Dicycloplatin

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Dicycloplatin
Dicycloplatin.png
Chemical structure of Dicycloplatin
Clinical data
Trade names Dicycloplatin
Synonyms Platinum(2+) 1-carboxycyclobutanecarboxylate ammoniate (1:2:2), 1,1-Cyclobutanedicarboxylic acid, compd. with (sp-4-2)-diammine(1,1-cyclobutanedi(carboxylato-kappaO)(2-))platinum (1:1)
Routes of
administration
Intravenous
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding < 88.7%
Elimination half-life 24.49 - 108.93 hours
Excretion Renal
Identifiers
CAS Number
ChemSpider
UNII
Chemical and physical data
Formula C12H20N2O8Pt
Molar mass 515.382 g/mol
3D model (JSmol)

Dicycloplatin is a chemotherapy medication used to treat a number of cancers which includes the Non-small-cell lung carcinoma and prostate cancer..[1]

Some side effects which are observed from the treatment by dicycloplatin are nausea, vomiting, thrombocytopenia, neutropenia, anemia, fatigue, anorexia, liver enzyme elevation and alopecia. The drugs is a form of Platinum-based antineoplastic and it works by causing the mitochondrial dysfunction which leads to the cell death[2].

Dicycloplatin was developed in China and it was used for phase I human trial clinical in 2006. The drug was approved for chemotherapy by the Chinese FDA in 2012.[3]

Medical uses[edit]

Dicycloplatin can inhibit the proliferation of tumor cells via the induction of apoptosis . It is used to treat a number types of cancer which are Non-small-cell lung carcinoma and prostate cancer[4].

Side effects[edit]

Similar to cisplatin and carboplatin, dicycloplatin also contains some side effects, which are nausea, vomiting, thrombocytopenia, neutropenia, anemia, fatigue, anorexia, liver enzyme elevation, and alopecia. However, with doses up to 350 mg/m(2), there is no significant toxicity; these effects are observed only at higher doses. Furthermore, the nephrotoxicity of dicycloplatin is reported to be less than that of cisplatin, and its myelosuppressive potency is similar to that of carboplatin.[5]

Chemical structure[edit]

Dicycloplatin consists of carboplatin and cyclobutane-1,1-dicarboxylic acid (CBDC) linked by the hydrogen bond. In the structure of dicycloplatin, there are two types of bond: O-H...O is the bond between the hydroxyl group of CBDC with carboxyl oxygen atom. It creates the one-dimensional polymer chain of carboplatin and CBDC. The second one is N-H...O which links between the ammonia group of carboplatin and oxygen of CBDC. It forms the two-dimensional polymer chain of carboplatin and CBDC. In aqueous solution, the 2D-hydrogen bonded polymeric structure of dicycloplatin is destroyed. Firstly, the bond between ammonia group of carboplatin and oxygen of CBDC breaks, thus inducing the formation of one-dimensional dicycloplatin. After that, the strong hydrogen bond breaks and creates an intermediate state of dicycloplatin. Finally, the rearrangement of different orientation of carboplatin and CBDC leads to the formation of intramolecular hydrogen bond and a supramolecule of dicycloplatin with two O-H...O and N-H...O is created [6].

Mechanism of action[edit]

Similar to carboplatin, dicycloplatin inhibits the proliferation of cancer cells by inducing cell apoptosis. When treated with dicycloplatin, some changes in the properties of Hep G2 cells are observed: the declination of Mitochondria Membrane Potential, the release of cytochrome c from mitocondria to cytosol, the activation of caspase-9, caspase-3 and the decrease of Bcl-2. [4] Those phenomena indicate the role of mitochondrial in the apoptosis by intrisic way [7]. Furthermore, the increase in caspase-8 activation is also observed. This can stimulate the apoptosis by activating downstream caspase-3 [8] or by cleaving Bid [9]. As a result, the cleavage of Bid (tBid) transfers to the mitochondria and induce mitochondrial dysfunction which promotes the release of cytochrome c from mitochondria to cytosol. [10]. From the dicycloplatin-treated Hep G2 cell, an excessive amount of reactive oxygen species was detected, [4] which plays an important role in the release of cytochrome c. In the mitochondria, the release of hemoprotein happens through 2-step process: Firstly, the dissociation of cytochrome c from its binding to cardiolipin happens. Due to the reactive oxygen species, the cardiolipin is oxidized, thus reducing the cytochrome c binding and increase the concentration of free cytochrome c [11]

Notes[edit]

  1. ^ D., Zhao; Y., Zhang; C., Xu; C., Dong; H., Lin; L., Zhang; C., Li; S., Ren; X., Wang; S., Yang; D., Han; X., Chen (February 2012). "Pharmacokinetics, Tissue Distribution, and Plasma Protein Binding Study of Platinum Originating from Dicycloplatin, a Novel Antitumor Supramolecule, in Rats and Dogs by ICP-MS". Biological Trace Element Research. 148: 203–208. doi:10.1007/s12011-012-9364-2. 
  2. ^ G.Q., Li; X.G., Chen; X.P., Wu; J.D., Xie; Y.J., Liang; X.Q., Zhao; W.Q, Chen; L.W., Fu (November 2012). "Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis". PLOS ONE. 7 (11). doi:10.1371/journal.pone.0048994. 
  3. ^ J.J, Yu; X.Q, Yang; Q.H, Song; M. D., Mueller; S. C., Remick (2014). "Dicycloplatin, a Novel Platinum Analog in Chemotherapy: Synthesis of Chinese Pre-clinical and Clinical Profile and Emerging Mechanistic Studies". ANTICANCER RESEARCH. 34: 455-464. 
  4. ^ a b c Guang-quan, Li; Xing-gui, Chen; Xing-ping, Wu; Jing-dun, Xie; Yong-ju, Liang; Xiao-qin, Zhao; Wei-qiang, Chen; Li-wu, Fu (November 2012). "Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis". PLOS ONE. 7 (11). doi:10.1371/journal.pone.0048994. 
  5. ^ Li.S; Huang H; Liao H; Zhan J; Guo Y; Zou BY; Jiang WQ; Guan ZZ; Yang XQ (2015). "Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results". International Journal of clinical pharmacology and therapeutics. 51 (2): 96-105. doi:10.5414/CP201761. 
  6. ^ Y., Xu Qing; J., Xiang Lin; S., Q.; TANG, Ka Luo; Y., Zhen Yun; Z., Xiao Feng; T., You Qi (June 2010). "Structural studies of dicycloplatin, an antitumor supramolecule". SCIENCE CHINA Chemistry. 53 (6): 1346–1351. 
  7. ^ R., Kumar; P.E., Herbert; A.N., Warrens (September 2005). "An introduction to death receptors in apoptosis". International Journal of Surgery. 3 (4): 268-277. doi:10.1016/j.ijsu.2005.05.002. 
  8. ^ Yang, BF; Xiao, C; Li, H; Yang, SJ (2007). "Resistance to Fas-mediated apoptosis in malignant tumours is rescued by KN-93 and cisplatin via downregulation of cFLIP expression and phosphorylation". Clinical and Experimental Pharmacology and Physiology. 34: 1245– 1251. doi:10.1111/j.1440-1681.2007.04711.x. 
  9. ^ Blomgran, R; Zheng, L; Stendahl, O (2007). "Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization". Journal of Leukocyte Biology. 81: 1213–1223. doi:10.1189/jlb.0506359. 
  10. ^ Yin, XM (2006). "Bid, a BH3-only multi-functional molecule, is at the cross road of life and death". Gene. 369: 7-19. doi:10.1016/j.gene.2005.10.038. 
  11. ^ Ott, M; Gogvadze, V; Orrenius, S; Zhivotovsky, B (May 2007). "Mitochondria, oxidative stress and cell death". Apoptosis. 12 (5): 913-922. doi:10.1007/s10495-007-0756-2.