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Pathway Description
Cyclophosphamide Action Pathway (New)
Homo sapiens
Drug Action Pathway
Cyclophosphamide is an antineoplastic alkylating agent used to treat lymphoma and leukemia. Cyclophosphamide is either injected or taken orally to enter the blood where it travels to the liver in order to be activated by various enzymes and cytochrome p450 isoforms (2A6, 2B6, 3A4, 2C9, 2C18, 2C19) eventually into aldophosphamide. Aldophosphamide is released into the bloodstream through Golgi apparatus vesicles. Aldophosphamide is then taken up by cancer cells into the cytosol where it is then degraded into acrolein and carboxyphosphamide but more importantly it turns into phosphoramide mustard, the main cytotoxic agent. Phosphoramide mustard carries out its cytotoxic events in three different ways. Firstly, it alkylates DNA bases resulting in the DNA becoming fragmented by repair enzymes trying to replace the alkylated bases with new ones. This prevents DNA synthesis and RNA transcription as the DNA is damaged and cannot be read properly. Phosphoramide mustard also works by creating crosslinks between DNA bases preventing DNA from being "unzipped" for replication or transcription. Lastly, phosphoramide mustard works by inducing the misfiring of nucleotides leading to single nucleotide polymorphisms that can possibly cause larger-scale problems in mutations. All three mechanisms of phosphoramide mustard inhibit cellular survival through replication and RNA synthesis, effectively killing the cancer cell. Because the metabolism of cyclophosphamide is linked with the production of the active cytotoxic agent, cyclophosphamide induces its own metabolism with results in an increase in blood plasma clearance (short half-lives). Cyclophosphamide also can cause adverse effects such as alopecia (spot baldness), sterility, birth defects, mutations, and other types of cancer. It is administered as an intravenous injection or an oral tablet.
References
Cyclophosphamide Pathway (New) References
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Fleming RA: An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):146S-154S.
Pubmed: 9322882
Shepherd G, Cyclophosphamide, Encyclopedia of Toxicology 2: 709-711, 2005
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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