User:Lilyyylaw/sandbox
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| Clinical data | |||
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| Trade names | Kymarabine, others | ||
| Other names | CCRIS 93; CCRIS-93; CCRIS93; NSC 281272; NSC-281272; NSC281272; Fazarabine. AraAC; Kymarabine | ||
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Fazarabine also called Arabinofuranosyl-5-azacytosine is the products of triazine base of 5-azacytidine and arabinose sugar of cytosine arabinoside, it is synthetic pyrimidine nucleoside.[1] This is an activity that particular against human solid cancers transplant which is colon, lung and breast cancers. National Cancer Institute for clinical development is an antineoplastic agent, they selected fazarabine as a cancer treatment due to there is a high level of activity to against sort of tumours and it has been proved by preclinical studies. They proved that therapeutic activity is a way that to against rodent and human leukaemias, transplantable rodent solid tumours, and human tumour xenografts. Compares with cytosine arabinoside, fazarabine has a higher ratio to against human solid tumours. Fazarabine is mediated by its appropriation into DNA and inhibition of DNA synthesis. It causing the tumour cell death and tumour necrosis and it testing the sensitivity of the drug to the tumour.[1]
Clinical Study[edit]
Phase II trial[edit]
There were 18 patients has joined the phase II trial of fazarabine and they all suffering from refractory metastatic colon cancer. They were testing the drug by administered for continuous infusion in three days for three to four weeks. In the previous phase, I study, 2 mg/m2/hr as the starting infusion. They predicted that the major toxicity was neutropenia and it has been confirmed. [2]The average time for cycle one was about 21 days and average granulocyte count of 437/microliters (range 36-1600/mL). The patient's recovery in a range of 4 days and only one patient was found out with the frequency of having a high body temperature and neutropenia during 43 cycles. When one of those have recovered, they should have to take care of is that thrombocytopenia with a feeling of sickness and fetch up.[2] However, there was no one have responded that thrombocytopenia. There is one case that had a fast rate of growing liver metastases within seven months. For the consideration, fazarabine narrow range is of toxicities so it can be considered that the combination with hematopoietic growth factors and the trials utilizing fazarabine can be examined in the future.[2]
Side effect[edit]
Toxicity[edit]
There is a number of phase 2 studies of fazarabine were published in solid cancer. Patients continuously taking the drug for three days. However, there are no serious clinical reactions were discovered in the patients who are suffering metastatic colorectal cancer and pancreatic cancer, stage IV breast cancer and bowel cancer, and lung cancer.[3] However, the patients who are using the drug for five days were reported disappointing results with the studies of head and neck cancer, high-grade gliomas, cervical cancer and ovarian cancer. There is no serious clinical reactions were discovered of this drug in phase 2 trial which has blocked the forward research.[3]
The circulation of the cycle is about 30 days. When is a grade 3 or 4 poisonous, the maximum of the rise is 41 mg/m2 per day in five working days were estimated for toxicity. There were some patients developed neutropenia. Fazarabine could be life-threatening. There was only one patient that has found that with a grade 4 nephrotoxicities that have been into some serious adverse effects.[2]
There is a study that explored the systems of native and obtained resistance to fazarabine. Deschloroketamine is a drug that has the ability to sense cancer cells. The results show that deschloroketamine level was decreased because of the leukaemia and the solid cancer cell is exhibiting resistance for fazarabine and a cross-resistance for fazarabine. However, fazarabine was protected by cladribine.[3]
Fazarabine demonstrated cytocidal activity against bowel cancer cells which is an activity outside the cell body from the DNA synthesis. The study was carried out by the murine who had leukaemias and solid cancers, it showed that fazarabine has marked anti-cancer cell activity in them and also showed that the functional of fazarabine is same as the oral administration compared with intraperitoneal drug administration.[3] Moreover, a study was carried out outside the body by testing cytarabine sensitive and the resistant in leukaemia cell verified the DNA hypomethylation potency of fazarabine. In some phase 1 studies were managed in the past ten years, the children and the adult with an obstinate or malignant tumour. The position of these studies is to investigate the toxicity, maximum tolerated dose, and therapeutic efficacy infusions low does for 3 days and the patients using the drug for 5 days. In those two programmes, the main dose-limiting toxicities detected was myelosuppression including granulocytopenia and thrombocytopenia. Other toxicities are middling nausea and vomiting which is not affected by how much the does was infused.[3]
Pharmacology[edit]
The promising preclinical data and reasonable toxicity were improved by the Gynecologic Oncology Group and they have studied fazarabine with cycle squamous cell cancer of the cervix in patients. It has been proven that cycle cervical cancer with the quantifiable disease by receiving fazarabine at the rage of 31 mg/m2 per day within five days.[2]
The starting dosage for the protocol was below average which is 0.19 mg/m2/hr infusion for three days continuously. The radioimmunoassay using ara-C antibody and [3H]ara-C has been developed to test the predicted low plasma drug degrees. That can evaluate the accuracy of fazarabine by testing the plasma and the urine with a number of 0.07 ng/ml. The benefits of using RIA is that it does not need the extraction of tests by just using RIA and HPLC.[4]
Fazarabine is a sterile lyophilised powder stored in a 60milligram bottle. Each bottle contains 70% of sterile and 30% of dimethyl sulfoxide diluent with water. Fazarabine in the 70% of dimethyl sulfoxide was transported through a length of polyolefin line infusion tubing into a 6% of dextrose which mixed with a 0.46% saline solution. Then the infusion will carry out at a rate of 1700milligram in one day through a peripheral venous catheter.[5]
At the start of the infusion, when the tube into the patients, the point of entry was kept close to the patients. That can prevent hydrolytic medicine from decomposition prior to intravascular transport. Dimethyl sulfoxide is a high concentration solution. To prevent it leaching of plasticizer from standard, it required a dilution.[5]
The steady-state plasma concentrations of fazarabine at different does level were analysed from the geometric mean data. Clearance was calculated by dividing the infusion rate by the steady-state plasma concentration. The steady-state plasma concentration ratio for fazarabine was calculated by dividing the cerebrospinal fluid steady-state concentration by the plasma steady-state concentration.[5]
Steady-state drug[edit]
The results of plasma tests from the patient who received a high dosage (181 mg/m2/hr) of fazarabine. Radioimmunoassay is tested to use and has a high rate of accuracy. After the infusion, the plasma levels in the patients were dropped with a terminal half-life of 5.6 +/- 2.0 hr. The standard the various dosages to 1.76 mg/m2/hr and the average AUC value was 4231 +/- 986 (ng/ml)hr. Plasma steady-state drug degrees can be reached in 2-4 hr and it is dependent on the infusion of dosage.[1]
Moreover, the standard average of plasma steady-state drug degrees was 59 +/- 12 ng/ml which is the range of the concentration for inhibiting malignant cell growth. The total clearance was 528 +/- 138 ml/(m2.min) which is fast and there is no relationship with the dose. The drug will be identified by NMR and HPLC which has a purity of more than 98%.[1]
Antitumor mechanisms[edit]
Fazarabine have extremely high activity in animal reproduction with rock-hard tumours which have been tested to some clinical cases. The cell revolution contains gemcitabine blocks which will be blocked in the S phase and it is similar to cytarabine. In the diphosphate structure, it is a suppressant of RNR. Gemcitabine could be examined as the controlling marketed nucleoside analogue, it is common to treat non-small cell lung disease, pancreatic, bladder, and breast disease.[6]
There are some Phase III studies for pancreatic and non-small cell lung disease, it has been proven synergistic in combination with pemetrexed, due to it pemetrexed will use up the supply of the purine and pyrimidine nucleotides which have been stored in the cell. Gemcitabine has been integrated into nascent DNA strands.[6]
The NCl drug and the tri phosphorylated was faulty incorporation into the nucleic acids so that they connected with the impediment of DNA methylation.[6]
Antileukaemia[edit]
The mechanism of fazarabine antileukaemia efficacy by infusing fazarabine into a patient continuously for 72 hours. For the patients who have relapsed acute leukaemia or chronic myelogenous in blastic phase. The patients who diagnosed with acute leukaemia or chronic myelogenous in blastic phase was relapsed on salvage chemotherapy. The initial dose was 3 mg/m2/hour in 72 hours. Results showed that the infusion in over 72 hours for 3 or 4 weeks, the MTD was 426 mg/m2/hour.[7]
Antitumor efficacy[edit]
There is one patient who had not to succeed in 5-fluorouracil and leucovorin treatment for metastatic colon cancer and he was given medical care at the 114/mg/m2/h does level had an incomplete return of pulmonary development supported for seven months. Thirteen patients had solid cancer, including one patient who sustained 15 cycles of treatment. The rest of the patients all had progressive disease.[8]
Synthesis[edit]
The ribose has been replaced by the 5-azaC analogue with the pentose sugar as the glucose moiety so that the 5 and 6-imino bond of the base will be reduced.[9]
This contributed to improving the aqueous stability over 5-azaC, fazarabine and dihydro-5-azacytidine. They are the prodrugs of metabolised in the body to the Deoxy sugars which added into DNA and inhibits DNA Methyltransferase. This combination is animated to fight the cancer cell and tumour xenograft animal reproduction. [9]
Fazarabine has shown activity in the group of 65 cultured human cancer lines of the National Cancer Institute. They discovered that fazarabine have a similar mode of action with cytarabine compare with other anticancer drugs.[10] The program aimed to investigate the system of action of fazarabine in P388 murine and Molt-4 human lymphoblasts in their body. They used chemical and enzymatic methods to produce authentic fazarabine nucleotide standards which were identified on high-performance liquid chromatography by comparing between pyrimidine nucleoside-5'-phosphates and enzymatic digestion.
Fazarabine is the combination of thymidine into DNA without affecting the synthesis of RNA and protein. Deoxycytidine surmounted the inhibition of DNA synthesis and it can prevent the cytotoxicity of the medicine to lymphoblasts by comparing the fazarabine intake and metabolism. Fazarabine was expeditiously phosphorylated in P388 cell which was incorporated into DNA. Alkaline elution researches established that exposure to the agent developed in the formation of alkaline labile sites. Furthermore, fazarabine also inhibited the methylation of deoxycytidine residues in DNA, however, the outcome was less obvious than that produced by 5-azacytidine. [10]
Overall, all the studies recommend that fazarabine presumably acts by arresting the synthesis and remodelling the structural integrity or functional competence of DNA.
References[edit]
- ^ a b c d PubChem. "Fazarabine". pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-12.
- ^ a b c d e "WikiGenes - Collaborative Publishing". WikiGenes - Collaborative Publishing. Retrieved 2019-05-12.
- ^ a b c d e Khushboo Agrawal, M.Sc (2017). EPIGENETIC STUDY OF 5-AZACYTIDINE NUCLEOSIDES AND THEIR DERIVATIVES. Palacký University Olomouc. p. 21.
- ^ PubChem. "Fazarabine". pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-12.
- ^ a b c Gillespie, Andrea (1989). Evaluation of Fazarabine. AACR. p. 5214.
- ^ a b c Avendano, Carmen (2015). Antimetabolites. Medicinal Chemistry of Anticancer Drugs.
- ^ Wilhelm, Martin; Obrien, Susan; Rios, Mary Beth; Estey, Elihu; Keating, Michael J.; Plunke'it, William; Sorenson, Mel; Kantarjian, Hagop M. (1999). "Phase I Study of Arabinosyl-5-zacytidine (Fazarabine) in Adult Acute Leukemia and Chronic Myelogenous Leukemia in Blastic Phase". Leukemia & Lymphoma. 34 (5–6): 511–518. doi:10.3109/10428199909058478. ISSN 1042-8194.
- ^ Richard, M (2017). Phase I and Pharmacological Trial of fazarabine (Arc-AC) with Granulocyte colony-stimulating factor. American Association for cancer. p. 4.
- ^ a b Fischer, Janos (2010). Analogue-based Drug Discovery III. England: WILEY-VCH. ISBN 978-3-527-33073-7.
- ^ a b Barchi, J. J.; Cooney, D. A.; Ahluwalia, G. S.; Gharehbaghi, K.; Covey, J. M.; Hochman, I.; Paull, K. D.; Jayaram, H. N. "Studies on the mechanism of action of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) in mammalian lymphoblasts". Journal of Experimental Therapeutics & Oncology. 1 (3): 191–203. ISSN 1359-4117. PMID 9414404.
See also[edit]
External links[edit]
- Phase I study by M.Wilhelm
- Phase II trial of fazarabine by Kevin P.Huddard
Category:Bioinorganic chemistry Category:Cancer treatments
Category:Medicinal inorganic chemistry Category:Cisplatin Category:Wikipedia medicine articles ready to translate Category:Metal-containing drugs