Chlornaphazine

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Chlornaphazine
Names
Preferred IUPAC name
N,N-Bis(2-chloroethyl)naphthalen-2-amine
Other names
Chlornapazine; 2-Naphthylbis(chloroethyl)amine
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
ECHA InfoCard
 100.007.078 Edit this at Wikidata
KEGG
UNII
  • InChI=1/C14H15Cl2N/c15-7-9-17(10-8-16)14-6-5-12-3-1-2-4-13(12)11-14/h1-6,11H,7-10H2
    Key: XCDXSSFOJZZGQC-UHFFFAOYAW
  • ClCCN(c2ccc1c(cccc1)c2)CCCl
Properties
C14H15Cl2N
Molar mass 268.18 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Chlornaphazine, a derivative of

Hodgkin's disease.[1] However, a high incidence of bladder cancers in patients receiving treatment with chlornaphthazine led to use of the drug being discontinued.[2]

The International Agency for Research on Cancer has listed chlornaphazine as a human carcinogen.[3]

Chlornaphazine appears as a brown solid or as colorless plates and has a boiling point of 210 °C at 5 mmHg.[4]

History

Medical use

Chlornaphazine was clinically used as a

cytostatic agent for the treatment of Hodgkin's disease and polycythemia vera in multiple countries including Denmark and Italy.[5]

Discontinued use

Chlornaphazine was discontinued as a clinical drug due to sufficient evidence for carcinogenicity in humans. The drug caused cancer of the urinary bladder. In the Medical Department of the Finsen Institute in Copenhagen, Danish researchers observed many patients over the years with polycythemia vera who had been administered different total doses of chlornaphazine.[6] The initial therapeutic results reported in 1961 indicated that 75% of 32 patients that used chlornaphazine experienced a favorable effect.[6] At the time of the analysis, seven patients died and in the autopsy of one of these patients, a carcinoma of the bladder was accidentally found.[6] In a subsequent study from the Medical Department of the Finsen Institute, 61 patients diagnosed with polycythemia vera that had been treated with chlornaphazine were followed.[5] It was found that among the 61 patients, eight patients developed an invasive carcinoma of the bladder, another eight patients had abnormal urinary cytology, and five patients had developed a papillary carcinoma grade II of the bladder.[5] This led to the discontinuation of chlornaphazine in Denmark in 1963.[7]

Mechanism of action

Chlornaphazine is a nitrogen mustard that was predominantly used in Scandinavia as a treatment for polycythemia and Hodgkin's disease.

alkylating agents. It exerts its cytotoxic action by attaching an alkyl group to a lone pair of electrons on an atom of a wide variety of biological molecules by nucleophilic substitution. Through this covalent modification of DNA, chlornaphazine can interfere with essential processes in cancer cells, including DNA replication and protein synthesis.[11] Since this drug is a bifunctional alkylator, it can react at two different sites in the DNA, forming intra- and interstrand cross-links.[11] The structural modifications of DNA caused by chlornaphazine lead to misreading of the DNA code, the inhibition of DNA, RNA, and protein synthesis, and programmed cell death.[12] Cancer cells are among the most affected since alkylating agents have their primary effect on rapidly proliferating cells which do not have time for DNA repair.[12]

Reactivity

The ability to alkylate DNA bases is the predominant aspect of the reactivity of chlornaphazine in the body. The N7 of guanine bases is the preferred position for alkylation since it is the most nucleophilic and accessible site.[13] The mechanism of reaction with DNA proceeds through two successive SN2 reactions in which the N(CH2CH2Cl)2 moiety of chlornaphazine is involved. In the first reaction, the nitrogen acts as a nucleophile to form an aziridinium ion by displacing the halogen.[13] The aziridinium ion is subsequently attacked by nucleophilic sites in DNA. When these two steps are repeated with the second CH2CH2Cl side chain, intra- or interstrand cross-links can be formed.

Metabolism

After oral administration and subsequent absorption, chlornaphazine is metabolized to 2-naphthylamine which is N-acetylated by N-acetyltransferase (NAT) 2 in the liver.[14][15] This is a detoxification reaction since it leads to the formation of non-reactive compounds. Alternatively, CYP1A2, a member of the cytochrome P450 superfamily may convert 2-naphthylamine in its N-hydroxy metabolite.[15] The N-hydroxy metabolite can be further metabolized in the liver or transported to the urinary bladder. In the liver, it can undergo S-glutathionylation catalyzed by glutathione S-transferase Mu 1 (GSTM1), which involves the substitution of the hydroxy group by glutathione.[15] This reaction leads to the detoxification of the N-hydroxy metabolite. The other biotransformation that may occur in the liver is the conjugation with glucuronic acid for which the cosubstrate uridine diphosphate-glucuronic acid (UDPGA) and enzyme UDP-glucuronosyltransferase are required.[16] The stability of the N-glucuronides at neutral pH allows the transport via the blood to the kidneys where they are excreted into the urine.[17] Under the mildly acidic conditions of the urine, the glucuronide is hydrolyzed, liberating the N-hydroxy metabolite in the bladder.[16] The bladder epithelium further activates the N-hydroxy amine to an arylnitrenium ion. A second mechanism through which the N-hydroxy metabolites can be activated to arylnitrenium ions is via NAT1-catalyzed O-acetylation in the bladder.[14] The products of chlornaphazine biotransformation are eliminated in the urine.

Efficacy

Due to its pronounced cytostatic effect, free solubility in water, and easy absorption from the intestinal tract, chlornaphazine appeared to be a suitable treatment for malignant systemic diseases such as Hodgkin's disease and polycythemia vera.

X-ray therapy.[10] Although chlornaphazine was an effective treatment for polycythemia vera, the risks of chlornaphazine were too high making alternative treatments more advantageous.[20]

Adverse effects

Initially, it was reported that chlornaphazine has no major adverse effects since no immediate side effects were found.

alopecia, anemia, pancytopenia, and amenorrhea.[12]

Toxicity

Cancer of the urinary bladder has been observed in many cases treated with chlornaphazine. It has been implied that the carcinogenic effect is caused by the metabolites, whereas the chemotherapeutic action is due to the drug itself.[24] Chlornaphazine contains a nitrogen mustard group at the basic molecule of 2-naphthylamine. The biotransformation of chlornaphazine involves the cleavage of the chloroethyl group, resulting in the formation of 2-naphthylamine.[25] The carcinogenic effect of this compound on the human urinary bladder is well known. The bioactivation of 2-naphthylamine in the liver and urinary bladder results in the formation of products that readily decompose to form reactive arylnitrenium ions. These ions are reactive electrophiles that form adducts by covalently binding to nucleophilic sites on proteins, DNA, and RNA.[14] The tumor induction of chlornaphazine derivatives is specific to the urinary bladder since the carcinogenic metabolites can only be liberated by the acidic environment of urine.

Effects on animals

The mutagenic effects of chornaphazine are studied in multiple animal models. Many studies have shown that rodents are inappropriate animal models to study the carcinogenicity of chlornaphazine due to differences in metabolic pathways between humans and rodents. Therefore, rodents treated with chlornaphazine usually do not develop bladder cancer like humans. Chlornaphazine was shown to cause chromosomal abnormalities in Chinese hamster lung cells, mutations in lymphoma cells of mice, and spontaneous in vitro synthesis of DNA in rat

liver adenomas, and cholangiomas.[36][37]

References

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  3. ^ N,N-Bis(2-Chloroethyl)-2-Naphthylamine (Chlornaphazine), International Agency for Research on Cancer
  4. ^ PubChem. "Chlornaphazine". pubchem.ncbi.nlm.nih.gov.
  5. ^ a b c Humans, IARC Working Group on the Evaluation of Carcinogenic Risks to (2012). CHLORNAPHAZINE. International Agency for Research on Cancer.
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  7. ^ Konz, J. (1994). SUBJECT: Review of ERM's Cancer Risk Assessment and Recommendations for Alternative Provisional Qualitative and Quantitative Assessments. Drake Chemical/Lock Haven, PA. p. 94.
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  15. ^ a b c Antonova, O; Toncheva, D; Grigorov, E (2015). Bladder cancer risk from the perspective of genetic polymorphisms in the carcinogen metabolizing enzymes. Journal of B.U.ON.: official journal of the Balkan Union of Oncology. pp. 1397–1406.
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  24. ^ Boyland, E (1967). Biochemical Aspects of Carcinogenesis with Special Reference to Alkylating Agents and Some Antibiotics. Berlin, Heidelberg: Potential Carcinogenic Hazards from Drugs. pp. 204–208.
  25. ^ Habs, M; Schmähl, D (1984). Long-term Toxic and Carcinogenic Effects of Cytostatic Drugs. Heidelberg: German Cancer Research Center. p. 201.
  26. ^ Genetic and related effects: An updating of selected IARC monographs from Volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl. 1987. pp. 1–729.
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  30. ^ a b Young, J.F.; Kadlubar, F.F. (1982). A pharmacokinetic model to predict exposure of the bladder epithelium to urinary N-hydroxyarylamine carcinogens as a function of urine pH, voiding interval, and resorption. Drug Metab Dispos. pp. 641–644.
  31. ^ Conzelman, G.M. Jr; Moulton, J.E. (1972). Dose-response relationships of the bladder tumorigen 2-naphthylamine: a study in beagle dogs. J Natl Cancer Inst. pp. 193–205.
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  33. ^ Conzelman, G.M Jr; Moulton, J.E.; Flanders, L.E.; Springer, K; Crout, D.W. (1969). Induction of transitional cell carcinomas of the urinary bladder in monkeys fed 2-naphthylamine. J Natl Cancer Inst. pp. 825–836.
  34. ^ Saffiotti, U; Cefis, F; Montesano, R; Sellakumar, A (1967). Induction of bladder cancer in hamsters fed aromatic amines. Bladder Cancer:. Deichmann, W., Lampe, KG, editors. pp. 129–135.
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  37. ^ Yoshida, M; Numoto, S; Otsuka, H (1979). Histopathological changes induced in the urinary bladder and liver of female BALB/c mice treated simultaneously with 2-naph-thylamine and cyclophosphamide. Gan. pp. 645–652.
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