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A unique insertion of low complexity amino acid sequence underlies protein-protein interaction in human malaria parasite orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase

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Asian Pacific Journal of Tropical Medicine 2014年第3期7卷 184-192页

作者： Waranya Imprasittichai Sittiruk Roytrakul Sudaratana R.Krungkrai Jcrapan Krungkrai Department of Biochemistry.Faculty of Medicine.Chulalongkorn University National Center for Genetic Engineering and Biotechnology Unit of Biochemistry.Department of Medical Science.Faculty of Science Rangsit University

Objective:To investigate the multienzyine complex formation of human malaria parasite Plasmodium falciparum[***)orotate phosphoribosyltransferase(OPRT)and orotidine5'-monophosphate decarboxylase(OMPDC),the fifth and sixth enzyme of the de novo pyrimidine biosynthetic ***,we have clearly established that the two enzymes in the malaria parasite exist physically as a heterotetrameric(OPRT)_2(OMPDG)_2 complex containing two subunits each of OPRT and *** that the complex have catalytic kinetic advantages over the monofunetional ***:Both enzymes were cloned and expressed as recombinant *** protein-protein interaction in the enzyme complex was identified using bifunctionul chemical cross-linker,liquid chromatography-mass spectrometric analysis and homology modeling,Results:The unique insertions of low complexity region at the a 2 and a 5 helices of the parasite OMPDC,characterized by single amino acid repeat sequence which was not found in homologous proteins from other organisms,was located on the OPRT-OMPDC *** structural models for the protein-prolein interaction of the helerotetrameric(OPRT)_2(OMPDC)_2multienzyme complex were ***:Based on the proteomic data and structural modeling,it is surmised that the human malaria parasite low complexity region is responsible for the OPRT-OMPDC *** structural complex of the parasite enzymes,thus,represents an efficient functional kinetic advantage,which in line with co-localization principles of evolutional origin,and allosteric control in protein-protein-interactions.

关键词： Malaria Plasmodium falciparum Pyrimidine biosynthesis orotate phosphoribosyltransferase Orotidine 5’-monophosphate decarboxylase Multienzyme complex Proteomics

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Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin orotate

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Journal of Cancer Therapy 2014年第5期5卷 427-441页

作者： Rashida A. Karmali Yulia Maxuitenko Greg Gorman Pharmaceutical Sciences Research Institute Samford University Birmingham USA SavviPharm Inc. and Tactical Therapeutics Inc. New York USA

Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardiomyopathy leading to congestive heart failure. While decreases in cardiotoxicity have been reported with liposomal doxorubicin, the long-term cardiac effects are not known. orotate salts of cytotoxic drugs have been shown to confer antitumor effects with a better safety profile than unconverted drug, and therefore may offer an improved approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt (DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O and liposomal doxorubicin formulations to determine DOX concentration in liver and heart;and to evaluate their effect on body weight. Non-tumored female, athymic NCr-nu/nu mice were treated with daunorubicin and daunorubicin orotate to evaluate tolerance. Results: DOX and DOX-O exhibited significant, similar levels of antitumor activity. Mice treated with DOX-O had a lower percentage body weight loss. In the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal doxorubicin was associated with the lowest percentage of body weight loss, but the highest concentration of DOX in heart. In daunorubicin tolerance experiments, animals showed a better tolerance for daunorubicin orotate as measured by a smaller percentage change in body weight. Conclusions: DOX-O is effective as an antitumor therapy and may offer a less toxic alternative to DOX for maintaining therapy. The lower percentage of body weight loss in animals treated with DOX-O and daunorubicin orotate is a measure of improved tolerance and may translate into better patient outcomes.

关键词： Safer Toxicity Profile Doxorubicin orotate

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Treatment with Paclitaxel orotate and Carboxyamidotriazole orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts

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Journal of Cancer Therapy 2013年第4期4卷 857-871页

作者： Rashida A. Karmali Yulia Maxuitenko Greg Gorman Cancer Therapeutics and Immunology Department Southern Research Institute Birmingham USA Pharmaceutical Sciences Research Institute Samford University Birmingham USA SavviPharm Inc. and Tactical Therapeutics Inc. New York USA

Background: Paclitaxel (PTX) is approved for the treatment of refractory ovarian cancer and breast cancer, but is problematic due to severe, dose-dependent, potentially irreversible neurotoxicity. Alternative formulations using nanoparticles and liposomes have been developed to avoid solvent-related toxicity. These formulations allow improved delivery;however, toxicity, compensatory signaling, and drug resistance still pose challenges. Conversion of cytotoxic agents to their orotate compounds offers a potentially improved approach by increasing bioavailability and reducing toxicity. orotate salts are neutral and acquire lipophilic properties, easing diffusion through lipid membranes. The orotate salt of PTX (PTXO) may yield an improved safety profile. Combination therapy with cytotoxic drugs, antiangiogenics and/or signal transduction pathway inhibitors has shown better efficacy than cytotoxic monotherapy. The combination of carboxyamidotriazole orotate (CTO, a calcium signal transduction pathway inhibitor) and PTX may be more effective than PTX alone at non-toxic doses. Materials and Methods: PTXO alone, and combinations of CTO with PTX and PTXO were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combinations. The tolerated combinations, PTX monotherapy, and PTXO monotherapy were then tested to evaluate their antitumor activity in female athymic NCr-nu/nu mice with subcutaneously implanted OVCAR-5 human ovarian tumor. Antitumor activity was measured by median time to doubling, median tumor growth delay, and mean percent body weight loss. Results: CTO, PTX, and PTXO showed significant inhibition of growth of the human OVCAR-5 ovarian tumor xenografts. The combination of low PTX and CTO, or high PTXO monotherapy, had significant efficacy and it was less toxic than high PTX as measured by body weight loss. Conclusions: Low-dose CTO is effective and has low toxicity, suggesting the potential for maintenance therapy for ovarian cancer. PTXO o

关键词： Paclitaxel orotate Paclitaxel Carboxyamidotriazole orotate Ovarian Cancer

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A predictive factor for the response to S-1 plus cisplatin in gastric cancer

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World Journal of Gastroenterology 2010年第36期16卷 4575-4582页

作者： Ikuko Miyazaki Takashi Kawai Youji Harada Fuminori Moriyasu Department of Gastroenterology and Hepatology Tokyo Medical University Hospital6-7-1 Nishi-ShinjukuShinjuku-kuTokyo 160-0023Japan Endoscope Center Tokyo Medical University Hospital6-7-1 Nishi-ShinjukuShinjuku-kuTokyo 160-0023Japan Department of Gastroenterology Toda Chuo General Hospital1-19-3 HonchoToda-shiSaitama 335-1132Japan

AIM:To prove that the protein expression level of thymidylate synthase is a predictive factor for the response to S-1/cisplatin(CDDP)chemotherapy in gastric ***:We measured the protein expression levels of thymidylate synthase(TS),dihydropyrimidine dehydrogenase(DPD),and orotate phosphoribosyltrans-ferase(OPRT)in advanced gastric *** S-1/CDDP chemotherapy,tumor specimens from primary sites were obtained by endoscopic biopsy and analyzed by enzyme-linked immunosorbent *** chemo-therapeutic effects on the primary sites were evaluated by endoscopic biopsy performed more than once after S-1/CDDP *** effects are a predictive factor for the response to S-1/CDDP chemotherapy inpatients with advanced gastric cancer,as evaluated by endoscopic biopsy over ***:The protein expression level of TS was significantly higher(P40 ng/mg ***:We have confirmed that the protein expression level of TS is a predictive factor for the response to S-1/CDDP chemotherapy in patients with advanced gastric cancer.

关键词： Gastric cancer Thymidylate synthase Dihy-dropyrimidine dehydrogenase orotate phosphoribosyl-transferase Biopsy

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OPRT Is a Potential Predictive Factor for the Response to S-1 in Gastric Cancer

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Journal of Cancer Therapy 2013年第1期4卷 104-111页

作者： Tao Li Meiha Leong Jing Yuan Juan Li Lin Chen Department of General Surgery Chinese PLA General Hospital Beijing China Department of Pathology Chinese PLA General Hospital Beijing China.

Objective: To analyze the impact of mRNA expression of oral fluoropyrimidine (S-1) metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase [OPRT]), on treatment outcomes in locally advanced gastric cancer patients receiving preoperative S-1 combined with oxaliplatin chemotherapy. Methods: Preoperative stage III gastric cancer patients received S-1 (80 mg/m2/day;days 1-14) and oxaliplatin (130 mg/m2;day 1) every 3 weeks and subsequently received gastrectomy with D1/D2 lymphadenectomy. Paired tumor and normal fresh frozen tissues were collected to evaluate mRNA levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase using quantitative reverse-transcriptase polymerase chain reaction. Results: Between December 2009 and October 2010, thirty-five patients were enrolled in this study. 24 (68.5%) patients had clinical tumor response and 10 (28.6%) patients achieved histological response. Quantitative reverse-transcriptase polymerase chain reaction results showed that orotate phosphoribo-syltransferase (OPRT) mRNA expression was significantly higher in histological responders than non-responders (3.75 vs. 1.81, P = 0.005). Diffuse-type gastric cancer patients demonstrated higher orotate phosphoribosyltransferase (OPRT) expression levels than intestinal-type ones (2.79 vs. 1.60, P = 0.014). Similar results were not found when comparing thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels. Conclusion: orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy. Mini Abstract: orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based ch

关键词： S-1 Chemotherapy Gastric Cancer orotate Phosphoribosyltransferase Biomarker

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