Personal Authors: Shahrzad, S., Bitsch, I.
Author Affiliation: Institute of Nutritional Sciences, Justus Liebig University, Wilhelm Street 20, D-35392 Giessen, Germany.
Editors: No editors
Document Title: Journal of Chromatography, B. Biomedical Sciences and Applications
Abstract:
Gallic acid occurs naturally in plants and has been found to be pharmacologically active as antioxidant, antimutagenic and anticarcinogenic agent. In this work, the metabolism of gallic acid in the human body was investigated. Two methods were developed for the identification and determination of gallic acid and its phenolic metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography using UV detection and involving isocratic elution. One of these methods enables the simultaneous separation and determination of gallic acid (GA), 4-O-methylgallic acid (4OMGA), pyrogallol (PY), 2-O-methylpyrogallol (2OMPY) and resorcinol (RE) in biological fluids. This method is of interest because it allows the separation of a large number of phenolic compounds by isocratic elution using a solution of 4.4.10-3M phosphoric acid in water as mobile phase. The analysis time for this method, however, is not optimal (57 min). After oral administration of 50 mg GA, 4OMGA rapidly appeared in the plasma and urine besides unchanged GA. Other phenolic compounds, PY, 2OMPY and RE, were not detected. The second method was developed to determine GA and 4OMGA with a short analysis time (25 min).
Publisher: Elsevier Science B.V.
TLS (Tumour Lysis Syndrome)
DCA-Drug Interactions
DCA and Caffeine
DCA and Chemotherapy
What is the status of DCA clinical trials?
Can I take DCA on my own?
Do I qualify for DCA treatment?
Is it available?
What is the cost?
What is the duration of treatment?
I don’t live near Toronto, can I still be treated?
How do I become a Medicor DCA patient?
Press articles about DCA
Gallic Acid Background
Gallic acid
| Gallic acid | |
|---|---|
 |
 |
| IUPAC name | |
| Other names | Gallic acid |
| Identifiers | |
| CAS number | [149-91-7] (Anhydrous) [5995-86-8] (Monohydrate) |
| SMILES | |
| Properties | |
| Molecular formula | C7H6O5 |
| Molar mass | 170.12 g/mol |
| Appearance | White, yellowish-white, or pale fawn-colored crystals. |
| Density | 1.7 g/cm3 (anhydrous) |
| Melting point | 250 °C, 523 K, 482 °F |
| Solubility in water | 1.1g/100ml water @ 20°C (anhydrous) 1.5g/100ml water @ 20°C (monohydrate) |
| Acidity (pKa) | COOH: 4.5, OH: 10. |
| Hazards | |
| MSDS | External MSDS |
| Main hazards | Irritant |
| Related compounds | |
| Related compounds | Benzoic acid, Phenol, Pyrogallol |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references |
|
Gallic acid is an organic acid, also known as 3,4,5-trihydroxybenzoic acid, found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and other plants.[1] The chemical formula is C6H2(OH)3COOH. Gallic acid is found both free and as part of tannins. Salts and esters of gallic acid are termed gallates. Despite its name, it does not contain gallium.
“Gallic acid seems to have anti-fungal and anti-viral properties. Gallic acid acts as a antioxidant and helps to protect our cells against oxidative damage. Gallic acid was found to show cytotoxicity against cancer cells, without harming healthy cells. Gallic acid is used a remote astringent in cases of internal haemorrhage. Gallic acid is also used to treat albuminuria and diabetes. Some ointment to treat psoriasis and external haemorrhoids contain gallic acid.”[2]
References
- ^ LD Reynolds and NG Wilson, “Scribes and Scholars” 3rd Ed. Oxford: 1991. pp193–4.
- phytochemicals.info
[edit] External links
DCA (dichloroacetate) is a drug that was recently found to induce the death of human breast, lung and brain cancer cells that were implanted into rats, while being non-toxic to healthy cells. This research was published in Cancer Cell, 11, 37–51, January 2007. DCA has been found to kill cancer cells by a newly discovered mechanism that appears to be common to several types of cancer. DCA works by turning on the natural cell suicide system which is suppressed in cancerous cells, thus allowing them to die on their own. No formal research has yet been done to determine if it will work on cancer within the human body.
Is DCA safe?
DCA has been used in humans to treat a rare disease called “congenital lactic acidosis”, and found to have some mild to moderate side effects. Our experience so far suggests that DCA is safe to use in cancer patients under close medical supervision.
Some animal studies show that DCA can itself cause liver cancer. These studies used doses which are over 1000 times higher than what would be prescribed for cancer treatment.
We think that DCA can have 2 main categories of side effects:
Neurological:
Nerve injury in the hands and feet (“peripheral neuropathy”). Neuropathy typically takes several weeks to months to develop, and is reversible if it is caught early. In the existing literature, neuropathy from DCA appears to be age-related. We use vitamin B1 (benfotiamine or thiamine) and R(+) alpha lipoic acid to prevent and reduce the severity of peripheral neuropathy.
Sedation, confusion, hallucinations, memory problems, hand tremors. These side effects appear to be dose-dependent, and age-dependent which is consistent with existing human research on DCA that we have reviewed.
We use sustained release R(+) alpha lipoic acid to prevent/reduce these side effects. Patient feedback suggests that this supplement is effective. If you are a Medicor patient, you will receive our latest dosing guidelines for benfotiamine and alpha lipoic acid.
Gastrointestinal:
Heartburn, nausea, vomiting, indigestion. These side effects may occur with DCA, and we routinely prescribe a proton pump inhibitor (e.g. pantoprazole) to prevent them.
Other Side Effects:
Some patients experience pain at the sites of their tumour(s) within the first few days of starting DCA. This may be an indicator of the effectiveness of DCA.
Most side effects reported so far have been mild or moderate. Patients experiencing moderate side effects are usually taken off DCA as a precaution. Most side effects typically resolve within days after stopping DCA. Neuropathy can take weeks or months to improve.
TLS (Tumour Lysis Syndrome)
This is a condition in which a large number of tumour cells are rapidly killed, causing a sudden release of the contents of the dead cells into the bloodstream. It can result in abnormal heart rhythms, and kidney failure. A detailed reference article can be found here. TLS occurs most commonly in patients with a large mass of tumour cells in the body who receive chemotherapy, especially with lymphomas or acute leukemia. We have not had a single case of TLS in over 260 patients treated with DCA alone. Since DCA can enhance the effect of chemotherapy in certain cases, it may be more likely to occur if DCA is combined with chemotherapy (especially without medical supervision).
DCA-Drug Interactions
We have observed that drugs that can cause confusion or hallucinations have a potential to interact with DCA. This may include cannabinoids, benzodiazepines and other CNS drugs. Patients should be given a specific medical advice.
All patients who receive DCA shall be closely monitored for drug side effects with routine check-ups, comprehensive lab tests, and imaging studies. A patients’ general condition, other medications, past medical history, and concurrent health problems shall be taken into account.
DCA and Caffeine
We have received a large number of inquiries about caffeine following some anecdotal reports of enhanced DCA effect with excessive tea/caffeine intake. After conducting a limited review of our DCA patients, we have noted that patients who have shown an excellent response to DCA do not take tea/coffee or caffeine or take it in minimal amounts (1-3 cups a day). Also a few patients with high tea/caffeine consumption (5- 10 cups per day) have shown no response to DCA.
There are a number of potential harmful effects of starting high dose caffeine including increased likelihood of seizures in brain tumour patients, abnormal heart rhythms, anxiety, and insomnia. The theory behind the potential benefit of caffeine + DCA is unconfirmed so we are taking a cautious approach for now. Medicor is presently recommending to most of their DCA patients who are thinking of starting high dose caffeine to use moderation and to check with your own doctor, naturopath or dietician for specific advice.
DCA and Chemotherapy
Until now, there has been no scientific evidence to support the use of DCA along with chemotherapy.
Medicor already had some exciting results showing that DCA can, in some cases, dramatically enhance the cancer-killing effects of chemo. However, there is a possibility that DCA can antagonize chemo as well. This is similar to single agent chemo being better than combination chemo for some patients. If you are a patient who is thinking of combining DCA and chemotherapy, we recommend you discuss the test with your oncologist. We also have more detailed information for physicians here.
Malignant ascites fluid samples and malignant pleural effusion samples can now be tested with ChemoFit, eliminating the need for a biopsy in some patients.
What is the status of DCA clinical trials?
Two DCA clinical trials have begun in Alberta. One will examine the effects of DCA on a type of brain tumour (50 patients), and the other will look at patients with various cancers (35 patients). If you are in the Edmonton area, we recommend you consider enrolling in one of the clinical trials. We have no further information about these trials.
Even though we have seen conclusive evidence of DCA’s effectiveness in various cancers, Medicor believes that it is essential for DCA clinical trials to be conducted. DCA is different from other drugs that undergo clinical trials because it is not a “new” drug. It has already been used for decades in humans, and has a relatively safe profile.
This means that the trials may take less time, but may still take years. Many cancer patients cannot wait this length of time. We are hopeful that information obtained from our experiences with DCA will supplement clinical trials, and help patients and the medical community.
Can I take DCA on my own?
We are aware of many patients who are currently self-medicating with DCA. Due to the complexity of cancer and its treatment, we recommend DCA to be taken only under medical supervision.
We respect the patient’s right to choose their treatment once they know all the potential risks and benefits. All of DCA patients understand that DCA is not yet scientifically proven as a cancer treatment.
Is DCA available?
Yes, but there can be different regulations in your country. You bear a risk of importing DCA.
What is the duration of treatment?
In order to determine if DCA is effective in treating your cancer, Medicor recommends at least one month of treatment. If your cancer responds to the drug, therapy may continue indefinitely. If you experience significant side effects, treatment will be stopped and may be restarted later.
Case Study 2: Melanoma with Brain Metastases
History
A 55 year old male attended the clinic seeking treatment for melanoma with brain metastases. It was diagnosed 2 years previously (changing pigmented lesion on the shoulder). This was treated surgically with excision and sentinel node dissection. One of 2 sentinel nodes contained metastatic melanoma. Surgery was followed by standard immunotherapy using interferon alpha for 1 year.
Five months prior to seeing us, the patient developed a solitary left frontal brain metastasis which was treated successfully with stereotactic radiation (Gamma Knife). Just prior to seeing us, the patient was diagnosed with recurrent multiple brain metastases on routine CT scan of the head. MRI 2 weeks prior to seeing us showed 4 brain lesions (see below). CT of the chest also showed over 100 lung lesions. He was offered whole brain radiation, but declined and started Temodal chemotherapy instead. This was stopped prior to completion of 1 cycle due to side effects.
The patient was otherwise healthy aside from hypertension. He was taking some natural supplements including IP6, omega 3,6,9 and Flor-Essence, but no other treatment medications. He had no neurological symptoms.
Findings
Body weight was 94kg. Physical examination revealed high blood pressure. There were no neurological findings. The rest of the examination was normal. Brain MRI report from 2 weeks previous to the first visit with us revealed 4 small brain metastases (see Fig. 2A)
Figure 2A
Treatment
We elected to try a combination of DCA + TM. The patient was started on DCA 27mg/kg/day (2500mg daily divided b.i.d) on a 2 week on / 1 week off cycle + TM 20mg p.o. six times daily. Pre-treatment ceruloplasmin was 310mg/L, and other blood tests were normal. The patient agreed to follow a copper-reduced diet (no liver or shellfish, copper-free bottled water).
The patient did not have any immediate side effects from DCA or TM. A repeat MRI was planned for 6 weeks into treatment to assess response, but the hospital had a cancellation and moved up the MRI (we were not aware of this otherwise we would have deferred it by about 1 month). It was unchanged, confirming at least 4 brain metastases (Fig. 2B).
Figure 2B
Figure 2C – a right occipital metastasis (arrow)
Figure 2D – left frontal metastasis (top arrow) and a right occipital metatstsis (bottom arrow)
DCA and TM were continued, and copper deficiency in the target range of 20-30% of normal was achieved by 6 weeks with mild neutropenia. TM was adjusted to maintain a ceruloplasmin of 90-100mg/L. The patient was able to maintain normal hemoglobin and a neutrophil count which varied between normal and slightly low using an average TM dose of 20mg t.i.d.
After 3 months of DCA + TM, the patient began to develop some numbness in the toes and fingers bilaterally. We presumed this was early DCA neuropathy. Since the patient was feeling generally well (no other new neurological symptoms to suggest growth of brain tumours), we stopped the DCA as a precaution. Nerve conduction testing was not done at the time as it was not required. TM was continued and copper deficiency was successfully maintained. The only other symptom noted was mild fatigue.
After a further 5 months (total 8 months of TM treatment), brain MRI was repeated. This revealed resolution of all metastases except 1 which was smaller then the previous scan (Fig. 2C). The numbness of the fingers and toes was nearly resolved at that point.
Figure 2E
Figure 2F - right occipital metastasis that was visible on last MRI (see arrow Fig. 2C) is no longer seen
Figure 2G – left frontal metastasis was 7mm on last MRI (Fig. 2D), now 5mm with no surrounding edema
The patient continues to do well on TM alone after a total of 11 months of treatment with no neurological or respiratory symptoms to suggest growth of brain or pulmonary metastases. The patient experiences a moderate amount of fatigue. Follow-up chest CT and brain MRI is planned.
Comments
In this case, we used a combination treatment of DCA and TM. We had experience with both DCA and TM separately and chose to combine them to optimal benefit. Since both medications are quite safe, work by different mechanisms (which could enhance the effect of each other and would likely have no interaction) and have been shown to be effective in other types of cancers, it was felt to be a good choice for this patient. The patient decided to try this combination after a detailed discussion of the various aspects of treatment.
This case illustrates an excellent response of melanoma to a combination of DCA and TM. In the absence of other active treatment, it appears that DCA contributed to the tumour shrinkage as evidenced by the post-treatment scans. DCA treatment was stopped because of side effects. Since TM was being given concurrently and seemed to be having the desirable effect of tumour stabilization, DCA was not restarted.
This case also illustrates the potential for “long-term” benefits of TM (approaching 1 year in this case, with no sign of deterioration). It may be possible to transform metastatic cancer from a fatal disease to a chronic disease with this medication, provided the body continues to tolerate long-term copper deficiency. One theory is that cancer which responds well to TM cannot become resistant since one of the raw materials essential for growth (copper) is deficient. This is different from standard receptor-blocking angiogenesis inhibitors which cancers eventually become resistant to.
We believe that DCA and TM in contributed to tumour shrinkage and tumour stabilization respectively in this case. Once DCA was stopped due to side effects, TM continued to stabilize the tumour potentially eliminating the need for continued DCA treatment. As long as the patients’ condition remains unchanged, we plan to continue this regimen with ongoing monitoring.
Sundaram Jagan, Gopalakrishnan Ramakrishnan, Pandi Anandakumar, Sattu Kamaraj, Thiruvengadam Devaki. Antiproliferative potential of gallic acid against diethylnitrosamine-induced rat hepatocellular carcinoma.Molecular and cellular biochemistry. 2008 Dec;319(1-2): 51-9
One of the focuses in current cancer chemoprevention studies is the search for nontoxic chemopreventive agents that inhibit the initiation of malignant transformation. Cancer biomarkers are quantifiable molecules involved in the physiologic or pathologic events occurring between exposure to carcinogens and the development, progression of cancer. Biomarkers may be the consequence of a continuous process, such as increased cell mass, or a discrete event, such as genetic mutation. Analysis of tumor markers can be used as an indicator of tumor response to therapy. Gallic acid is a naturally available polyphenol, possess strong antioxidant activity with a capacity to inhibit the formation of tumors in several cancer models. In the present study, we investigated the antiproliferative effect of gallic acid during diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in male wistar albino rats. DEN treatment resulted in increased levels of aspartatetransaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, 5′-nucleotidase, bilirubin, alpha-fetoprotein, carcinoembryonic antigen, argyophillic nucleolar organizing regions, and proliferating cell nuclear antigen. Gallic acid treatment significantly attenuated these alterations and decreased the levels of AgNORs and PCNA. These finding suggests that gallic acid is a potent antiproliferative agent against DEN-induced HCC.
For the first time in the world, on December 7, 2007 Medicor Cancer Centres Inc publicly shared its observational data from the treatment of 118 cancer patients with DCA. In March 2008 we updated its data from treating over 175 patients.
As of August 2008, Medicor Cancer Centres has treated over 265 cancer patients with DCA.
Results of the analysis of our latest data are very similar to their two earlier reports.
They continue to see responses to DCA treatment in a variety of cancers including but not limited to lung, brain, colon, breast, ovary and pancreas. While they cannot comment on the cancer- specific response rates with confidence due to the relatively low numbers, their overall positive response rate continues to be between 60 – 70%. A positive response can be in the form of tumour shrinkage, cancer marker reduction, blood test improvement, symptomatic improvement, disease stabilization or a combination of any of these. In 30 – 40% of their patients they have not seen a response to treatment which is similar to our previous experience. This group includes patients whose disease progresses in spite of DCA treatment as well as patients where they are uncertain of the response to DCA treatment. Note that their reported response rate is not directly comparable to published response rates for chemotherapy and other standard cancer treatments.
Due to the consistently similar results of their latest analyses to the previous updates in December 2007 and March 2008, they presented some case reports of their therapies instead of a complete observational data update. If their data starts to show significant differences from their last update, they will post their new findings.
The case reports presented here are not necessarily chosen based on the best responses to treatment but are a mix of their earlier experiences, variation in responses and tumor types, and combination therapies.
The purpose of sharing these case reports on our website is to reach as wide an audience as possible with the hope that it may give support and encouragement to other cancer patients and health care providers everywhere. These case reports are for information only and should not be used as a guide to self medicate. We plan to update these with new cases regularly.
History A 44 year old male came for consultation regarding treatment of glioblastoma multiforme (brain tumour). He had been diagnosed by MRI 4 months previously when he developed numbness of the left side of his face and left hand. The tumour was located in the right thalamus expanding towards the brainstem and hippocampus. A needle biopsy was obtained, showing grade IV astrocytoma (also called “glioblastoma multiforme”). Due to the location of the tumour deep within the brain, it was considered inoperable. The patient was treated with steroids, 60Gy of radiotherapy and Temodal chemotherapy 140mg daily. There was initial improvement, but the cancer then began to progress again. The patient was offered further chemotherapy with a different Temodal regimen, but he declined due to low success with that drug previously. Past health problems included depression, non-specific muscle aches and joint pains and prostatitis. Surgical history included appendectomy and recent brain biopsy. There was a significant history of heart disease in the patient’s family, but no cancer. The patient smoked for 8 years, but quit 7 years previously. Alcohol consumption was 2-3 standard drinks per week. Medications at the time of consultation were Oxycontin 20mg p.o. b.i.d. for headache, Lyrica 150mg p.o. b.i.d. for tumour pain, lactulose as needed for constipation, Maxeran 10mg as needed for nausea, and Cipralex for depression. Dexamethasone had been stopped after radiation. The patient had no allergies. Significant symptoms included intermittent vomiting, intermittent constipation, dizziness, headaches, numbness of the left arm, stiffness of both arms, and a pressure feeling of the posterior neck. Findings Examination revealed a healthy-looking male in no distress with normal vital signs and a weight of 69kg. There was mild hyperesthesia of the left side of the body including the left arm and leg. There was also a mild sensory deficit of the left arm, with mild impairment of coordination and mild reduction of power. Cranial nerves were normal. Mental status was normal. Speech was normal. General examination of other systems was normal. Treatment The patient wished to have aggressive treatment so we decided to start a combination of DCA and TM. He was started with DCA 29mg/kg/day (1000mg p.o. b.i.d) on a 2 week on / 1 week off cycle. The initial TM dose was 20mg 6 times a day. He was supplemented with zinc acetate 50mg p.o. t.i.d., vitamin B1 100mg p.o. t.i.d., and R+SR alpha lipoic acid 150mg p.o. t.i.d. He was also started on Nexium 20mg p.o. q.d. to prevent GI upset. The patient was also started back on low dose dexamethasone intermittently (2mg daily only if needed) to control vomiting. Initial ceruloplasmin was 347mg/L, hemoglobin was 135g/L and white cell count was 3.0 (ANC 1.84). The patient developed some increase in numbness after 2 months of therapy, so the dose was reduced to 500mg p.o. t.i.d. (25mg/kg/day) as a precaution. Nerve conduction testing was recommended, but the patient’s specialist did not arrange the test. Copper deficiency was achieved with TM and zinc. Due to a delay in getting the blood test results, the ceruloplasmin went as low as 60mg/L, and resulted in significant anemia and neutropenia. The patients developed pneumonia requiring hospitalization and i.v. antibiotics. TM treatment was interrupted to allow the white cell count to come back up. Fortunately he quickly recovered as soon as the neutrophil count improved. Ceruloplasmin in the range of 110 to 130mg/L was subsequently maintained with some difficulty (ceruloplasmin target was < 105mg/L but could not be maintained due to recurrent neutropenia). Zinc acetate was stopped due to copper lowering which was too rapid to allow fine adjustment given the delay in receiving blood results. The patient experienced stabilization of his cancer-related symptoms, and stopped the dexamethasone. The pre-treatment MRI images were not readily available (the patient was not from Canada) and the translated MRI report did not specify tumour size. After 4 months of DCA/TM treatment a brain MRI was done. The tumour was measured to be 34.4mm x 29.6mm in the largest dimensions: The patient continued DCA/TM with no serious side effects. After about 7 months of DCA/TM treatment the tumour had reduced in size to 31.5 x 25.9 mm in the largest dimensions on MRI: The patient wished to add curcumin at approximately 8 months into treatment. Curcumin 500mg (from A.O.R.) 1 capsule t.i.d. was started. After about 10 months of DCA/TM treatment the tumour had reduced in size to 26.7 x 25.1 mm in the largest dimensions The patient is presently feeling well, pain is controlled, and he is leading an active life. He experiences occasional bouts of depression. Nerve conduction studies are planned for routine monitoring, and DCA/TM treatment is ongoing. Comments This patient represents the longest duration of DCA treatment for our clinic to date (nearly 1 year). We are not clear if this patient developed mild neuropathy, or had a temporary worsening of numbness caused by his cancer. With glioblastoma being one of the most aggressive brain cancers in adults, it is remarkable that this patient is experiencing prolonged and increasing improvement with DCA and TM. The role of angiogenesis inhibiting drugs (like Avastin) in the treatment of glioblastoma is now being recognized. This case supports the principle of using angiogenesis inhibiting treatment for glioblastoma (using TM). This case also demonstrates the critical role of ongoing monitoring. While these medications are relatively safe, monitoring and adjustment of dosage, side effects and blood tests cannot be over emphasized. In this case, the tumour was quite big to start with, has not completely regressed but continues to shrink with ongoing DCA treatment. In addition the side effects are mild and tolerable. These findings are in contrast to case 2 above where DCA treatment has been discontinued because majority of the small metastasized tumors have regressed and intolerable side effects. In both this case and case 2, the benefits of TM in tumour stabilization are very encouraging. This patient has shown us that, once again, it may be possible to transform aggressive cancer from a fatal disease to a chronic disease with simple medications like DCA and/or TM.
History
A 67 year old male was referred to us for palliative management of right-sided pleural mesothelioma with thoracic and abdominal metastases. Other than a history of hypertension, the patient was previously well.
Symptoms included cough, exertional dyspnea, constipation (small bowel movements every 2-3 days), abdominal bloating, and frequent burping. Pain assessment revealed constant right-sided dull aching chest pain, intensity 4-5/10, and generalized intermittent, crampy abdominal pain, intensity 5/10.
Medications included hydromorphone syrup 0.3mg p.o. q.i.d., docusate sodium, lactulose, ramipril, folic acid, and salbutamol inhaler.
Findings
Examination revealed decreased right chest expansion with dullness and reduced air entry over the entire right lung field, tympanic abdomen with marked distention, and increased bowel sounds. Neurological exam was normal. There was a large right axillary node. There were cutaneous metastases on the right chest. Body weight was 72kg. Blood urea was 10.7 mmol/L and creatinine was 130 umol/L.
Abdominal CT showed ascites and peritoneal metastases, with compression of the colon in the region of the splenic flexure and proximal dilatation (Fig. 1A).
Figure 1A – dilated transverse colon, full of air (red arrow), hepatic flexure and right colon backed up with stool (yellow arrows), collapsed left colon after splenic flexure (green arrow)
Our assessment of the clinical condition was of incomplete large bowel obstruction, and mild renal failure.
Treatment
The patient was started on DCA 14mg/kg/day (500mg p.o. b.i.d.), supplemented with vitamin B1 300mg p.o. t.i.d. to prevent peripheral neuropathy. He was also started on pantoprazole 40mg p.o. q.d. to prevent GI upset. There was no improvement in pain, or abdominal distension. The patient remained constipated and developed intermittent vomiting. High enemas and increased oral laxative were ineffective. Gastroenterology was consulted regarding insertion of a bowel stent, but they felt the risk of bowel perforation would be high.
After 10 days, we felt there was no benefit so the DCA was increased to 21mg/kg/d (500mg p.o. t.i.d.). Hydromorphone PCA (patient controlled analgesia) was started for pain control at 0.2mg/hr s.c. with patient-controlled bolus does.
After 1 week of DCA at 21mg/kg/d, the patient remained nauseated, constipated, and also developed bilateral leg edema. Abdominal distention persisted. Albumin was 24 g/L, creatinine remained high at 135 umol/L, urea at 10.7 mmol/L. The disease was felt to be worsening and there were no DCA side effects, so the DCA was increased to 42mg/kg/d (1000mg p.o. t.i.d.) in a final attempt to halt tumour progression.
Within 3 days of this increase, there was a marked improvement in appetite and energy level. By 5 days following the dose increase, there was marked reduction in abdominal distention and pain. Several large bowel movements occurred for the fist time in weeks, and leg swelling resolved. The pain level decreased to the point that the patient experienced a relative overdose of hydromorphone, so the infusion was stopped. Renal function was normalized (urea 6.0, creatinine 101).
DCA was then stopped due to development of confusion, agitation and tremors. These side effects resolved within 4 days. After 20 days off DCA, there was clinical evidence of disease progression, and no lingering DCA side effects. A 1 day trial of DCA 500mg p.o. b.i.d. was associated with mild memory problems, so it was stopped. The right axillary tumour was measured to be 3.5 x 5.5 cm.
After another 2 weeks without DCA, the axillary tumour had grown to 4.2 x 6.0cm. At that time, DCA was re-started at 38mg/kg/d with R alpha lipoic acid (to reduce CNS side effects). After 5 days of DCA, the axillary tumour had shrunk to 3.6 x 5.5 cm. DCA had to be stopped again because of mild delirium. It was not restarted.
Then patient’s disease progressed and several weeks later he died due to complications of the cancer.
Comments
This case illustrates one of our earliest experiences with DCA treatment. With our limited experience at that time we felt it was safer to start with a low dose of DCA. Since the condition of the patient was quite advanced, the dose of DCA had to be adjusted quite rapidly and monitored closely. While the lower doses of DCA had almost no effect, a higher dose resulted in quick symptomatic improvement suggesting a response to treatment, and illustrating effectiveness of high dose DCA in a case of mesothelioma. We believe the DCA was responsible for clearing this patient’s bowel obstruction and improving his renal function, since his cancer was constantly progressing prior to DCA and he was not taking any other treatment medications at the time.
DCA also contributed to measurable shrinkage of the axillary tumour. While this showed the effectiveness of DCA, in this particular case it did not have much overall clinical benefit for the patient at his advanced stage.
The side effects were a limiting factor at this higher dose. We noticed side effects of confusion and hallucinations, which resolved in a few days after stopping DCA. We continue to notice these side effects in some of our other patients. They typically resolve within a few days of stopping DCA treatment.
With our experience we now are aware of the benefits of adding R alpha lipoic acid in reducing the CNS side effects. In this case it appears that R alpha lipoic acid was helpful in reducing the DCA-related side effects of confusion/hallucination. It could not however, eliminate the side effects for continued treatment with DCA.
Komal Raina, Subapriya Rajamanickam, Gagan Deep, Meenakshi Singh, Rajesh Agarwal, Chapla Agarwal. Molecular cancer therapeutics. 2008 May;7(5): 1258-67
Abstract
Our recent studies have identified gallic acid as one of the major constituents of grape seed extract showing strong in vitro anticancer efficacy against human prostate cancer cells. Herein, for the first time, we established the in vivo chemopreventive efficacy of gallic acid against prostate cancer by evaluating its activity against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. At 4 weeks of age, male TRAMP mice were fed with drinking water supplemented with 0.3% and 1% (w/v) gallic acid until 24 weeks of age. Positive control group was fed with regular drinking water for the same period. Our results showed that gallic acid-fed groups had a higher incidence of differentiated lower-grade prostatic tumorsat the expense of strong decrease ( approximately 60%; P < 0.01) in poorly differentiated tumors. Immunohistochemical analysis of prostate tissue showed a decrease in proliferative index by 36% to 41% (P < 0.05) in 0.3% to 1% gallic acid-fed groups, with an increase in the apoptotic cells by 3-fold (P < 0.05). Further, both doses of gallic acid completely diminished the expression of Cdc2 in the prostatic tissue together with strong decrease in the expression of Cdk2, Cdk4, and Cdk6. The protein levels of cyclin B1 and E were also decreased by gallic acid feeding. Together, for the first time, we identified that oral gallic acid feeding inhibitsprostate cancer growth and progression to advanced-stage adenocarcinoma in TRAMP mice via a strong suppression of cell cycle progression and cell proliferation and an increase in apoptosis.
