Chemotherapeutic agents methotrexate

Other useful targets for pharmaceutical agents are thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis (Fig. 22-49). One inhibitor that acts on thymidylate synthase, fluorouracil, is an important chemotherapeutic agent. Fluorouracil itself is not the enzyme inhibitor. In the cell, salvage pathways convert it to the deoxynucleoside monophosphate FdUMP, which binds to and inactivates the enzyme. Inhibition by FdUMP (Fig. 22-50) is a classic example of mechanism-based enzyme inactivation. Another prominent chemotherapeutic agent, methotrexate, is an inhibitor of dihydrofolate reductase. This folate analog acts as a competitive inhibitor the enzyme binds methotrexate with about 100 times higher affinity than dihydrofolate. Aminopterin is a related compound that acts similarly. 

Several drugs interfere with the normal biodistribution of Tc-pertechnetate (Hla-dik et al. 1987). Thus, cancer chemotherapeutic agents (methotrexate) can affect brain scintigraphy atropine, isoprenaline, and analgesics interfere in abdominal imaging iodine and other blockers (perchlorate, perrhenate) can modify thyroid uptake. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Neutropenia is a condition characterized by a decrease in blood neutrophil count below 1.5 X 109 cells per litre a normal blood count is (2.0-7.5) X 109 cells per litre. Its clinical symptoms include the occurrence of frequent and usually serious infections, often requiring hospitalization. Neutropenia may be caused by a number of factors (Table 10.6), at least some of which are responsive to CSF treatment. Particularly noteworthy is neutropenia triggered by administration of chemotherapeutic drugs to cancer patients. Chemotherapeutic agents (e.g. cyclophosphamide, doxorubicin and methotrexate), when administered at therapeutically effective doses, often induce the destruction of stem cells and/or compromise stem cell differentiation. 

Methotrexate is an antimetabolite chemotherapeutic agent, which may also be used for severe resistant psoriasis. The dose is usually administered orally once a week. Haematological and biochemical parameters are monitored throughout treatment. 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

B. Indications and use Oncaspar is indicated for patients with ALL who require L-asparaginase in their treatment regimen but have developed hypersensitivity to the native forms of the enzyme. Oncaspar, like native L-asparaginase, is generally used in combination with other chemotherapeutic agents, such as vincristine, methotrexate, cytarabine, daunorubicin, and doxorubicin. 

Osiris reported that MSC are able to survive, differentiate and produce hematopoietic cytokines when treated for 24 h with chemotherapeutic agents, such as methotrexate (0.75 or 450 mg/kg) or cisplatin (1 mg/kg), but not doxorubicin (1 mg/kg), suggesting that MSC could be used during the treatment of certain types of cancer [433228]. 

H FIGURE 22-49 Thymidylate synthesis and folate metabolism as targets of chemotherapy, (a) During thymidylate synthesis, /V5,N10-methylenetetrahydrofolate is converted to 7,8-dihydrofolate the N5,N10-methylenetetrahydrofolate is regenerated in two steps (see Fig. 22-44). This cycle is a major target of several chemotherapeutic agents, (b) Fluorouracil and methotrexate are important chemotherapeutic agents. In cells, fluorouracil is converted to FdUMP, which... 

B7. Bruckner, H. W., Schreiber, C., and Waxman, S., Interaction of chemotherapeutic agents with methotrexate and 5-fluorouracil and its effect on de nova DNA synthesis. Cancer. Res. 35, 801-806 (1975). 

High-dose therapy with certain chemotherapeutic agents, including cytosine arabinoside, cyclophosphamide, methotrexate, and 5-fluorouracil, has been implicated in conjunctivitis. However, it appears that low-dose therapy with the anticancer agent tamoxifen is infrequently associated with anterior segment toxicity. 

The data on reported cases of neurological disorders after intrathecal chemotherapy with methotrexate or cytosine arabinoside that could be attributed to benzyl alcohol or to other preservatives have been reviewed in the context of a case of flaccid paraplegia after intrathecal administration of cytosine arabinoside diluted in bacteriostatic water containing 1.5% benzyl alcohol (1). Most commonly, flaccid paraparesis, with absent reflexes, developed rapidly, often with pain and anesthesia. Very often there was full recovery. The prognosis depended mainly on the concentration of the preservative and on the time of exposure. In some cases, the paralysis ascended to cause respiratory distress, cardiac arrest, and death. Only preservative-free sterile CSF substitute or saline, or preferably the patient s own CSF, should be used to dilute chemotherapeutic agents (SEDA-11, 475). 

Huennekens. F.M. (1994) The methotrexate story a paradigm for development cancer chemotherapeutic agents. Adv. Enzyme J egu/., 34,397-419. 

A combination of chemotherapeutic agents and some phenothiazines changed their physicochemical properties. The neuroleptic protonated phenothiazine derivatives, including promethazine, promazine, triflupromazine, methotrimeprazine, propiomazine, trifluoperazine and fluphenazine, were complexed with water-insoluble chemotherapeutic agents such as 5-fluoro-uracil (5-FU), methotrexate (MTX) and sulindac, as well as with components of biomembrane and synthetic phospholipids considered as possible models... 

Chemotherapy-induced acral erythema (Cl AE), atoxic reaction to a number of different chemotherapeutic agents, causes a symmetrical, painful erythema of the palms and soles, often culminating in the formation of vesicles or bullae. Some of the well known chemotherapeutic agents responsible are cytarabine, fluorouracil and methotrexate. 

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