for those running out of options--the latest--from San Antonio

[Lani]

these two drugs are already on the market for treatment of high blood presssure and seizures:

PLoS ONE. 2006 Dec 20;1(1):e98.
A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer.

Arce C,
Perez-Plasencia C,
Gonzalez-Fierro A,
de la Cruz-Hernandez E,
Revilla-Vazquez A,
Chavez-Blanco A,
Trejo-Becerril C,
Perez-Cardenas E,
Taja-Chayeb L,
Bargallo E,
Villarreal P,
Ramirez T,
Vela T,
Candelaria M,
Camargo MF,
Robles E,
Duenas-Gonzalez A.
Division de Investigacion Clinica, Instituto Nacional de Cancerologia INCAN, Mexico City, Mexico.
BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.
PMID: 17183730 [PubMed - as supplied by publisher]

[StephN]

Hi Lani -
a close reading here eveals the operative words

"for Locally Advanced Breast Cancer."

That parameter would leave a LOT of us out.
Correct me if I have misread - but these drugs would not have sent my extensive liver mets into the stratoshpere.

There may come a time when those with distant mets could give this a try.

[Lani]

is because of another article I found here on her2support about the combination of 3 relatively common drugs which was found to markedly decrease the growth of several cancers--I gave this information to a friend in Denmark who had esophageal cancer, whom the Danish health service had just left to die without trying any chemo, immuno or radiation therapy.

Since these drugs are relatively innocuous, a suggestion to one's oncologist couldn't hurt. They would probably look for evidence of adverse drug interactions, check liver and kidney functions in order to estimate a dosage and try a small dose just to see if it might make a difference, hence the suggestion for those running out of options. When there are options, the oncologists would probably be hesitant to try such a ploy.

Will try to retrieve that article on the 3 common drugs to see if it compares with these 2.

Merry Christmas,
Lani

[Lani]

“Unusual three-drug combo inhibits growth of aggressive tumors”

“An experimental anti-cancer regimen combined a diuretic, a Parkinson’s disease medication and a drug ordinarily used to reverse the effect of sedatives. The unusual mixture inhibited the growth of aggressive prostate tumors in laboartory mice in research conducted at Washington University School of Medicine in St. Louis.

Although their drug choices may seem capricious, the researchers weren’t randomy pulling drugs from their shelves. They made their discovery using sophisticated methods for delving into the unique metabolism of cancer cells and then choosing compounds likely to interfere with their growth.

‘This study, led by Joseph Ippolito, a very talented M.D./Ph.D. student, demonstrates the importance of looking at tumor metabolism,’ says senior author Jeffrey I. Gordon, M.D., director of the Center for Genome Sciences at the School of Medicine. ‘Using a broad array of technology, we’ve obtained a view of the tumor cells’ metabolome (the set of small-molecule metabolites found within cells) and revealed aspects that were not expected and could be exploited.’

The findings, published in a recent article in the Proceedings of the National Academy of Sciences, expand upon earlier work by the research group, which demonstrated that aggressive types of neuroendocrine tumors - seen in some types of lung, thyroid and prostate cancers - produce high amounts of a chemical called GABA, a neurotransmitter.

Because of the abundance of GABA in these tumors, the authors previously proposed that the chemical could potentially serve as a marker for poor-prognosis neuroendocrine tumors. But the latest findings also show that the techniques used to decipher the biochemistry of the tumors can effectively be applied to seek drugs that will affect tumor metabolism.

The techniques link DNA microarray technology - which can pinpoint highly active genes in the tumors - to precise measurements of abundant metabolites and their potential byproducts within intact tumor cells using nuclear magnetic resonance (nMR) spectroscopy and mass spectometry. Software programs take this information and provide testable predictions about how these substances might drive the special metabolism of cancerous cells.

Investigating experimental mice that develop metastatic tumors of the prostate’s neuroendocrine cells, the researchers discovered that the tumor cells relied on molecules that transmit signals betweeen neurons. They found that the tumor cellls respond to GABA as well as to two other neurotransmiitters, glycine and glutamate.

‘The question was, “What are these neural signaling molecules doing in tumor cells found outside the central nervous system?”’ says lead author Joseph E. Ippolito.

The reserachers demonstrated that the tumor cells have receptors on their surface that recognize these neurotransmtters and are activated by them. In addition, the tumor cells

[Lani]

directly convert GABA and glutamate into sources of energy. Moreover, glycine was involved in a mechanism that increased the amount of fatty acids - an important source of energy - in the bloodstream of the lab mice.

‘We showed that the neurotramsitters GABA, glycine and gluatate not only stimulate proliferation of the tumor cells, but they also are able secure sources of energy for the cells,’ Ippolito says. ‘In a way, the tumor cells eat their own words.’

‘Having identified a key vulnerability in these aggressive neuroendicrine tumor cells, the researchers looked for a way to exploit it. They selected agents already approved for medical use by the Food and Drug Administration.

Two drugs - amiloride, a diuretic and carbidopa, used to treat Parkinson’s disease - exert their effects by inhibiting the very same mechanisms the research group had identified as important for the tumor cells’ energy-gathering reactions.

They combined these two drugs with a third drug, flumazenil, which is ordinarily used to reverse the effects of sedatives. Flumazenil binds to GABA receptors on the surface of nerve cells, and the researchers theorized that it could also inhibit GABA signaling between tumor cells.

‘We propose that this might be a potential therapeutic regimen for patients with aggressive neuroendocrine tumors,’ says Ippolito. ‘Since the drugs are already FDA approved, they could be more quickly used as experimental therapeutics.’

Examination of gene expression profiles of more than 400 human cancers showed that the genes encoding the enzymes vital to these aggressive neuroendocrine tumors were also expressed at high levels in some non-neuroendocrine cancers. This suggests that the three-drug therapy could work for many kinds of cancers, according to the study authors.

‘This approach is very powerful,’ says Gordon. ‘By combining a variety of experiemental and computational methods that monitor the expression of genes encoding enzymes and their biochemical products, we can explore the metabolism of these cells, looking for unusual pathways that might reveal their potenial vulnerabilities. Then we can see if medications already exist - ones whose mechanism of action is known and whose safety has been established - that can be used to target components of these unusual pathways, test them in animal models of human cancer, and if the results look promising, bring them to the patient’s bedside as part of a carefully controlled clinical trial.’

###

Ippolito JE, Merritt ME, Backhed F, Moulder KL, Mennerick S, Manchester JK, Gammon ST, Piwnica-Worms D, Gordon JI, Linkage between cellular communications, energy utilization and proliferation in metastatic neuroendocrine cancers. Proceedings of the National Academy of Sciences 2006 AUG 15; 103(33):12505-10

[Christine MH-UK]

I know someone whose sister is dying of esophageal cancer, having exhausted all options, so I am interested.

Take care,

Christine

[Lani]

I am unaware if his Danish doctors were even willing to try it. Since they offered him nothing I really can't see what he had to lose...

[Bev]

Isn't this more or less AC? The drugs sound familiar. BB

[Lani]

these are antihypertensive (anti high blood pressure) medications and a mild drug against a mild form of epilepsy.

[Lani]

the doxyrubicin is indeed adriamycin by another name
cyclophosphamide is the C in AC

But the point of this study was the addition of hydralazine and valproate--they just had to add it to AC as all clinical trials must add to what is felt to be an appropriate effective treatment to see if the addition is better. Just as they did not test herceptin by itself, but rather how much improvement there was in survival, time to progression, etc by adding herceptin to chemotherapy.