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This is an old revision of this page, as edited by ThiloZ (talk | contribs) at 14:14, 28 January 2021 (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.). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Satraplatin

Clinical data
Other names	BMY 45594 BMS 182751 (OC-6-43)-bis(acetato)amminedichlorocyclohexylamine platinum(IV)
Routes of administration	Oral
ATC code	L01XA04 (WHO)
Identifiers
IUPAC name (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum
CAS Number	129580-63-8
PubChem CID	123974
UNII	8D7B37T28G
ChEBI	CHEBI:85609
CompTox Dashboard (EPA)	DTXSID00926438
Chemical and physical data
Formula	C10H22Cl2N2O4Pt
Molar mass	500.28 g·mol
3D model (JSmol)	Interactive image
SMILES Cl(Cl)(OC(=O)C)(OC(=O)C)()C1CCCCC1
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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

1. Satraplatin — Spectrum Pharmaceuticals Archived 2007-07-04 at the Wayback Machine
2. 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.
3. ^ 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.
4. ^ 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.

• Coordination compounds
• Platinum(IV) compounds
• Acetates
• Platinum-based antineoplastic agents
• Ammine complexes