Clinical evidence for overcoming capecitabine resistance in a woman with breast cancer terminating in radiologically occult micronodular pseudo-cirrhosis with portal hypertension: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report a case of stage IV breast cancer terminating in an unusual picture of radiologically occult micronodular pseudo-cirrhosis. Contrast-enhanced computed tomography showed no evidence of metastatic breast cancer within the liver. Unlike the few previously reported cases of intrasinusoidal spread of breast cancer, our patient was palliated with a transjugular intrahepatic portosystemic shunt along with salvage chemohormonal therapy. In addition, our patient demonstrated proof of the principle of the dependence of capecitabine (Xeloda) efficacy on dose scheduling as predicted by laboratory studies based on Gompertzian tumor growth and the Norton-Simon hypothesis.</p> <p>Case presentation</p> <p>We report the case of a 52-year-old Caucasian woman who developed radiological signs of portal hypertension without radiological evidence of hepatic metastasis five years after being diagnosed with metastatic breast cancer. She was receiving chemotherapy for stage IV breast cancer initially thought to be metastatic only to the bones. During salvage therapy with high-dose estradiol (Estradiol valerate), vinorelbine (Navelbine) and bevacizumab (Avastin), she suddenly developed signs of portal hypertension confirmed on computed tomography and by portal and systemic venous pressure measurements. Drug toxicity due to bevacizumab (Avastin) was initially and incorrectly entertained as a cause. The patient underwent palliative transjugular intrahepatic portosystemic shunt and transhepatic venous liver biopsy, which revealed the presence of rapidly progressive and uncontrolled metastatic breast cancer. The new discovery of radiologically occult intrasinusodal hepatic metastases with secondary micronodular cirrhosis was found to be the cause of her sudden onset portal hypertension. The patient's resistance to capecitabine (Xeloda) was reversed by changing the schedule of medication to biweekly 7/7 (7 days ingesting drug alternating with 7 days off drug) from the 14/7 (14 days ingesting drug alternating with a 7 day rest period) day schedule approved by the US Food and Drug Administration.</p> <p>Conclusion</p> <p>This case report demonstrates an unusual presentation of radiographically occult hepatic metastasis from breast cancer palliated with transjugular intrahepatic portosystemic shunt. All patients with advanced breast cancer developing unexpected portal hypertension should be considered candidates for liver biopsy despite normal computed tomography of the liver imaging results. This is the first report of a reversal of clinical resistance to capecitabine (Xeloda) by changing from the schedule of 14/7 day to a biweekly 7/7 day schedule. This suggests that a biweekly schedule may be best for some patients.</p

Control of prostate cancer associated with withdrawal of a supplement containing folic acid, L-methyltetrahydrofolate and vitamin B12: a case report

<p>Abstract</p> <p>Introduction</p> <p>This is the first report of possible direct stimulation of hormone-resistant prostate cancer or interference of docetaxel cytotoxicity of prostate cancer in a patient with biochemical relapse of prostatic-specific antigen. This observation is of clinical and metabolic importance, especially at a time when more than 80 countries have fortified food supplies with folic acid and some contemplate further fortification with vitamin B₁₂.</p> <p>Case presentation</p> <p>Our patient is a 71-year-old Caucasian man who had been diagnosed in 1997 with prostate cancer, stage T1c, and Gleason score 3+4 = 7. His primary treatment included intermittent androgen deprivation therapy including leuprolide + bicalutamide + deutasteride, ketoconazole + hydrocortisone, nilandrone and flutamide to resistance defined as biochemical relapse of PSA. While undergoing docetaxel therapy to treat a continually increasing prostate-specific antigen level, withdrawal of 10 daily doses of a supplement containing 500 μg of vitamin B₁₂as cyanocobalamin, as well as 400 μg of folic acid as pteroylglutamic acid and 400 μg of L-5-methyltetrahydrofolate for a combined total of 800 μg of mixed folates, was associated with a return to a normal serum prostatic-specific antigen level.</p> <p>Conclusion</p> <p>This case report illustrates the importance of the effects of supplements containing large amounts of folic acid, L-5-methyltetrahydrofolate, and cyanocobalamin on the metabolism of prostate cancer cells directly and/or B vitamin interference with docetaxel efficacy. Physicians caring for patients with prostate cancer undergoing watchful waiting, hormone therapy, and/or chemotherapy should consider the possible acceleration of tumor growth and/or metastasis and the development of drug resistance associated with supplement ingestion. We describe several pathways of metabolic and epigenetic interactions that could affect the observed changes in serum levels of prostate-specific antigen.</p

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum

BACKGROUND: All flour in the USA is fortified with folic acid at a level of 140 μg/100 g which is estimated to supply an extra 100 μg daily to the average diet. Some researchers have advocated that this be increased to double and even four times this amount. Based on previous research these higher levels are likely to lead to the appearance of unmetabolised vitamin in the circulation, which may have safety implications for sub-groups of the population. The UK and the Republic of Ireland will likely introduce mandatory fortification also in the next year or so. The aim of this study was to capture the short-term effect of folic acid fortification on unmetabolised folic acid in serum after chronic consumption of folic acid. METHODS: After pre-saturation with 400 μg folic acid supplements daily for 14-weeks, healthy folate replete adults (n = 20) consumed folic acid fortified bread, at three different levels (400 μg, 200 μg, 100 μg) over a period of one week each. The dose was administered in two-equal sized slices consumed at 09.00 hrs and 13.00 hrs. Serum samples for total folate and folic acid were collected at baseline, after 14-weeks of supplementation, and pre and post (at 1, 2, 3 and 4 hours) each dose tested. RESULTS: Unmetabolised folic acid was detected after the 14-week supplementation period. Folic acid was not detected in either the 200 μg or 100 μg (current US regime) doses tested but was present at the highest level (400 μg) tested. CONCLUSION: Our findings suggest that persons exposed to the current US fortification programme supplying an average of 100 μg per day or less are unlikely to have unmetabolised folic acid in serum. It also seems that daily consumption of the higher level of 200 μg or less is unlikely to be problematic. Increasing the level however to 400 μg on the other hand is likely to lead to unmetabolised folic acid appearance

Prostate tumor attenuation in the nu/nu murine model due to anti-sarcosine antibodies in folate-targeted liposomes

Herein, we describe the preparation of liposomes with folate-targeting properties for the encapsulation of anti-sarcosine antibodies (antisarAbs@LIP) and sarcosine (sar@LIP). The competitive inhibitory effects of exogenously added folic acid supported the role of folate targeting in liposome internalization. We examined the effects of repeated administration on mice PC-3 xenografts. Sar@LIP treatment significantly increased tumor volume and weight compared to controls treated with empty liposomes. Moreover, antisarAbs@LIP administration exhibited a mild antitumor effect. We also identified differences in gene expression patterns post-treatment. Furthermore, Sar@LIP treatment resulted in decreased amounts of tumor zinc ions and total metallothioneins. Examination of the spatial distribution across the tumor sections revealed a sarcosine-related decline of the MT1X isoform within the marginal regions but an elevation after antisarAbs@LIP administration. Our exploratory results demonstrate the importance of sarcosine as an oncometabolite in PCa. Moreover, we have shown that sarcosine can be a potential target for anticancer strategies in management of PCa