Chlornaphazine

Last updated
Chlornaphazine
Chlornaphazine.svg
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 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
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 2-naphthylamine, is a nitrogen mustard that was developed in the 1950s for the treatment of polycythemia and 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]

Contents

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. [8] The possibility of nitrogen mustards to chemically inhibit abnormal cell growth was explored and accelerated through wartime studies of the physiological effects of war gases. [9] The war gas known as nitrogen mustard appeared to be a potential drug for the treatment of leukemia, Hodgkin's disease, and lymphadenopathies in general due to its destructive effect on the bone marrow and particularly on the hemopoietic system. [9] The anti-carcinoma activity of nitrogen mustards is based on their action on mitosis, inhibiting the growth of both normal and abnormal dividing cells. [10] Due to the undesirable side effects of nitrogen mustard, chlornaphazine, another member of the nitrogen mustard series with a similar tumor-inhibiting capacity was developed. Just like the other active nitrogen mustards, chlornaphazine belongs to the direct-acting 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

Jar of chlornaphazine used by J.F. Wilkinson in chemotherapy trials, 1950s Chlornaphazine.jpg
Jar of chlornaphazine used by J.F. Wilkinson in chemotherapy trials, 1950s

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. [19] Chlornaphazine was an effective medicine for treating fever, weight loss, itching, and sweating which are symptoms of advanced stages of Hodgkin's disease. [19] These beneficial effects were notable when 200-400 mg chlornaphazine was administered daily for months to years. [19] Hodgkin's disease can be treated with chemotherapy consisting of chlornaphazine alone or in combination with other cytostatic drugs. [20] A study that investigated the efficacy of cytostatic treatment for Hodgkin's disease reported that 73% of the patients went into complete remission after receiving cytostatic drugs for 23 months. [20] Chemotherapy can also be combined with radiotherapy. To patients who became resistant to radiation, nitrogen mustards such as chlornaphazine could be administered. [10] In patients with Hodgkin's disease treated with nitrogen mustards tumor masses regressed rapidly. [10] However, tumors reoccurred more rapidly compared to 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. [21]

Adverse effects

Initially, it was reported that chlornaphazine has no major adverse effects since no immediate side effects were found. [19] However, years later, multiple cases were reported of patients treated with chlornaphazine for Hodgkin's disease who were diagnosed with bladder cancer several years after the chlornaphazine treatment had been stopped. [22] In addition, 30% of the polycythemia patients treated with chlornaphazine had developed bladder cancer. [23] These cases and additional research shed light on this alarming side effect of chlornaphazine. It was concluded that chlornaphazine treatment can induce bladder cancer 3 to 10 years after treatment. [24]  Development of bladder cancer was only observed in patients who had received a minimal total dose of 100 g chlornaphazine and therefore this late adverse effect is dose-dependent. [6] Common adverse effects of alkylating agents in general are increased risk of malignancy, impaired spermatogenesis, intestinal mucosal damage, 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. [25] 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. [26] 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 hepatocytes. [27] [28] In addition, chlornaphazine induces chromosomal abnormalities in erythrocytes in both mouse and rat bone marrow. [28] It has been reported that chornaphazine is a genetic hazard to the offspring of mice previously exposed to this drug since it is highly mutagenic in post-meiotic male germ cells. [29] Moreover, mice injected with chlornaphazine intraperitoneally developed lung tumors whereas rats injected with chlornaphazine subcutaneously developed local sarcomas. [30] In contrast to rodents, dogs are suitable for studying bladder carcinogens, such as chlornaphazine, since the metabolism of aromatic amines in dogs is similar to that in humans due to the comparable urine pH and urination frequency of both species. [31] Animal experiments had also been performed to expand the knowledge of the carcinogenic effects of chlornaphazine's metabolite 2-naphthylamine. Like in humans, 2-naphthylamine induces bladder tumors in dogs, [32] [33] monkeys, [34] and hamsters. [35] Bladder cancer can be induced in rats, but 2-naphthylamine is a very weak carcinogen in rats due to their urine pH, urination frequency, and resorption. [31] [36] In mice, 2-naphthylamine caused an increase in hepatomas, liver adenomas, and cholangiomas. [37] [38]

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 the type of cancer treatment that uses one or more anti-cancer drugs in a standard regimen. Chemotherapy may be given with a curative intent, or it may aim only 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.

<span class="mw-page-title-main">Mutagen</span> Physical or chemical agent that increases the rate of genetic mutation

In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

<span class="mw-page-title-main">Azathioprine</span> Immunosuppressive medication

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.

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

Sudan I is an organic compound, typically classified as an azo dye. It is an orange-red solid that is added to colorize waxes, oils, petrol, solvents, and polishes. Historically, Sudan I serves as a food coloring agent, especially for curry powder and chili powder. Owing to its classification as a category 3 carcinogenic hazard by the International Agency for Research on Cancer, Sudan I, along with its derivatives Sudan III and Sudan IV, have been banned in many countries including the United States and European Union. Nevertheless, Sudan I remains valuable as a coloring reagent for non-food-related uses, such as in the formulation of orange-colored smoke.

<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">Chlormethine</span> Chemical compound

Chlormethine, also known as mechlorethamine, mustine, HN2, and embikhin (эмбихин), is a nitrogen mustard sold under the brand name Mustargen among others. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.

<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.

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

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

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

Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma. For CLL it is a preferred treatment. It is given by mouth.

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

Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.

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

Lomustine 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.

4-Aminobiphenyl (4-ABP) is an organic compound with the formula C6H5C6H4NH2. It is an amine derivative of biphenyl. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this aryl-amine can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder cancer in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.

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

Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder and neurogenic detrusor overactivity (NDO). It may help with incontinence, urinary frequency, and urinary urgency.

<span class="mw-page-title-main">DNA adduct</span> Segment of DNA bound to a cancer-causing chemical

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

<span class="mw-page-title-main">Alkylating antineoplastic agent</span> Pharmaceutical drugs

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

<i>o</i>-Toluidine Aryl amine

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor.

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

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.

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

Semustine is an alkylating nitrosourea compound used in chemotherapy treatment of various types of tumours. Due to its lipophilic property, semustine can cross the blood-brain barrier for the chemotherapy of brain tumours, where it interferes with DNA replication in the rapidly-dividing tumour cells. Semustine, just as lomustine, is administered orally. Evidence has been found that treatment with semustine can cause acute leukaemia as a delayed effect in very rare cases.

<span class="mw-page-title-main">2-Acetylaminofluorene</span> Chemical compound

2-Acetylaminofluorene is a carcinogenic and mutagenic derivative of fluorene. It is used as a biochemical tool in the study of carcinogenesis. It induces tumors in a number of species in the liver, bladder and kidney. The metabolism of this compound in the body by means of biotransformation reactions is the key to its carcinogenicity. 2-AAF is a substrate for cytochrome P-450 (CYP) enzyme, which is a part of a super family found in almost all organisms. This reaction results in the formation of hydroxyacetylaminofluorene which is a proximal carcinogen and is more potent than the parent molecule. The N-hydroxy metabolite undergoes several enzymatic and non-enzymatic rearrangements. It can be O-acetylated by cytosolic N-acetyltransferase enzyme to yield N-acetyl-N-acetoxyaminofluorene. This intermediate can spontaneously rearrange to form the arylamidonium ion and a carbonium ion which can interact directly with DNA to produce DNA adducts. In addition to esterification by acetylation, the N-hydroxy derivative can be O-sulfated by cytosolic sulfur transferase enzyme giving rise to the N-acetyl-N-sulfoxy product.

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

Apaziquone is an indolequinone that is a bioreductive prodrug similar to the older chemotherapeutic agent mitomycin C. In hypoxic cells, such as those on the inner surface of the urinary bladder, apaziquone is converted to active metabolites by intracellular reductases. The active metabolites alkylate DNA and lead to apoptosis. This activity is preferentially expressed in neoplastic cells.

References

  1. ↑ Videbaek, A.; Kaae, S. (1954). "2-Naphthylbis(chloroethyl)amine in the treatment of malignant diseases, particularly Hodgkin's disease". Acta Medica Scandinavica. 149 (5): 361–368. doi:10.1111/j.0954-6820.1954.tb11446.x. PMID   13180246.
  2. ↑ Benedicte Laursen (1970). "Cancer of the Bladder in Patients Treated with Chlornaphazine". Br Med J. 3 (5724): 684–685. doi:10.1136/bmj.3.5724.684. PMC   1701774 . PMID   5470116.
  3. ↑ N,N-Bis(2-Chloroethyl)-2-Naphthylamine (Chlornaphazine), International Agency for Research on Cancer
  4. ↑ PubChem. "Chlornaphazine". pubchem.ncbi.nlm.nih.gov.
  5. 1 2 3 Humans, IARC Working Group on the Evaluation of Carcinogenic Risks to (2012). CHLORNAPHAZINE. International Agency for Research on Cancer.
  6. 1 2 3 4 Thiede, Torben; Chievitz, Eva; Christensen, Børge Chr. (1964). "Chlornaphazine as a Bladder Carcinogen". Acta Medica Scandinavica. 175 (6): 721–725. doi:10.1111/j.0954-6820.1964.tb00628.x. PMID   14171978.
  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.
  8. ↑ Clark, T. J. H. (1970). "Inspiratory Obstruction". BMJ. 3 (5724): 682–684. doi:10.1136/bmj.3.5724.682. ISSN   0959-8138. PMC   1701769 . PMID   5470115.
  9. 1 2 Davis, W. (1957). Some attempts at chemotherapy of cancer. Postgraduate Medical Journal. p. 540.
  10. 1 2 3 4 Garai, O. (1948). "Nitrogen Mustard". Postgraduate Medical Journal. 24 (272): 307–311. doi:10.1136/pgmj.24.272.307. ISSN   0032-5473. PMC   2529779 . PMID   18864652.
  11. 1 2 Bordin, Diana L.; Lima, Michelle; Lenz, Guido; Saffi, Jenifer; Meira, Lisiane B.; Mésange, Paul; Soares, Daniele G.; Larsen, Annette K.; Escargueil, Alexandre E.; Henriques, João A. P. (2013). "DNA alkylation damage and autophagy induction". Mutation Research/Reviews in Mutation Research. 753 (2): 91–99. Bibcode:2013MRRMR.753...91B. doi:10.1016/j.mrrev.2013.07.001. ISSN   1383-5742. PMID   23872363.
  12. 1 2 3 "Alkylating Agents", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID   31643188
  13. 1 2 Karmakar, Subhendu; Maji, Moumita; Mukherjee, Arindam (2019). "Modulation of the reactivity of nitrogen mustards by metal complexation: approaches to modify their therapeutic properties". Dalton Transactions. 48 (4): 1144–1160. doi:10.1039/C8DT04503H. ISSN   1477-9234. PMID   30629051. S2CID   58571271.
  14. 1 2 3 Wang, Shuang; Hanna, Daniel; Sugamori, Kim S.; Grant, Denis M. (2019). "Primary aromatic amines and cancer: Novel mechanistic insights using 4-aminobiphenyl as a model carcinogen". Pharmacology & Therapeutics. 200: 179–189. doi:10.1016/j.pharmthera.2019.05.004. ISSN   0163-7258. PMID   31075357. S2CID   149454319.
  15. 1 2 3 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.
  16. 1 2 Freudenthal, Ralph I.; Stephens, Ellen; Anderson, Daniel P. (1999). "Determining the Potential of Aromatic Amines to Induce Cancer of the Urinary Bladder". International Journal of Toxicology. 18 (5): 353–359. doi: 10.1080/109158199225260 . ISSN   1091-5818. S2CID   86180301.
  17. ↑ Poupko, Jay M.; Hearn, William Lee; Radomski, Jack L. (1979). "N-Glucuronidation of N-hydroxy aromatic amines: A mechanism for their transport and bladder-specific carcinogenicity". Toxicology and Applied Pharmacology. 50 (3): 479–484. Bibcode:1979ToxAP..50..479P. doi:10.1016/0041-008X(79)90401-0. ISSN   0041-008X. PMID   516060.
  18. ↑ "751.510 | Collections Online". collections.thackraymuseum.co.uk. Retrieved 2024-08-08.
  19. 1 2 3 4 VIDEBaeK, Aage (1964). "Ghlornaphazin (Erysan®) May Induce Cancer of the Urinary Bladder". Acta Medica Scandinavica. 176 (1): 45–50. doi:10.1111/j.0954-6820.1964.tb00643.x.
  20. 1 2 Andersen, E.; Christensen, B. Egelund; Videbaek, Aa. (1972). "Treatment of Hodgkin's Disease: Results Obtained by Individualized Treatment Using Radiotherapy and Cytostatics". Scandinavian Journal of Haematology. 9 (1–6): 625–638. doi:10.1111/j.1600-0609.1972.tb00994.x. PMID   4630133.
  21. ↑ Schottenfeld, D. (1982). "Cancer Risks of Medical Treatment". CA: A Cancer Journal for Clinicians. 32 (5): 258–279. doi: 10.3322/canjclin.32.5.258 . ISSN   0007-9235. S2CID   221546560.
  22. ↑ Laursen, B. (1970). "Cancer of the Bladder in Patients Treated with Chlornaphazine". BMJ. 3 (5724): 684–685. doi:10.1136/bmj.3.5724.684. ISSN   0959-8138. PMC   1701774 . PMID   5470116.
  23. ↑ Schmähl, D. (1981). "Iatrogenic carcinogenesis". Journal of Cancer Research and Clinical Oncology. 99 (1–2): 71–75. doi:10.1007/BF00412444. ISSN   0171-5216. PMID   7251640. S2CID   33262182.
  24. ↑ Thiede, Torben; Christensen, Børge Chr. (1969). "BLADDER TUMOURS INDUCED BY CHLORNAPHAZINE: A Five-year Follow-up Study of Chlornaphazine-treated Patients with Polycythaemia". Acta Medica Scandinavica. 185 (1–6): 133–137. doi:10.1111/j.0954-6820.1969.tb07309.x. PMID   5257690.
  25. ↑ 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.
  26. ↑ Habs, M; Schmähl, D (1984). Long-term Toxic and Carcinogenic Effects of Cytostatic Drugs. Heidelberg: German Cancer Research Center. p. 201.
  27. ↑ 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.
  28. 1 2 Ashby, J.; Loquet, C.; Ishidate, M.; Callander, R. D.; Albanese, R. (1988). "Mutagenicity to bacteria, cultured cells, and rodents of the human carcinogen chlornaphazine". Environmental Mutagenesis. 12 (4): 365–374. doi:10.1002/em.2860120405. PMID   3056719.
  29. ↑ Barnett, Lois B; Lewis, Susan E (2003). "Chlornaphazine and chlorambucil induce dominant lethal mutations in male mice". Mutation Research/Reviews in Mutation Research. Special Issue in Honor of James V. Neel. 543 (2): 145–154. Bibcode:2003MRRMR.543..145B. doi:10.1016/S1383-5742(03)00012-7. ISSN   1383-5742. PMID   12644184.
  30. ↑ Hottendorf, Girard H. (1985). "Carcinogenicity Testing of Antitumor Agents". Toxicologic Pathology. 13 (3): 192–199. doi: 10.1177/019262338501300305 . ISSN   0192-6233. PMID   4070930. S2CID   29805276.
  31. 1 2 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.
  32. ↑ 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.
  33. ↑ Purchase, I F; Kalinowski, A E; Ishmael, J; Wilson, J; Gore, C W; Chart, I S (1981). "Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs". British Journal of Cancer. 44 (6): 892–901. doi:10.1038/bjc.1981.289. ISSN   0007-0920. PMC   2010866 . PMID   7326199.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ Hicks, R M; Wright, R; Wakefield, J S J (1982). "The induction of rat bladder cancer by 2-naphthylamine". British Journal of Cancer. 46 (4): 646–661. doi:10.1038/bjc.1982.250. ISSN   0007-0920. PMC   2011196 . PMID   7138770.
  37. ↑ Bonser, Georgiana M; Clayson, D B; Jull, J W (1956). "The Induction of Tumours of the Subcutaneous Tissues, Liver and Intestine in the Mouse by Certain Dyestuffs and their Intermediates". British Journal of Cancer. 10 (4): 653–667. doi:10.1038/bjc.1956.79. ISSN   0007-0920. PMC   2073864 . PMID   13426377.
  38. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.