| Revision as of 18:33, 19 December 2020 editBoghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,805 edits consistent citation formatting← Previous edit | Revision as of 14:14, 28 January 2021 edit undoThiloZ (talk | contribs)9 edits Update on clinical data (SPARC Trial with PFS but no OS benefit, mode of action, availability (Satraplatin currently is not available), regulatory status (FDA und EMA rejected market application), more detailed description of saftey profile. Mentioning of penetration of blood brain barrier.Tags: references removed Visual editNext edit → | ||
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| | SMILES = Cl(Cl)(OC(=O)C)(OC(=O)C)()C1CCCCC1 | | SMILES = Cl(Cl)(OC(=O)C)(OC(=O)C)()C1CCCCC1 | ||
| }} | }} | ||
| '''Satraplatin''' (], codenamed '''JM216''') is a 4th generation ] agent. The lipophilicity and stability allows its oral administration that offers multiple advantages over the commonly used platinum drugs such as cisplatin, carboplatin or oxaliplatin - all must be given intravenously. Its oral bioavailability and intermittent dosing makes it uniquely convenient both for patients and care providers. It seems to be comparable in efficacy to more established platinum drugs in multiple common human malignancies in preclinical experiments and clinical trials. | |||
| '''Satraplatin''' (], codenamed '''JM216''') is a ] agent that is under investigation as one treatment of patients with advanced ] who have failed previous ]. It has not yet received approval from the U.S. ].<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://semanticscholar.org/paper/55b1f126bf345c8c6660e9ce6ed022606a983c7b | hdl-access = free | hdl = 2123/14271 | author-link1 = Nial J. Wheate }}</ref> First mentioned in the medical literature in 1993,<ref>{{cite journal | vauthors = Kelland LR, Abel G, McKeage MJ, Jones M, Goddard PM, Valenti M, Murrer BA, Harrap KR | display-authors = 6 | title = Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug | journal = Cancer Research | volume = 53 | issue = 11 | pages = 2581–6 | date = June 1993 | pmid = 8388318 | url = http://cancerres.aacrjournals.org/cgi/reprint/53/11/2581.pdf | author-link8 = Kenneth Harrap }}</ref> satraplatin is the first orally active platinum-based chemotherapeutic drug;<ref name = ChoyParkYao>{{cite journal | vauthors = Choy H, Park C, Yao M | title = Current status and future prospects for satraplatin, an oral platinum analogue | journal = Clinical Cancer Research | volume = 14 | issue = 6 | pages = 1633–8 | date = March 2008 | pmid = 18347164 | doi = 10.1158/1078-0432.CCR-07-2176 | doi-access = free }}</ref> other available platinum analogues—], ], and ]—must be given ]. | |||
| == Mode of action == | |||
| It is made available in the United States jointly by ] and GPC Biotech under the name SPERA (SatraPlatin Expanded Rapid Access). | |||
| ⚫ | The proposed mode of action is that the compound binds to the ] of cancer cells rendering them incapable of ].<ref> {{webarchive|url=https://web.archive.org/web/20070704183648/http://www.spectrumpharm.com/satraplatin.html|date=2007-07-04}}</ref> In addition also some cisplatin resistant tumour cell lines were sensitive to satraplatin treatment in vitro. This may be due to an altered mechanism of cellular uptake (satraplatin by passive diffusion instead of active transport for e.g. cisplatin). | ||
| ⚫ | |||
| == Medical use == | == Medical use == | ||
| Satraplatin |
Satraplatin has been developed for the treatment of men with chemorefractory HRPC for several reasons. Its relative ease of administration, potential lack of cross-resistance with other platinum agents, clinical benefits seen in early studies of HRPC, and an unmet need in this patient population after ] failure. The only Phase III trial with satraplatin (SPARC Trial) was conducted in pretreated metastatic castrate-resistant prostate cancer (CRPC), revealing an improvement in progression-free survival (PFS). A 33% reduction (hazard ratio = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo <ref>{{Cite journal|last=Sternberg|first=Cora N.|last2=Petrylak|first2=Daniel P.|last3=Sartor|first3=Oliver|last4=Witjes|first4=J. Alfred|last5=Demkow|first5=Tomasz|last6=Ferrero|first6=Jean-Marc|last7=Eymard|first7=Jean-Christophe|last8=Falcon|first8=Silvia|last9=Calabrò|first9=Fabio|last10=James|first10=Nicholas|last11=Bodrogi|first11=Istvan|date=2009-11-10|title=Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial|url=https://pubmed.ncbi.nlm.nih.gov/19805692/|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=27|issue=32|pages=5431–5438|doi=10.1200/JCO.2008.20.1228|issn=1527-7755|pmid=19805692}}</ref> . No difference in overall survival was seen. The favorable safety profile was confirmed. Despite this significant PFS-benefit, a FDA or ] - approved indication has not yet been achieved. | ||
| Satraplatin |
Satraplatin appears to have clinical activity against a variety of malignancies such as ], ] and ]. Especially in combination with radiotherapy, excellent efficacy has been shown in squamous cell carcinoma. Of 8 patients, 7 achieved a complete remission. | ||
| == Side effects == | == Side effects == | ||
| Satraplatin is similar in toxicity profile to carboplatin, with no nephrotoxicity, neurotoxicity, or ototoxicity observed. Moreover, it is much better tolerated than cisplatin and does not require hydration for each dose. A somewhat more intense hematotoxicity is observed. ], diarrhea, constipation, nausea or vomiting, increase risk of infection, bruising.<ref name=":1">{{cite journal|vauthors=Bhargava A, Vaishampayan UN|date=November 2009|title=Satraplatin: leading the new generation of oral platinum agents|journal=Expert Opinion on Investigational Drugs|volume=18|issue=11|pages=1787–97|doi=10.1517/13543780903362437|pmc=3856359|pmid=19888874}}</ref> | |||
| ], diarrhea, constipation, nausea or vomiting, increase risk of infection, bruising.<ref name=":1" /> | |||
| == Possible risks and complications == | == Possible risks and complications == | ||
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| * Use ]: Satraplatin may harm a developing baby. It is important to use effective contraception while taking this drug and for at least a few months afterwards<ref name=":1" /> | * Use ]: Satraplatin may harm a developing baby. It is important to use effective contraception while taking this drug and for at least a few months afterwards<ref name=":1" /> | ||
| == Mechanism of action == | == Detailed Mechanism of action == | ||
| Many human tumors including testicular, bladder, lung, head, neck, and cervical cancers have been treated with platinum compounds.<ref name=":1" /> All of the marketed platinum analogues must be administered via intravenous infusion is one of the main disadvantages for these platinum compounds due to severe, dose-limiting effects. An acquired resistance to cisplatin/carboplatin in ovarian cancer was discovered due to insufficient amounts of platinum reaching the target DNA or failure to achieve cell death. These drawbacks led to the development of the next generation of platinum analogues such as satraplatin<ref name=":1" /> | Many human tumors including testicular, bladder, lung, head, neck, and cervical cancers have been treated with platinum compounds.<ref name=":1" /> All of the marketed platinum analogues must be administered via intravenous infusion is one of the main disadvantages for these platinum compounds due to severe, dose-limiting effects. An acquired resistance to cisplatin/carboplatin in ovarian cancer was discovered due to insufficient amounts of platinum reaching the target DNA or failure to achieve cell death. These drawbacks led to the development of the next generation of platinum analogues such as satraplatin<ref name=":1" /> | ||
| Satraplatin is a prodrug, meaning it is metabolized in the body and transformed into its working form. The two polar acetate groups on satraplatin increase the drugs ], which in turn allows for a large fraction of the administered dose to make it into the bloodstream where metabolism begins. Once the molecule makes it to the bloodstream the drug loses its acetate groups. At this point the drug is structurally similar to ] with the exception of one cyclohexylamine group in place of an amine group. Since the drug is now structurally similar to cisplatin its mechanism of action is also very similar. The chlorine atoms are displaced and the platinum atom in the drug binds to guanine residues in DNA. This unfortunately happens to not only cancer cells but other regular functioning cells as well causing some of the harsh side effects. By binding to guanine residues satraplatin inhibits DNA replication and transcription which leads to subsequent ]. Where satraplatin differs is its cyclohexamine group. In cisplatin the two amine groups are symmetrical while satraplatin's cyclohexamine makes it asymmetrical which contributes to some of the drug's special properties.<ref name = |
Satraplatin is a prodrug, meaning it is metabolized in the body and transformed into its working form. The two polar acetate groups on satraplatin increase the drugs ], which in turn allows for a large fraction of the administered dose to make it into the bloodstream where metabolism begins. Once the molecule makes it to the bloodstream the drug loses its acetate groups. At this point the drug is structurally similar to ] with the exception of one cyclohexylamine group in place of an amine group. Since the drug is now structurally similar to cisplatin its mechanism of action is also very similar. The chlorine atoms are displaced and the platinum atom in the drug binds to guanine residues in DNA. This unfortunately happens to not only cancer cells but other regular functioning cells as well causing some of the harsh side effects. By binding to guanine residues satraplatin inhibits DNA replication and transcription which leads to subsequent ]. Where satraplatin differs is its cyclohexamine group. In cisplatin the two amine groups are symmetrical while satraplatin's cyclohexamine makes it asymmetrical which contributes to some of the drug's special properties.<ref name="ChoyParkYao">{{cite journal|vauthors=Choy H, Park C, Yao M|date=March 2008|title=Current status and future prospects for satraplatin, an oral platinum analogue|journal=Clinical Cancer Research|volume=14|issue=6|pages=1633–8|doi=10.1158/1078-0432.CCR-07-2176|pmid=18347164|doi-access=free}}</ref> | ||
| A large problem with cisplatin and other platinum based anti-cancer drugs is that the body can develop resistance to them. A major way that this happens is through a mammalian nucleotide excision repair pathway which repairs damaged DNA. However, some studies show that satraplatin compared to other platinum anti-cancer drugs can be elusive and are not recognized by the DNA repair proteins due to the different adducts on the molecule (cyclohexamine). Since satraplatin is not recognized by the DNA repair proteins the DNA remains damaged, the DNA cannot be replicated, the cell dies, and the problem of resistance is solved.<ref name = ChoyParkYao /> | A large problem with cisplatin and other platinum based anti-cancer drugs is that the body can develop resistance to them. A major way that this happens is through a mammalian nucleotide excision repair pathway which repairs damaged DNA. However, some studies show that satraplatin compared to other platinum anti-cancer drugs can be elusive and are not recognized by the DNA repair proteins due to the different adducts on the molecule (cyclohexamine). Since satraplatin is not recognized by the DNA repair proteins the DNA remains damaged, the DNA cannot be replicated, the cell dies, and the problem of resistance is solved.<ref name = ChoyParkYao /> | ||
Revision as of 14:14, 28 January 2021
Pharmaceutical compound | |
 | |
| Clinical data | |
|---|---|
| Other names | BMY 45594 BMS 182751 (OC-6-43)-bis(acetato)amminedichlorocyclohexylamine platinum(IV) |
| Routes of administration | Oral |
| ATC code | |
| Identifiers | |
IUPAC name
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| CAS Number | |
| PubChem CID | |
| UNII | |
| ChEBI | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C10H22Cl2N2O4Pt |
| Molar mass | 500.28 g·mol |
| 3D model (JSmol) | |
SMILES
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| (what is this?) (verify) | |
Satraplatin (INN, codenamed JM216) is a 4th generation platinum-based antineoplastic agent. The lipophilicity and stability allows its oral administration that offers multiple advantages over the commonly used platinum drugs such as cisplatin, carboplatin or oxaliplatin - all must be given intravenously. Its oral bioavailability and intermittent dosing makes it uniquely convenient both for patients and care providers. It seems to be comparable in efficacy to more established platinum drugs in multiple common human malignancies in preclinical experiments and clinical trials.
Mode of action
The proposed mode of action is that the compound binds to the DNA of cancer cells rendering them incapable of dividing. In addition also some cisplatin resistant tumour cell lines were sensitive to satraplatin treatment in vitro. This may be due to an altered mechanism of cellular uptake (satraplatin by passive diffusion instead of active transport for e.g. cisplatin).
Medical use
Satraplatin has been developed for the treatment of men with chemorefractory HRPC for several reasons. Its relative ease of administration, potential lack of cross-resistance with other platinum agents, clinical benefits seen in early studies of HRPC, and an unmet need in this patient population after Docetaxel failure. The only Phase III trial with satraplatin (SPARC Trial) was conducted in pretreated metastatic castrate-resistant prostate cancer (CRPC), revealing an improvement in progression-free survival (PFS). A 33% reduction (hazard ratio = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo . No difference in overall survival was seen. The favorable safety profile was confirmed. Despite this significant PFS-benefit, a FDA or EMA - approved indication has not yet been achieved.
Satraplatin appears to have clinical activity against a variety of malignancies such as Breast Cancer, Prostate cancer and Lung cancer. Especially in combination with radiotherapy, excellent efficacy has been shown in squamous cell carcinoma. Of 8 patients, 7 achieved a complete remission.
Side effects
Satraplatin is similar in toxicity profile to carboplatin, with no nephrotoxicity, neurotoxicity, or ototoxicity observed. Moreover, it is much better tolerated than cisplatin and does not require hydration for each dose. A somewhat more intense hematotoxicity is observed. Anemia, diarrhea, constipation, nausea or vomiting, increase risk of infection, bruising.
Possible risks and complications
- Thrombus: Cancer can increase the risk of developing a blood clot, and chemotherapy may increase this risk further. A blood clot may cause symptoms such as pain, redness and swelling in a leg, or breathlessness and chest pain. Most clots can be treated with drugs that thin the blood.
- Fertility: Satraplatin can effect a females ability to become pregnant and may cause a male to become sterile
- Use Contraception: Satraplatin may harm a developing baby. It is important to use effective contraception while taking this drug and for at least a few months afterwards
Detailed Mechanism of action
Many human tumors including testicular, bladder, lung, head, neck, and cervical cancers have been treated with platinum compounds. All of the marketed platinum analogues must be administered via intravenous infusion is one of the main disadvantages for these platinum compounds due to severe, dose-limiting effects. An acquired resistance to cisplatin/carboplatin in ovarian cancer was discovered due to insufficient amounts of platinum reaching the target DNA or failure to achieve cell death. These drawbacks led to the development of the next generation of platinum analogues such as satraplatin
Satraplatin is a prodrug, meaning it is metabolized in the body and transformed into its working form. The two polar acetate groups on satraplatin increase the drugs bioavailability, which in turn allows for a large fraction of the administered dose to make it into the bloodstream where metabolism begins. Once the molecule makes it to the bloodstream the drug loses its acetate groups. At this point the drug is structurally similar to cisplatin with the exception of one cyclohexylamine group in place of an amine group. Since the drug is now structurally similar to cisplatin its mechanism of action is also very similar. The chlorine atoms are displaced and the platinum atom in the drug binds to guanine residues in DNA. This unfortunately happens to not only cancer cells but other regular functioning cells as well causing some of the harsh side effects. By binding to guanine residues satraplatin inhibits DNA replication and transcription which leads to subsequent apoptosis. Where satraplatin differs is its cyclohexamine group. In cisplatin the two amine groups are symmetrical while satraplatin's cyclohexamine makes it asymmetrical which contributes to some of the drug's special properties.
A large problem with cisplatin and other platinum based anti-cancer drugs is that the body can develop resistance to them. A major way that this happens is through a mammalian nucleotide excision repair pathway which repairs damaged DNA. However, some studies show that satraplatin compared to other platinum anti-cancer drugs can be elusive and are not recognized by the DNA repair proteins due to the different adducts on the molecule (cyclohexamine). Since satraplatin is not recognized by the DNA repair proteins the DNA remains damaged, the DNA cannot be replicated, the cell dies, and the problem of resistance is solved.
References
- Satraplatin — Spectrum Pharmaceuticals Archived 2007-07-04 at the Wayback Machine
- Sternberg, Cora N.; Petrylak, Daniel P.; Sartor, Oliver; Witjes, J. Alfred; Demkow, Tomasz; Ferrero, Jean-Marc; Eymard, Jean-Christophe; Falcon, Silvia; Calabrò, Fabio; James, Nicholas; Bodrogi, Istvan (2009-11-10). "Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 27 (32): 5431–5438. doi:10.1200/JCO.2008.20.1228. ISSN 1527-7755. PMID 19805692.
- ^ Bhargava A, Vaishampayan UN (November 2009). "Satraplatin: leading the new generation of oral platinum agents". Expert Opinion on Investigational Drugs. 18 (11): 1787–97. doi:10.1517/13543780903362437. PMC 3856359. PMID 19888874.
- ^ Choy H, Park C, Yao M (March 2008). "Current status and future prospects for satraplatin, an oral platinum analogue". Clinical Cancer Research. 14 (6): 1633–8. doi:10.1158/1078-0432.CCR-07-2176. PMID 18347164.
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