Antiproliferative agent

Methotrexate is a folic acid analog. It inhibits folic acid synthetic pathways and DNA synthesis (Bannwarth et al., 1994). Methotrexate is widely used in the treatment of breast and other cancers. Methotrexate has recently gained favor for, and is approved for, the treatment of rheumatoid arthritis in adults who have severe active classical rheumatoid arthritis (O Dell, 2004). It is also used to treat psoriasis and graft vs host disease. 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Mycophenolate mofetil has replaced azathioprine as the major antiproliferative agent used to prevent transplant rejection. It is usually used in combination with glucocorticoids and a calcineurin inhibitor (Mele and Halloran, 2000). 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

Sirohmus is used for the prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoid. In patients at high risk for nephrotoxicity it has been combined with glucocorticoids and mycophenolate to avoid permanent renal damage (Kahan and Camardo, 2001). 

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Antiperspirant sticks Antiplasticization Antiprex Antiprogestin Antiprogestins Antiproliferative agents Antiprotozoal... 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

Antiproliferative agents Methylating agents Chlor-oethylating agents... 

MPA derivatives have replaced azathioprine as the antiproliferative agent of choice in most organ transplant centers. The MPA derivatives generally are considered to provide a more specific immunosuppressive effect compared with azathioprine. Mycophenolate mofetil and enteric-coated mycophe-nolic acid have similar safety and efficacy data in renal transplant recipients. 

The optimal timing of laser or surgical trabeculectomy is controversial, ranging from initial therapy to after failure of third- or fourth-line drug therapy. Antiproliferative agents such as fluorouradl and mitomycin C are used to modify the healing process and maintain patency. 

DKPs have been investigated as antiproliferative agents through the inhibition of DNA topoisomerase 11. ... 

Artemisinin, a tetracyclic 1,2,4-trioxane isolated from Artemisia annua L., is currently recommended as a first-line agent against Plasmodium falciparum malaria. Artemisinin and its synthetic derivatives have also been shown to be promising prototypes for the development of new antiproliferative agents. This chapter presents the recent advances on the analytic methods for extraction and quantification of artemisinin from A. annua plants as well as the biological properties of this natural product. 

Table 15.1 Molecular Targets of Resveratrol as an Antiproliferative Agent...

A number of 1,3-selenazole and 1,3-selenazine derivatives have been reported as antiproliferative agents. The most active against human fibrosarcoma HT-1080 cells were 1,3-selenazines (166) [269], Further, certain 2-phosphonoalkylben-zisoselenazol-3(2//)-ones (167) were synthesized and their potent activity against human carcinoma cells in vitro was reported [164],... 

T ble 2 Preclinical studies of antimigratory and antiproliferative agents for their ability to prevent restenosis ... 

Paclitaxel is a well-established antiproliferative agent with a microtubule-targeting pharmacologic activity (37,42,43). As an anticancer agent, paclitaxel causes polymerization and stabilization of microtubules (43-45). The stabilization of microtubule dynamics by paclitaxel can interrupt many cellular processes, including cell division, migration, activation, maintenance of cytoskeletal framework, and intracellular as well as transmembrane protein transport (42,46,47). 

The last remaining question is if AVI-4126 will find a place in future therapeutic regimens for the prevention of restenosis this answer might be found in the results of phase II clinical studies currently being conducted, such as AVAIL. Our recent data on six-month follow-up on the patients enrolled in the AVAIL study (87) showed that AVI-4126 is effective in reducing neointimal formation, particularly when locally delivered in high dose. We also concluded that local delivery of antisense is safe and feasible, The results indicate that antisense (AVI-4126) can be as effective in prevention of the restenosis as most of the well-known antiproliferative agents do, but in contrast to other chemotherapeutics (paclitaxel, actinomycin D) c-myc antisense inhibits cell cycle in the G-1 phase, which make its effect less toxic and comparable with that of rapamycin. 

Hamels D, Dansette PM, Hillard EA, Top S, Vessieres A, Herson P, Jaouen G, Mansuy D (2009) Ferrocenyl quinone methides as strong antiproliferative agents formation by metabolic and chemical oxidation of ferrocenyl phenols. Angew Chemlnt Ed Engl 48 9124-9126... 

J.P. Whitten et al, US Patent 6,933,396 (August 23, 2005) Assignee Cylene Pharmaceuticals Utility Antiprolification Agents... 

Xanthone epoxides, (I), and 4-morpholinobut-2-yn derivatives, (II), prepared by Lin (1) and Bombardelli (2), respectively, were effective as antiproliferative agents and in containing the spread of abnormal cell growth. 

Table 1 Selected bicyclicpyrknidone derivatives and their corresponding mass spectra characterization. All experimental derivatives were effective as antiproliferative agents...

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