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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 447613838 |
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| IUPAC_name = |
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| image = Triplatin tetranitrate.svg |
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| IUPAC_name = |
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| image = Triplatin tetranitrate.svg |
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| width = 300 |
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| CAS_number = <!--172903-00-3, provided in ''WHO Drug Information''--> |
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<!--Clinical data--> |
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| CAS_supplemental = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| ATC_supplemental = |
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| pregnancy_category = |
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| PubChem = |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| DrugBank = |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| C=12|H=54|Cl=2|N=14|O=12|Pt=3 |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| molecular_weight = 1242.8018 g/mol |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| synonyms = BBR3464 |
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| bioavailability = |
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| protein_bound = |
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<!--Pharmacokinetic data--> |
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| excretion = |
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| metabolism = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| elimination_half-life = |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category= |
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<!--Identifiers--> |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| CAS_number_Ref = {{cascite|changed|CAS}} |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| CAS_number = 172903-00-3<!--172903-00-3, provided in ''WHO Drug Information'' and chebi, and unii--> |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| UNII = HAJ1000ARC |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| routes_of_administration = |
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| ChEBI = 85611 |
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| ATC_prefix = none |
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| ATC_supplemental = |
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| PubChem = 91825660 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID = 34999760 |
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<!--Chemical data--> |
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| C=12 | H=50 | Cl=2 | N=14 | O=12 | Pt=3 |
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| synonyms = |
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| StdInChI=1S/2C6H16N2.2ClH.4NO3.6H3N.3Pt/c2*7-5-3-1-2-4-6-8;;;4*2-1(3)4;;;;;;;;;/h2*1-8H2;2*1H;;;;;6*1H3;;;/q;;;;4*-1;;;;;;;3*+2/p-2 |
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| StdInChIKey = RMFNGLHOFHJMHN-UHFFFAOYSA-L |
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| SMILES = ()=O.()=O.Cl()()CCCCCC()()CCCCCC()()Cl.()=O.()=O |
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'''Triplatin tetranitrate''' (]; also known as '''BBR3464''') is a new ]-based ] ] that is ] undergoing ]s throughout the world for the treatment of human ]. It is a trinuclear platinum ], with ] and ] ]s. The drug acts by forming coordinate ] ]s with cellular ], preventing ] and ], and through this inducing ]. It is structurally similar to, but in a different family from, the anticancer drugs ], ] and ]. |
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'''Triplatin tetranitrate''' (]; also known as '''BBR3464''') is a ] that underwent ]s for the treatment of human ].<ref>{{cite journal | vauthors = Wheate NJ, Walker S, Craig GE, Oun R | title = The status of platinum anticancer drugs in the clinic and in clinical trials | journal = Dalton Transactions | volume = 39 | issue = 35 | pages = 8113–27 | date = September 2010 | pmid = 20593091 | doi = 10.1039/C0DT00292E | url = https://ses.library.usyd.edu.au/bitstream/2123/9269/2/41%20Dalton%20perspective.pdf | hdl = 2123/14271 | authorlink1 = Nial J. Wheate | hdl-access = free }}</ref> The drug acts by forming ]s with cellular ], preventing ] and ], thereby inducing ]. Other platinum-containing anticancer drugs include ], ], and ].<ref>{{cite journal | vauthors = Farrell NP | title = Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets | journal = Chemical Society Reviews | volume = 44 | issue = 24 | pages = 8773–85 | date = December 2015 | pmid = 25951946 | doi = 10.1039/c5cs00201j | s2cid = 5171072 }}</ref> |
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== History == |
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==Drug development== |
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It was invented by Professor Nicholas Farrell at ] in the ]. The development of this drug came from his earlier work looking at dinuclear platinum derivatives of cisplatin, research he began in the late 1980s. Similar work was also being undertaken by Dr John Broomhead at the ] in Australia. BBR3464 was patented in the mid-1990s and was originally licensed to the pharmaceutical company ]. In preclinical trials, it demonstrated cytotoxic activity in cancer cell lines which have either intrinsic or acquired resistance to cisplatin. On this basis it entered Phase I (Toxicity) clinical trials under the auspices of Novuspharma before the rights were transferred to Cell Therapeutics. |
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Triplatin belongs to the anticancer class of polynuclear platinum complexes (PPCs), developed in the laboratory of Professor Nicholas Farrell, where one or more platinum centers are linked by amine ligands. BBR3464 was patented in the mid-1990s and clinical development and licensing was performed initially by Boehringer Mannheim Italia and eventually by the pharmaceutical company Roche, when clinical development was led by Novuspharma. In preclinical trials it demonstrated cytotoxic activity in cancer cell lines that had either intrinsic or acquired resistance to cisplatin. Triplatin remains the only “non-classical” platinum drug (not based on the cisplatin structure) to have entered human clinical trials. Phase I and Phase II clinical results have been summarized.<ref>{{cite journal |last1=Farrell |first1=Nicholas P. | name-list-style = vanc |title=Progress in Platinum-Derived Drug Development. |journal=Drugs of the Future |date=2012 |volume=37 |issue=11 |pages=795–806 |doi=10.1358/dof.2012.037.011.1830167|s2cid=75603138 }}</ref> |
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This drug is currently undergoing Phase II (Efficacy) trials with mixed results. So far trials of the drug with patients suffering from ovarian cancer, small cell lung cancer and gastric or gastro-oesophageal adenocarcinomas have been reported in the literature. |
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== Mode of action == |
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== Mode of action == |
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The main target of triplatin is cellular DNA, similar to cisplatin. The drug forms novel adducts with DNA, structurally distinct from those formed by cisplatin. More recently, cellular accumulation mediated by heparan sulfate proteoglycans and high-affinity ] (GAG) binding indicates that cationic PPCs are intrinsically dual-function agents, acting by mechanisms discrete from the neutral, mononuclear agents.<ref>{{cite journal | vauthors = Tsotsoros SD, Lutz PB, Daniel AG, Peterson EJ, de Paiva RE, Rivera E, Qu Y, Bayse CA, Farrell NP | display-authors = 6 | title = 2+ for HIVNCp7 targeting | journal = Chemical Science | volume = 8 | issue = 2 | pages = 1269–1281 | date = February 2017 | pmid = 28451269 | pmc = 5355868 | doi = 10.1039/c6sc02515c }}</ref> |
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The main target of triplatin is cellular DNA, similar to cisplatin. Outside of the cell, the concentration of chloride (approx. 100 millimolar) prevents the drugs from hydrolysing, but once inside the cell, where the concentration of chloride drops to between 4 and 20 millimolar, the chloride ligands of BBR3464 come off and the drug is capable of forming coordinate covalent bonds with purine bases on DNA. The novel adducts BBR3464 forms with DNA are though to be the mechanism by which this drug acts; the adducts are able to prevent DNA transcription and replication, thus inducing cell apoptosis. |
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== Side-effects == |
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All platinum based drugs, and particularly BBR3464, cause large dose limiting side-effects. For BBR3464 these are largely diarrhea, cramps and vomiting, but are so severe that the maximum tolerated dose (MTD) in humans is between 0.9 to 1.1 milligrams per square metre. This is considerably lower than the MTD for all the platinum based drugs currently used in the clinic, like cisplatin (60–120 mg) and carboplatin (approx. 800 mg). |
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==References== |
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*Wheate, Nial J. and Collins, J. Grant (2003). Multi-nuclear platinum complexes as anti-cancer drugs. ''Coord Chem Rev'', '''241''', 133–145. {{DOI|10.1016/S0010-8545(03)00050-X}}. |
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== Side effects == |
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*Wheate, Nial J. and Collins, J. Grant (2005). Multi-nuclear platinum drugs: A new paradigm in chemotherapy. ''Curr Med Chem Anticancer Agents'', '''5''', 267–279. PMID 15992354. |
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In phase I studies, when given once every 28 days, the main dose-limiting toxicities (DLT) of Triplatin (BBR 3464) were neutropenia and diarrhea encountered at a dose level of 1.1 mg/m2. Diarrhea was treatable with loperamide.<ref>{{cite journal | vauthors = Gourley C, Cassidy J, Edwards C, Samuel L, Bisset D, Camboni G, Young A, Boyle D, Jodrell D | display-authors = 6 | title = A phase I study of the trinuclear platinum compound, BBR 3464, in combination with protracted venous infusional 5-fluorouracil in patients with advanced cancer | journal = Cancer Chemotherapy and Pharmacology | volume = 53 | issue = 2 | pages = 95–101 | date = February 2004 | pmid = 14605864 | doi = 10.1007/s00280-003-0721-x | s2cid = 19707262 }}</ref> Lack of nephrotoxicity and low urinary excretion supported use of drug without hydration.<ref>{{cite journal | vauthors = Sessa C, Capri G, Gianni L, Peccatori F, Grasselli G, Bauer J, Zucchetti M, Viganò L, Gatti A, Minoia C, Liati P, Van den Bosch S, Bernareggi A, Camboni G, Marsoni S | display-authors = 6 | title = Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex | journal = Annals of Oncology | volume = 11 | issue = 8 | pages = 977–83 | date = August 2000 | pmid = 11038034 | doi = 10.1023/a:1008302309734 | doi-access = free }}</ref> |
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== References == |
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{{reflist}} |
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{{Chemotherapeutic agents}} |
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{{Chemotherapeutic agents}} |
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{{Platinum compounds}} |
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