Amifostine

Last updated
Amifostine
Amifostine.svg
Clinical data
AHFS/Drugs.com Monograph
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability complete
Elimination half-life 8 minutes
Identifiers
  • 2-(3-aminopropylamino)ethylsulfanylphosphonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.161.827 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H15N2O3PS
Molar mass 214.22 g·mol−1
3D model (JSmol)
  • O=P(O)(O)SCCNCCCN
  • InChI=1S/C5H15N2O3PS/c6-2-1-3-7-4-5-12-11(8,9)10/h7H,1-6H2,(H2,8,9,10) Yes check.svgY
  • Key:JKOQGQFVAUAYPM-UHFFFAOYSA-N Yes check.svgY
   (verify)

Amifostine (ethiofos) is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by Clinigen Group under the trade name Ethyol.

Contents

Indications

Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agents (e.g. cyclophosphamide) and platinum-containing agents (e.g. cisplatin). It is also used to decrease the cumulative nephrotoxicity associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck cancer.

Amifostine was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer. However, while nephroprotection was observed, the probability that amifostine could protect tumors could not be excluded. Additional data have shown that amifostine-mediated tumor protection, in any clinical scenario, is unlikely.

Pharmacokinetics

WR-1065, 2-((aminopropyl)amino)ethanethiol, the active metabolite of amifostine WR-1065 skeletal.svg
WR-1065, 2-((aminopropyl)amino)ethanethiol, the active metabolite of amifostine

Amifostine is an organic thiophosphate prodrug which is hydrolysed in vivo by alkaline phosphatase to the active cytoprotective thiol metabolite, WR-1065. The selective protection of non-malignant tissues is believed to be due to higher alkaline phosphatase activity, higher pH, and vascular permeation of normal tissues.

Amifostine can be administered intravenously or subcutaneously after reconstitution with normal saline. Infusions lasting less than 15 minutes decrease the risk of adverse effects. The patient should be well-hydrated prior to administration.

Mechanism of action

Inside cells, amifostine detoxifies reactive metabolites of platinum and alkylating agents, as well as scavenges free radicals. [1] [2] Other possible effects include accelerated DNA repair, [1] induction of cellular hypoxia, [1] inhibition of apoptosis, [2] alteration of gene expression [2] and modification of enzyme activity. [2] Amifostine is believed to radioprotect normal tissue via Warburg-type effects. [3]

Adverse effects

Common side effects of amifostine include hypocalcemia, diarrhea, nausea, vomiting, sneezing, somnolence, and hiccups. Serious side effects include: hypotension (found in 62% of patients), erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis, immune hypersensitivity syndrome, erythroderma, anaphylaxis, and loss of consciousness (rare).

Contraindications

Contraindications to receiving amifostine include hypersensitivity to amifostine and aminothiol compounds like WR-1065. Ethyol contains mannitol.

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

<span class="mw-page-title-main">Malignancy</span> Tendency of a medical condition to become progressively worse

Malignancy is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.

<span class="mw-page-title-main">Head and neck cancer</span> Cancer arises in the head or neck region

Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms predominantly include a sore that does not heal or a change in the voice. In those with advanced disease, there may be unusual bleeding, facial pain, numbness or swelling, and visible lumps on the outside of the neck or oral cavity. Given the location of these cancers, trouble breathing may also be present.

<span class="mw-page-title-main">Cisplatin</span> Pharmaceutical drug

Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. It is given by injection into a vein.

<span class="mw-page-title-main">Cyclophosphamide</span> Medication used as chemotherapy and to suppress the immune system

Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.

<span class="mw-page-title-main">Tirapazamine</span> Chemical compound

Tirapazamine (SR-[[4233]]) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of oxygen (hypoxia). Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia. Thus, tirapazamine is activated to its toxic form preferentially in the hypoxic areas of solid tumors. Cells in these regions are resistant to killing by radiotherapy and most anticancer drugs. Thus the combination of tirapazamine with conventional anticancer treatments is particularly effective. As of 2006, tirapazamine is undergoing phase III testing in patients with head and neck cancer and gynecological cancer, and similar trials are being undertaken for other solid tumor types.

<span class="mw-page-title-main">Altretamine</span> Chemical compound

Altretamine, also called hexamethylmelamine, is an antineoplastic agent. It was approved by the U.S. FDA in 1990.

<span class="mw-page-title-main">Lomustine</span> Chemical compound

Lomustine (INN); abbreviated as CCNU; original brand name CeeNU, now marketed as Gleostine) is an alkylating nitrosourea compound used in chemotherapy. It is closely related to semustine and is in the same family as streptozotocin. It is a highly lipid-soluble drug, thus it crosses the blood–brain barrier. This property makes it ideal for treating brain tumors, which is its primary use, although it is also used to treat Hodgkin lymphoma as a second-line option. It has also been used in veterinary practice as a treatment for cancers in cats and dogs.

<span class="mw-page-title-main">Crosslinking of DNA</span> Phenomenon in genetics

In genetics, crosslinking of DNA occurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them. This crosslink can occur within the same strand (intrastrand) or between opposite strands of double-stranded DNA (interstrand). These adducts interfere with cellular metabolism, such as DNA replication and transcription, triggering cell death. These crosslinks can, however, be repaired through excision or recombination pathways.

An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA.

<span class="mw-page-title-main">Satraplatin</span> Chemical compound

Satraplatin is a platinum-based antineoplastic agent that was under investigation as a treatment of patients with advanced prostate cancer who have failed previous chemotherapy. It has not yet received approval from the U.S. Food and Drug Administration. First mentioned in the medical literature in 1993, satraplatin is the first orally active platinum-based chemotherapeutic drug; other available platinum analogues—cisplatin, carboplatin, and oxaliplatin—must be given intravenously.

<span class="mw-page-title-main">Radiosensitizer</span>

A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer.

<span class="mw-page-title-main">Chlornaphazine</span> Chemical compound

Chlornaphazine, a derivative of 2-naphthylamine, is a nitrogen mustard that was developed in the 1950s for the treatment of polycythemia and Hodgkin's disease. However, a high incidence of bladder cancers in patients receiving treatment with chlornaphthazine led to use of the drug being discontinued.

Lipoplatin is a nanoparticle of 110 nm average diameter composed of lipids and cisplatin. This new drug has successfully finished Phase I, Phase II, and Phase III human clinical trials. It has shown superiority to cisplatin in combination with paclitaxel as a chemotherapy regimen in non-small cell lung cancer (NSCLC) adenocarcinomas.

Platinum-based antineoplastic drugs are chemotherapeutic agents used to treat cancer. Their active moieties are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. In this form of chemotherapy, commonly used drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development. Addition of platinum-based chemotherapy drugs to chemoradiation in women with early cervical cancer seems to improve survival and reduce risk of recurrence.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Arabinopyranosyl-<i>N</i>-methyl-<i>N</i>-nitrosourea Chemical compound

Arabinopyranosyl-N-methyl-N-nitrosourea, also known as Aranose (Араноза) is a cytostatic anticancer chemotherapeutic drug of an alkylating type. Chemically it is a nitrosourea derivative. It was developed in the Soviet Union in the 1970s. It was claimed by its developers that its advantages over other nitrosoureas are a relatively low hematological toxicity and a wider therapeutic index, which allows for its outpatient administration.

References

  1. 1 2 3 Kouvaris JR, Kouloulias VE, Vlahos LJ (June 2007). "Amifostine: the first selective-target and broad-spectrum radioprotector". Oncologist. 12 (6): 738–47. doi: 10.1634/theoncologist.12-6-738 . PMID   17602063.
  2. 1 2 3 4 "Amifostine : BC Cancer Agency". British Columbia Cancer Agency. 2006-03-01. Archived from the original on 2015-03-14. Retrieved 2011-01-01.
  3. Koukourakis, Michael I.; Giatromanolaki, Alexandra; Zois, Christos E.; Kalamida, Dimitra; Pouliliou, Stamatia; Karagounis, Ilias V.; Yeh, Tzu-Lan; Abboud, Martine I.; Claridge, Timothy D. W. (2016-08-10). "Normal tissue radioprotection by amifostine via Warburg-type effects". Scientific Reports. 6: 30986. Bibcode:2016NatSR...630986K. doi:10.1038/srep30986. ISSN   2045-2322. PMC   4978965 . PMID   27507219.