61825-94-3 Usage
Indications and Usage
Oxaliplatin, also called Eloxatin or Eloxatine, is a platinum derivative.
Used clinically to treat patients with metastatic colorectal cancer after failure of fluorouracil treatment, can be used alone or in combination with 5-fluorouracil. It is the third-generation platinum antitumor compound after cisplatin and carboplatin, and so far the only platinum-based drug with significant effectiveness against colorectal cancer. It also inhibits proliferation of ovarian cancer and melanoma cell lines.
Mechanisms of Action
Acts on DNA through production of alkylating conjugates, inhibiting its synthesis and reproduction by forming interchain and intrachain cross-links.
Adverse Effects
Hematopoietec system: Oxaliplatin has a certain blood toxicity. When used alone, it can cause the following adverse effects: anemia, leukopenia, neutropenia, thrombocytopenia, sometimes reaching grade 3 or 4. Increases hematologic toxicities such as neutropenia and thrombocytopenia when combined with 5-fluorouracil.
Digestive system: can cause nausea, vomiting, and diarrhea when used alone. These symptoms can sometimes be very serious. These side effects are significantly exacerbated when used in combination with 5-fluorouacil. Use of prophylactic and/or therapeutic antiemetic drugs is recommended.
Nervous system: Peripheral sensory neuropathy characterized by peripheral neuritis. Sometimes associated with convulsions and sensory disturbances in the mouth, upper respiratory tract, and upper GI tract.
Description
Different sources of media describe the Description of 61825-94-3 differently. You can refer to the following data:
1. Oxaliplatin is a platinum-containing DNA-crosslinking agent. It induces the formation of DNA inter- and intrastrand crosslinks and DNA-protein crosslinks, inhibits DNA and RNA synthesis, and induces apoptosis in cancer cells. Oxaliplatin is cytotoxic to cisplatin-sensitive A2780(1A9) and KB-3-1 cells and cisplatin-resistant A2780-E(80) and KB-CP20 cells (IC50s = 0.12, 0.39, 4.7, and 2.7 μM, respectively). It reduces tumor growth in an HCCLM3 mouse xenograft model when administered at doses of 5 or 10 mg/kg once per week. Formulations containing oxaliplatin have been used in the treatment of advanced colorectal cancer and as an adjuvant in stage III colon cancer.
2. Eloxatin was launched in France for second-line treatment of metastatic
colorectal cancer. Oxaliplatin is a second generation platinum drug prepared in three
steps from either k2tCl4 or K2Ptl4. It has an antitumor spectrum similar to cisplatin,
however, it is more effective against L1210 leukemia and cisplatin resistant L1210. It
is also effective against B16 melanoma but has a dose limiting toxicity of peripheral
sensory neuropathy that is reversible upon cessation of the drug. The (R,R)-
enantiomer has greater activity than the (S,S)-isomer but this is tumor line
dependent, e.g., there was no difference found for P-388 or Sarcoma 180. Clinical
drug administration based on circadium timing showed it was better tolerated when
given 16 h after the onset of light. Oxaliplatin binds to guanineN7 and can lead to
bidentate chelation that results in the bending of DNA. This feature is recognized by
high mobility group proteins (HMG) which impedes repair reactions and stops
replication and transcription.
Chemical Properties
White Crystalline Solid
Originator
Bebiopharm (Switzerland)
Uses
Different sources of media describe the Uses of 61825-94-3 differently. You can refer to the following data:
1. Third generation platinum complex. An antitumor agent with activity against colorectal cancer. Cytotoxicity follows the formation of adducts with DNA. Antineoplastic.
2. A potent anti-neoplastic agent that binds to DNA and shows efficacy in Cisplatin resistant cell lines
3. Oxaliplatin is a platinum-based antineoplastic agent that functions by forming DNA adducts specifically in cancer cells, preventing DNA replication and transcription which leads to cell death. Oxaliplatin has cytotoxic effects in a broad range of cell lines, including colon, ovarian, and lung cancer, with IC50 values ranging from 0.5-240, 0.12-19.8, and 2.6-6.1 μM, respectively. Through its general cytotoxic effects, oxaliplatin has anti-tumor activity against advanced colorectal cancer and is typically administered with fluorouracil and leucovorin in a combination known as FOLFOX.
4. A antitumor agent with activity against colorectal cancer. Cytotoxicity follows the formation of adducts with DNA
Brand name
Eloxatin (Sanofi Aventis).
General Description
Oxaliplatin is available in 50- and 100-mg vials for IV administrationin the treatment of ovarian cancer, metastaticcolorectal cancer, and early stage colon cancer in combinationwith 5-fluorouracil/leucovorin. The activation of theagent occurs in low-chloride environments to give theaquated species, which subsequently reacts with DNA in amanner similar to cisplatin. The mechanisms of resistance aresimilar for the two agents; however, oxaliplatin is not recognizedby MMR enzymes and does not show cross-resistancewith cisplatin. The agent is widely distributed, highly proteinbound (85%–88%), and irreversibly binds to erythrocytes.Numerous metabolites have been identified many of whichare produced as a result of nonenzymatic processes and includechloro-, dichloro-, monoaquo-, and diaquo-species.The parent and metabolites are eliminated primarily in theurine with a long terminal elimination half-life of 240 hours.Neurotoxicity is dose limiting and normally presents as peripheralneuropathy, which may be exacerbated by exposureto low temperatures. The neurotoxicity is normally reversiblein contrast to that seen with cisplatin, which may be irreversible.Other adverse effects include nausea, vomiting, diarrhea,myelosuppression, and hypersensitivity reactions.Ototoxicity and renal toxicity occur only rarely in contrast tocisplatin.
Biological Activity
Antitumor agent that forms platinum-DNA adducts. Causes intra- and interstrand DNA crosslinks blocking DNA replication and transcription. Displays higher cytotoxicity and lower nephrotoxicity than analog cisplatin (cis-Diaminodichloroplatinum ) and shows antitumor activity in cell lines with acquired cisplatin resistance.
Biochem/physiol Actions
Oxaliplatin a platinum analogue, causes DNA damage and cell death by binding to DNA and forming inter and intrastrand crosslinks preventing replication and transcription. Oxaliplatin is an anti-tumor agent with activity against colorectal cancer; cytotoxicity follows the formation of adducts with DNA. Oxaliplatin is an approved drug for treating colorectal cancer. It is an active ingredient in FOLFOX (Folinic acid:5-FU:oxaliplatin in the ratio 1:10:1 of micromolar concentrations respectively). Oxaliplatin causes both acute and chronic neurotoxicity in patients in a dose dependent manner and is reversible either by reducing or stopping the drug.
Safety Profile
A poison by intraperitoneal route. When heated to decomposition it emits toxic vapors of NOx and Pt.
in vitro
oxaliplatin is active against human melanoma cell lines c32 and g361 with the ic50 values of 0.98 mm and 0.14 mm, respectively. oxaliplatin effectively inhibited bladder carcinoma cell lines rt4 and tccsup, ovarian carcinoma cell line a2780, colon carcinoma cell line ht-29, glioblastoma cell lines u-87mg and u-373mg, and melanoma cell lines sk-mel-2 and ht-144 with the ic50 values of 11 μm, 15 μm, 0.17 μm, 0.97 μm, 17.6 μm, 2.95 μm, 30.9 μm and 7.85 μm, respectively.
in vivo
a weekly injection of oxaliplatin (10 mg/kg, i.p.) to nude mice bearing hepatocellular hcclm3 tumors significantly reduces tumor volume and apoptotic index. oxaliplatin (5 mg/kg, i.v. on days 1, 5 and 9) was active on t-leukemia-lymphoma l40 akr with t/c of 1.77. oxaliplatin was also efficient on intracerebrally grafted l1210 leukemia, b16 melanoma xenografts, ma 16-c xenografts, lewis lung xenografts and c26 colon carcinoma xenografts. oxaliplatin induced impairment of retrograde neuronal transport in mice.
references
[1]. culy cr, clemett d, wiseman lr. oxaliplatin.a review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies.drugs. 2000 oct;60(4):895-924.[2]. raymond e, faivre s, chaney s et al. cellular and molecular pharmacology of oxaliplatin. mol cancer ther. 2002 jan;1(3):227-35.[3]. stein a, arnold d. oxaliplatin: a review of approved uses. expert opin pharmacother. 2012 jan;13(1):125-37.[4]. hoff pm, saad ed, costa f et al. literature review and practical aspects on the management of oxaliplatin-associated toxicity. clin colorectal cancer. 2012 jun;11(2):93-100.[5]. hall md, et al. say no to dmso: dimethylsulfoxide inactivates cisplatin, carboplatin, and other platinum complexes. cancer res. 2014 jul 15;74(14):3913-22.
Check Digit Verification of cas no
The CAS Registry Mumber 61825-94-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,1,8,2 and 5 respectively; the second part has 2 digits, 9 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 61825-94:
(7*6)+(6*1)+(5*8)+(4*2)+(3*5)+(2*9)+(1*4)=133
133 % 10 = 3
So 61825-94-3 is a valid CAS Registry Number.
InChI:InChI=1/C6H14N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-6H,1-4,7-8H2;(H,3,4)(H,5,6);/q;;+2/p-2/t5-,6-;;/m1../s1/rC8H14N2O4Pt/c11-7-8(12)14-15(13-7)9-5-3-1-2-4-6(5)10-15/h5-6H,1-4,9-10H2/t5-,6-/m1/s1
61825-94-3Relevant articles and documents
A Dual Killing Strategy: Photocatalytic Generation of Singlet Oxygen with Concomitant PtIV Prodrug Activation
Norman, Daniel J.,Gambardella, Alessia,Mount, Andrew R.,Murray, Alan F.,Bradley, Mark
, p. 14189 - 14192 (2019)
A ruthenium-based mitochondrial-targeting photosensitiser that undergoes efficient cell uptake, enables the rapid catalytic conversion of PtIV prodrugs into their active PtII counterparts, and drives the generation of singlet oxygen was designed. This dual mode of action drives two orthogonal cancer-cell killing mechanisms with temporal and spatial control. The designed photosensitiser was shown to elicit cell death of a panel of cancer cell lines including those showing oxaliplatin-resistance.
Phorbiplatin, a Highly Potent Pt(IV) Antitumor Prodrug That Can Be Controllably Activated by Red Light
Wang, Zhigang,Wang, Na,Cheng, Shun-Cheung,Xu, Kai,Deng, Zhiqin,Chen, Shu,Xu, Zoufeng,Xie, Kai,Tse, Man-Kit,Shi, Peng,Hirao, Hajime,Ko, Chi-Chiu,Zhu, Guangyu
, p. 3151 - 3165 (2019)
Selective activation of prodrugs within a tumor is particularly attractive because of their low damage to normal tissue. Here, we report the design, photoactivation mechanism, and antitumor activity of a red-light-activatable Pt(IV) prodrug based on oxaliplatin, a first-line clinical antineoplastic. This small-molecule prodrug, designated as phorbiplatin, has controllable activation property: it is shown to be inert in the dark but under short-period irradiation with low intensity of red light (7 mW/cm2), without the need of any external catalyst, phorbiplatin is rapidly reduced to oxaliplatin. The prodrug displays photocytotoxicity that is up to 1,786 times greater than that of oxaliplatin in human carcinoma cells, and it is also significantly active in vivo. The controllable activation property and superior antitumor activity of phorbiplatin may suggest a novel strategy for the design of visible light-activatable platinum prodrugs to reduce the adverse effects and conquer drug resistance of traditional platinum chemotherapy. Currently, most of the small-molecule anticancer drugs used in clinics do not have controllable activation properties, leading to undesired side effects. Anticancer drugs with “on-site” activation properties are highly demanded. Here, we report the development of a small-molecule anticancer prodrug that can be controllably activated by a red light. The prodrug is stable in the dark even in a reducing environment and shows minimum dark toxicity to the cells. Under irradiation with low intensity of red light, the prodrug utilizes a unique photoactivation mechanism to be quickly and efficiently activated, releasing oxaliplatin, a widely used antineoplastic agent. The activated prodrug displays significantly increased cytotoxicity in human cancer cells compared with oxaliplatin, and it is able to kill tumor cells much more efficiently than oxaliplatin in a mouse tumor model. Our work significantly contributes to the development of photoactivatable anticancer prodrugs, especially by red light. We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinum(IV) antitumor prodrug that can be controllably activated by red light. Phorbiplatin maintains its integrity without irradiation, but under irradiation with red light, the prodrug is quickly and efficiently activated, releasing oxaliplatin and PPA. The prodrug shows significant antitumor activity both in vitro and in vivo.
Electrodrugs: An electrochemical prodrug activation strategy
Norman, Daniel J.,González-Fernández, Eva,Clavadetscher, Jessica,Tucker, Lulu,Staderini, Matteo,Mount, Andrew R.,Murray, Alan F.,Bradley, Mark
, p. 9242 - 9245 (2018)
The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.
Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues
Chen, Shu,Gunawan, Yuliana F.,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
supporting information, (2020/08/24)
Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.
