and prolong life in non-obese/severe combined immunodeficient (NOD/SCID) mice that had human NSCLC grafted to their lungs. This study attempted to mimic human cancer conditions more closely by delaying treatment until the tumors were well-established. In addition to control mice that were untreated, the researchers randomized one third of the mice to receive standard chemotherapy.

They found that NOD/SCID mice treated with the standard chemotherapy agent, cisplatin, had a 16 percent longer median survival time than untreated mice (p= 0.05). Mice treated with α-CbT, however, had an increased median survival time of 1.7-fold over the cisplatin-treated mice and 2.1-fold over the no-treatment controls (p=0.0005). Though the clinical trials to establish the claim and to to explore the widest range of possibilities of intervention on the α7-nAChRs. Congrats...

Ref :Inhibition of Nonneuronal 7-Nicotinic Receptor for Lung Cancer Treatment; Am. J. Respir. Crit. Care Med., Jun 2009; 179: 1141 - 1150

One-Cycle BE500P Seems Safe for High-Risk Early Testicular Cancer

 

Bleomycin                                                                             etoposide

Cisplatin

In continuation of my update on etoposide and cisplatin

For high-risk stage 1 nonseminoma germ cell tumors of the testis (NSGCTT), one cycle of adjuvant bleomycin, etoposide (500 mg/m²), and cisplatin (BE500P) is safe, resulting in a two-year malignant recurrence (MR) rate of 1.3 percent, similar to that reported for two cycles of BE360P, according to a study published online Jan. 1 in European Urology.

Michael Cullen, M.D., from the University Hospitals Birmingham NHS Foundation Trust in the United Kingdom, and colleagues compared recurrence rates for one cycle of BE500P to recurrence rates for two cycles of BE360P among 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT registered in a single-arm prospective study.

Patients were followed for a median of 49 months. Ten patients with increasing tumor markers were excluded at baseline. The researchers found that four patients had MR at six, seven, 13, and 27 months; all were treated with secondary chemotherapy, and at five years, three remained recurrence-free. The rate of two-year MR was 1.3 percent (95 percent confidence interval, 0.3 to 3.7 percent). Nonmalignant recurrences developed in three patients who had localized differentiated teratoma; after surgery, they were rendered disease-free. In 6.8 percent of patients, grade 3 to 4 febrile neutropenia occurred.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one -- making their treatment shorter, kinder, and cheaper," a coauthor said in a statement.

https://www.europeanurology.com/article/S0302-2838(19)30895-4/fulltext
https://en.wikipedia.org/wiki/Bleomycin
https://en.wikipedia.org/wiki/Etoposide
https://en.wikipedia.org/wiki/Cisplatin

Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven

In continuation of my update on crizotinib

The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

After its assessment in 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) therefore now reassessed the added benefit of the drug in comparison with the appropriate comparator therapy - and found out: An added benefit of crizotinib for the first-line treatment of advanced bronchial carcinoma is not proven.

Carboplatin only in advanced risk of cisplatin side effects

Advanced bronchial carcinoma can only be treated palliatively. The Federal Joint Committee (G-BA) specified several appropriate comparator therapies for this. Either cisplatin in combination with a third-generation cytostatic agent was to be used in the control arm, or - in case of an increased risk of cisplatin side effects - carboplatin with a third-generation cytostatic agent. Monotherapy with gemcitabine or vinorelbine was an alternative option for patients with already severe limitations.

Use of carboplatin attached to condition

The drug manufacturer did not use the latter option and only submitted data from a randomized study in which crizotinib was directly compared with cisplatin or carboplatin, each in combination with the cytostatic agent pemetrexed. Carboplatin is not approved for the treatment of advanced non-small cell lung cancer, but can be prescribed in so-called off-label use. This is only the case for patients with an advanced risk of cisplatin side effects, e.g. in neuropathy, hearing impairment or susceptibility to nausea, renal insufficiency or cardiac failure.

The only submitted study did not fulfil the condition

Almost half of the participants received carboplatin in the control arm of the PROFILE 1014 study; the criteria for this individual medical decision were not comprehensible. A large proportion of the patients in the control arm did not correspond to the criteria of the Pharmaceutical Directive for the off-label use of carboplatin. Patients with neuropathy, renal insufficiency or cardiac failure were excluded from participation in the study and only about two and six per cent of the participants had notable hearing impairment or nausea as accompanying disease.

Hence the control group of the study did not adequately represent the appropriate comparator therapy. The data submitted were therefore unsuitable for the derivation of an added benefit of crizotinib in comparison with this comparator therapy.

Added benefit of crizotinib drug for first-line treatment of advanced bronchial carcinoma not proven: The drug crizotinib (trade name: Xalkori) has been available since 2012 for patients with advanced non-small cell lung cancer (bronchial carcinoma) who have a high activity of the enzyme anaplastic lymphoma kinase (ALK) and have already received another treatment. In November 2015, the approval was extended to first-line treatment.

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/

Drug candidate delivered by plant-virus-based carrier shows promise for triple-negative breast cancer

In continuation of my update on phenanthriplatin

In a pair of firsts, researchers at Case Western Reserve University and Massachusetts Institute of Technology have shown that the drug candidate phenanthriplatin can be more effective than an approved drug in vivo, and that a plant-virus-based carrier successfully delivers a drug in vivo. 

phenanthriplatin

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin -carrying nanoparticles were four times smaller than those treated either with cisplatin, a common and related chemotherapy drug, or free phenanthriplatin injected intravenously into circulation.

The scientists believe the work, reported in the journal ACS Nano, is a promising step toward clinical trials.

"We may have found the perfect carrier for this particular drug candidate," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve, who has spent 10 years studying the use of plant viruses for medical purposes.

She teamed with Stephen J. Lippard, Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin. They form bifunctional cross-links with DNA in cancer cells, which block the DNA from transcribing genes and result in cell death, Lippard explained.

Despite widespread use, cisplatin has been shown to cure only testicular cancer, and many cancers have or develop immunity to the drug.

Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

In fact, his lab found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone and other tissues. The molecule also appears to avoid defense mechanisms that convey resistance.

But when injected into mouse models of cancer, the drug candidate performed no better than standard platins.

Lippard realized phenanthriplatin wasn't reaching its target. He had a drug delivery problem.

He found a potential solution while visiting Case Western Reserve's campus and heard Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery more than a year ago.

"I envisioned that TMV would be the perfect vehicle," Lippard said. "So we had a beer and formed a collaboration."

The long, thin tobacco mosaic virus nanoparticles are naturals for delivering the drug candidate into tumors, said Steinmetz, who was appointed by the Case Western Reserve School of Medicine.

The virus particles, which won't infect humans, are hollow. A central tube about 4 nanometers in diameter runs the length of the shell and the lining carries a negative charge.

Phenanthriplatin is about 1 nanometer across and, when treated with silver nitrate, has a strong positive charge. It readily enters and binds to the central lining.

The elongated shape of the nanoparticle causes it to tumble along the margins of blood vessels, remain unnoticed by immune cells and pass through the leaky vasculature of tumors and accumulate inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. The pH is much lower than in the circulating blood, Steinmetz explained. The shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription, leading to greater amounts of cell death through apoptosis than cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor led to its improved performance over cisplatin or free phenanthriplatin.

Lippard and Steinmetz continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, use in other types of cancers, the addition of agents on the exterior of the shell to increase accumulation inside tumors and more.

Turmeric component (curcumin) enhances chemotherapy's suppression of head and neck cancer

In continuation of my update on Curcumin, I found this info interesting to share with.., i.e.,  researchers with UCLA's Jonsson Cancer Center have found, when combined with the drug Cisplatin, turmeric enhances the chemotherapy's suppression of head and neck cancer cell growth. Previous studies have shown it can suppress the growth of certain cancers. The study, done in cells in Petri dishes and then in mouse models is of great importance.

A 2005 study by Wang and Srivatsan first showed that curcumin suppressed the growth of head and neck cancer cells, first in cells and then in mouse models. In the animal studies, the curcumin was applied directly onto the tumors in paste form because it did not dissolve in saline, which would have allowed it to be injected. n need of a better way to deliver the curcumin, the team collaborated with Dr. Kapil Mehta of M.D. Anderson Cancer Center and found that encapsulating the curcumin in a liposome, an artificially prepared vehicle that enclosed the spice component within its membrane, made the treatment injectable. The curcumin was injected into the tail vein of a mouse, where it circulated into the blood stream, slowing down and eventually stopping the cancer growth, a study in 2008 found.

"This was a very positive finding, developing an efficient way to deliver the treatment," Wang said. "Our study also showed that the curcumin was very well tolerated."

In this study, the team wanted to combine the curcumin with the chemotherapeutic drug Cisplatin, which is very toxic at the doses needed to fight head and neck cancers, damaging kidneys, the ears and the bone marrow. They hoped that if they added curcumin to the mix, they might be able to lower the Cisplatin dose and cause less organ damage. Their finding, that the curcumin made the Cisplatin work better, was very promising.

More....

New drug candidate shows promise against cancer - MIT Media Relations

Drugs containing platinum are among the most powerful and widely used cancer drugs. However, such drugs have toxic side effects, and cancer cells can eventually become resistant to them. Stephen J Lippard, Chemistry Professor, MIT who has spent much of his career studying platinum drugs, has now identified a compound that kills cancer cells better than cisplatin, the most commonly used platinum anticancer drug. The new compound may be able to evade cancer-cell resistance to conventional platinum compounds.

“I’ve long believed that there’s something special about platinum and its ability to treat cancer. Using new variants, we might have a chance of applying platinum to a broader range of cancer types, more successfully,” said Lippard. Lippard is senior author of a paper describing the new drug candidate, known as phenanthriplatin - which is cis-[Pt(NH₃)₂(phenanthridine)Cl]NO_3.

Active ingredient of ipecac syrup inhibits growth of cancer cells

An old home remedy called ipecac syrup, once stocked in medicine cabinets in case of accidental poisoning, is showing promise as a new chemotherapy drug for bladder cancer.

Years ago, ipecac syrup was used to induce vomiting in poisoning cases. Now a Loyola University Medical Center study has found that the active ingredient of ipecac syrup effectively inhibits the growth of bladder cancer cells, especially when combined with a standard chemotherapy drug.

In the new study, Loyola researchers exposed cell lines of normal and cancerous bladder cells to emetine alone and to emetine plus cisplatin. (Cisplatin is the standard chemotherapy drug for advanced bladder cancer.)

• Emetine alone inhibits the proliferation of bladder cancer cell lines.
• Emetine acts synergistically with cisplatin to inhibit bladder cancer proliferation better than either drug does alone.
• Emetine has little effect on normal cells.

Bladder cancer is the fourth most common cancer in men and the 9th most common cancer in women. But even with aggressive surgery and chemotherapy, the five-year survival rate for patients with advanced Stage 4 bladder cancer is only 4 to 20 percent.

"There is an urgent need to develop new drug combinations," Dr. Gupta said. "Our study demonstrates that combining emetine with cisplatin is potentially beneficial, and merits further study in clinical trials."

Dr. Gupta is an assistant professor in the departments of Urology and Surgery and in the Oncology Research Institute of Loyola University Chicago Stritch School of Medicine. Dr. Foreman is an associate professor in the Department of Pathology and the Oncology Research Institute. Other authors are John Jesse III, a Stritch student, and Paul Kuo, MD, FACS, chair of Loyola's Department of Surgery and director of the Oncology Research Institute.

Ref : http://loyolamedicine.org/newswire/news/familiar-remedy-shows-promise-new-chemo-drug-bladder-cancer

Active ingredient of ipecac syrup inhibits growth of cancer cells

Metformin along with chemotherapy/radiation improves outcomes in head and neck cancer patients

In continuation of my update on metformin

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

"In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation," she says. "Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin--1,000 milligrams twice a day--to experience positive results.

"In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective."

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

"This is part of an ongoing clinical trial," says Wise-Draper. "We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients' tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.
"Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation."

She adds that there wasn't a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

"These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin," Wise-Draper says. "The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size."

Picoplatin a better drug than oxaliplatin for colorectal cancer !

In one of my earlier blog, I did mention about the Cisplatin (Cisplatin doubles lung cancer survival time in mice !).

About Cis-platin & other drivatives:

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) is a platinum-based chemotherapy drug used to treat various types of cancers, (sarcomas, some carcinomas (small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).

Now its the turn of Picoplatin [see structure , Amminedichloro(2-methylpyridine)platinium)], Poniard Pharmaceuticals, Inc. has come up with some interesting results from its Phase 2 trial of picoplatin in patients with metastatic colorectal cancer (CRC). Picoplatin, given once every four weeks in combination with 5-fluorouracil and leucovorin in the FOLPI regimen, has comparable efficacy to oxaliplatin, given in combination with 5-fluorouracil and leucovorin in the modified FOLFOX-6 regimen, as a first-line therapy for CRC, as assessed by one-year survival rate, progression-free survival (PFS) and disease control. The company claims that, (from the updated proof-of-concept Phase 2 safety and efficacy results) picoplatin could be superior to oxaliplatin as a neuropathy-sparing alternative when used in combination as a first-line treatment for metastatic colorectal cancer.

Source : http://investor.poniard.com/ReleaseDetail.cfm?ReleaseID=424813.

VAL-083 drug compound shows promise against non-small cell lung cancer

We know that, VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused apoptosis.

DelMar Pharmaceuticals, Inc., (OTCQB: DMPI), a clinical-stage oncology company, today announced the presentation of promising new data supporting the activity of its lead drug compound, VAL-083, in the treatment of non-small cell lung cancer (NSCLC) at the AACR's New Horizons in Cancer Research: Harnessing Breakthroughs – Targeting Cures. The conference takes place October 9th to 12th in Pudong, Shanghai.

"The data presented today showed that VAL-083 is superior to cisplatin in both tumor models that are sensitive and resistant to tyrosine kinase inhibitors and has synergistic effect in combination with cisplatin," said Jeffrey Bacha, president and CEO of DelMar Pharmaceuticals. "This data suggests important clinical and market potential of VAL-083 in non-small cell lung cancer."

DelMar's lead clinical compound, VAL-083 (dianhydrogalactitol) is a first-in-class alkylating agent with a novel cytotoxic mechanism distinct from other alkylating agents used in the treatment of cancer.

In historical studies sponsored by the National Cancer Institute in the United States, VAL-083 exhibited clinical activity against a range of tumor types including CNS tumors, solid tumors and hematologic malignancies. VAL-083 is approved in China for the treatment ofchronic myelogenous leukemia (CML) and lung cancer (Approval No. Guoyao Zhunzi H45021133; manufactured by Guangxi Wuzhou Pharmaceutical (Group) Co. Ltd.)

NSCLC is usually treated with either tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) or platinum-based regimens (e.g. cisplatin). TKIs have resulted in vastly improved outcomes for patients with EGFR mutations; however, TKI resistance has emerged as a significant unmet medical need, and long-term prognosis with platinum-based therapies is poor. Compared to other countries, Asian patients with NSCLC have a higher incidence of EGFR mutations (up to 60 percent; compared to 10-20 percent in Western populations) and are more susceptible to TKI resistance.

Additionally, NSCLC patients have a high incidence of brain metastases, which is associated with a poor prognosis. The median overall survival time for patients with stage IV NSCLC is four months, while one-year and five-year survival is less than 16 percent and 2 percent, respectively. VAL-083 can cross the blood-brain barrier and is currently being evaluated in the United States in a Phase 1/2 clinical trial to treat the most common form of brain cancer, glioblastoma multiforme (GBM).

 

VAL-083 drug compound shows promise against non-small cell lung cancer

Triapine with cisplatin a new standard of care for cervical cancer?

In continuation of my update on cancer drug development,   I found this  info interesting to share with. Researchers  lead by Dr. Charles Kunos at the Ireland Cancer Center of University Hospitals (UH)  have found that,  Triapine, (3-aminopyridine-2-carbox -aldehyde   thiosemicarbazone, see structure), which suppresses tumor growth shows a great deal of promise for cervical cancer patients who are at high risk for relapse and cancer-related death. 

The phase I study found that the chemotherapy medicine  Triapine, was well tolerated in combination with standard-of-care cisplatin chemotherapy and radiation treatment in women with cervical cancer. This regimen provided both significant reduction in cancer disease and cancer control.

In the study   (ten-patient study) patients,  were treated three times weekly with Triapine (a potent Ribonucleotide Reductase Inhibitor) in combination with weekly cisplatin treatment and daily pelvic radiation therapy over five weeks.  The researchers claims that  "a 100% complete response rate was observed and no disease progression was documented through 18 months of median follow-up."A phase two follow-up study is ongoing at the Ireland Cancer Center. UH Case Medical Center  Hope this new found combintaton will be  a promising new treatment to help women fight this aggressive disease in the days to come...

Ref : http://clincancerres.aacrjournals.org/content/16/4/1298.abstract?sid=f3df7c2d-9e46-4baf-b47b-83d310b87641

Cisplatin anti-cancer drug binds pervasively to RNA....

In continuation of my update on Cisplatin.....

An anti-cancer drug used extensively in chemotherapy binds pervasively to RNA -- up to 20-fold more than it does to DNA, a surprise finding that suggests new targeting approaches might be useful, according to University of Oregon researchers, lead by Victoria J. DeRose

Ref : http://uonews.uoregon.edu/archive/news-release/2011/11/cancer-drug-cisplatin-found-bind-glue-cellular-rna

Cisplatin plus radiotherapy and HDRB proves beneficial in stage IIIB cervical cancer

In continuation of my update on cis-platin

Cisplatin plus radiotherapy and HDRB proves beneficial in stage IIIB cervical cancer

Oncolytics Biotech's REOLYSIN combined with paclitaxel and carboplatin well tolerated for advanced cancers

In continuation of my follow up on cisplatin derivatives, I find this article interesting to share with.....

Oncolytics Biotech's REOLYSIN combined with paclitaxel and carboplatin well tolerated for advanced cancers