CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose Requirement.

CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose Requirement.

Filed under: Drug and Alcohol Rehabilitation

Ann Rehabil Med. 2012 Dec; 36(6): 857-60
Kim YB, Ko MJ, Lee DG, Do JG, Hwang JH

Warfarin is a frequently prescribed anticoagulant in rehabilitation patients. Adverse drug reactions of warfarin were reported as bleeding and cutaneous microvascular thrombosis. Major bleeding, such as intracranial hemorrhage and psoas hematoma, in patients receiving anticoagulation therapy is a rare condition, but sometimes very serious complication that can even be fatal. Patient-specific factors (eg, age, body size, race, concurrent diseases, and medications) explain some of the individual variability in warfarin dose, but genetic factors, which influence warfarin response, explain a significantly higher proportion of the variability in the dose. There are two identified genes that are responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and VKORC1, which codes for warfarin’s target, vitamin K epoxide reductase. We report a case of intolerance to warfarin dosing, due to impaired drug metabolism in a patient with CYP2C9(*)1/(*)3 and VKORC 1173TT. Fortunately, there are no severe complications.
HubMed – drug

Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer.

Filed under: Drug and Alcohol Rehabilitation

Cancer Med. 2012 Dec; 1(3): 318-27
Haque R, Ahmed SA, Fisher A, Avila CC, Shi J, Guo A, Craig Cheetham T, Schottinger JE

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0-IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ?80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28-0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30-0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36-0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.
HubMed – drug

Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer.

Filed under: Drug and Alcohol Rehabilitation

Cancer Med. 2012 Oct; 1(2): 218-29
Horio M, Kato T, Mii S, Enomoto A, Asai M, Asai N, Murakumo Y, Shibata K, Kikkawa F, Takahashi M

Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.
HubMed – drug

EGFR targeting monoclonal antibody combines with an mTOR inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs.

Filed under: Drug and Alcohol Rehabilitation

Cancer Med. 2012 Oct; 1(2): 114-27
James R, Vishwakarma S, Chivukula IV, Basavaraj C, Melarkode R, Montero E, Nair P

Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, has been used extensively in many solid tumors and confers significant survival advantage. The antibody has limited skin toxicity and is generally well tolerated. Similar to other anti-EGFR therapies, patients may relapse a few months after treatment. In this study we show for the first time, the use of Nimotuzumab along with Sirolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in Nimotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while Sirolimus (25 nmol/L) affects the signal downstream to mammalian target of rapamycin (mTOR), Nimotuzumab (83 nmol/L) downregulates pTYR, pMAPK and pSTAT3 by 40%, 20% and 30%, respectively. The combination, targeting these two different signaling hubs, may be associated with the synergistic inhibition observed. In vivo, the use of half human therapeutic equivalent doses for both the drugs substantially reduces tumors established in nude as well as severe combined immunodeficiency (SCID) mice by EGFR overexpressing A-431 cells. The drug combination reduces cell proliferation and the expression of signal transduction molecules. Treated tumors are better differentiated as compared with those established in the control mice. Tumor microarray demonstrates that Nimotuzumab and the combination groups segregate independently to the Sirolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with Nimotuzumab and Sirolimus downstream pathways inhibition. These results would suggest that this nontoxic drug combination improves therapeutic benefit even in patients with low-EGFR expression and severely immunocompromised because of their current medication.
HubMed – drug

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