Arabinopyranosyl-N-methyl-N-nitrosourea

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 (compared to other nitrosoureas available at that time) and a wider therapeutic index, which allows for its outpatient administration.[1]

Arabinopyranosyl-N-methyl-N-nitrosourea
Clinical data
Trade namesAranose
Other namesArabinopyranosyl methylnitrosourea; 3-(α-L-Arabinopyranosyl)-1-methyl-1-nitrosourea
AHFS/Drugs.comMonograph
Pregnancy
category
  • D
Routes of
administration		Intravenously
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100%
Protein binding50%
MetabolismHepatic
Identifiers
  • 1-Methyl-1-nitroso-3-[(2R,3R,4S,5S)-3,4,5-trihydroxyoxan-2-yl]urea
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC7H13N3O6
Molar mass235.194595 g·mol−1
3D model (JSmol)
  • CN(C(=O)NC1C(C(C(CO1)O)O)O)N=O
  • InChI=1S/C7H13N3O6/c1-10(9-15)7(14)8-6-5(13)4(12)3(11)2-16-6/h3-6,11-13H,2H2,1H3,(H,8,14)/t3-,4-,5+,6+/m0/s1 checkY
  • Key:BADMGRJDJPQBLS-UNTFVMJOSA-N checkY
  (verify)

History

It was first synthesized in late 1970s in the Laboratory of Organic Synthesis of Soviet Cancer Research Institute (which belonged to Academy of Medical Sciences of the USSR). Its first clinical trials in USSR were conducted in the late 1980s. Those trials confirmed its potential clinical efficacy in melanoma and better relative safety & improved tolerability over other nitrosourea antineoplastic compounds available at that time. In 1996 the compound obtained a Russian Pharmacologic Committee (a Russian analog of the U.S. Food and Drug Administration (FDA) and EMA in the European Community) regulatory approval for its use in melanoma under the trade name Aranoza.

Chemical structure

The compound is basically a conjugate between the well-known cytotoxic and mutagenic residue of N-nitroso-N-methylurea and the sugar L-arabinose. The L-arabinose is a well-known component of some other effective anticancer drug molecules, including cytarabine (cytosine arabinoside) and fludarabine (2-fluoro-arabinoside of the nucleoside adenosine). The presence of L-arabinoside residue in the molecule greatly improves its penetration into malignant cells and its blood–brain barrier penetration and, while maintaining or even increasing anticancer activity, reduces the toxicity for normally fast dividing cells (bone marrow cells and mucosa of the gastro-intestinal system), improving the concentration ratio "tumor / normal tissue".

Mechanism of action

Alkylating DNA with DNA intra-strand adducts and, more problematic to the cell, cross-linking between strands. This, in turn, inhibits mitosis and promotes apoptosis of the cell affected.

Types of cancer for which it is indicated

Melanoma of the skin and eye, together with dacarbazine and interferon-alpha in combination chemotherapy.[2] During preclinical trials it also shown some potential promise (in combination chemotherapy with cisplatin and gemcitabine[3] or with cisplatin and irinotecan[4]) for experimental non-squamous cell lung cancer.

Main side effects

Like many other cytotoxic drugs, it can often cause alopecia, headache, muscle pain, joint pain, nausea and vomiting, myelosuppression with leukopenia (especially neutropenia), lymphopenia, thrombocytopenia, anemia and immunosuppression. At therapeutic doses, those side effects are usually relatively milder compared with carmustine and lomustine.

References
  1. Pokrovskiĭ VS, Treshchalin MI, Bodiagin DA, Treshchalina EM (May 2010). "[Hematological toxicity of some combined chemotherapy schemes involving aranoza]". Eksperimental'naia i Klinicheskaia Farmakologiia. 73 (5): 36–40. PMID 20597370.
  2. Gershanovich ML, Akimov MA (2004). "[Chemoimmunotherapy with dacarbazine and aranose combined with interferon-alpha in disseminated cutaneous melanoma]". Voprosy Onkologii. 50 (2): 179–83. PMID 15176220.
  3. Pokrovsky VS, Lesnaya NA, Romanenko VI, Treshalina EM (December 2009). "Efficiency and tolerance of aranose combinations with cisplatin and gemcitabine in experimental lung cancer". Bulletin of Experimental Biology and Medicine. 148 (6): 911–4. doi:10.1007/s10517-010-0850-2. PMID 21116505. S2CID 7295889.
  4. Pokrovskiĭ VS, Lesnaia NA, Romanenko VI, Treshchalina EM (2009). "[Pre-clinical study of combined aranosa, cisplatin and irinotecan in the treatment of experimental lung cancer]". Voprosy Onkologii. 55 (3): 341–4. PMID 19670735.
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