Project topics and materials
Get Complete Project Material File(s) Now! »
Introduction
Methotrexate (MTX) was developed 50 years ago and was primarily used to treat malignancies such as breast cancer (Dollery, 1999). It can however also be used in the treatment of autoimmune diseases such as rheumatoid arthritis (RA), graft vs host disease (GVD), psoriasis and Chron’s disease. This antiinflammatory use started about 15 years ago in the treatment of RA (Majumdar & Aggarwal, 2001).
History of MTX
Folic acid is a vitamin in the B-complex family. After its identification and synthesis, researchers started to synthesize analogues of folic acid in which small changes were made to the molecule (Jukes, 1978). The first analogue researched was “crude x-methyl folic acid” which was prepared by using butyraldehyde in the synthetic reaction.
Structure of Methotrexate (British Pharmacopoeia, 1999)
Methotrexate (C20H22N8O5) is a mixture of 4-amino-10-methylfolic acid and is part of the antimetabolite drug group which includes oncology medication and immune suppressants (Sommers, 2001; United States Pharmacopoeia, 1999; Dollery, 1999). It is a yellow to orange-brown crystalline powder and is presently used as an anti-metabolite in the treatment of cancer or in the treatment of auto-immune and other inflammatory disorders. Its structure can
be seen in Figure.
Mechanism of action of methotrexate
The first target identified for MTX was the enzyme dihydrofolate reductase (DHFR). DHFR catalyzes the reduction of dihydrofolate (FH2) to tetrahydrofolate (FH4). MTX is similar in structure to dihydrofolate (FH2) and is a competitive inhibitor of DHFR with the result that the tetrahydrofolate
(FH4), essential for DNA synthesis, is then not produced. This interferes with the mitosis of cancerous cells by inhibiting the de novo synthetic pathways for purines, pyrimidines, formation of polyamines and transmethylation of DNA, RNA, phospholipids and proteins (Lee & Weinblatt, 2001)(Figure 1.3 and Figure 1.4).
CHAPTER 1
1. Introduction
1.1 History of methotrexate
1.2 Mechanism of action of methotrexate as anti-inflammatory and as anti-cancer drug
1.3 Pharmacokinetics of methotrexate
1.4 Drug resistance and drug-drug-interactions
1.5 Toxicity
1.6 Drug delivery systems
1.7 Hypothesis, aim and objective
1.8 Ethical considerations and funding
CHAPTER 2
2. In vitro cytotoxicity
2.1 Introduction
2.2 Materials and methods
2.3 Results
2.4 Discussion
CHAPTER 3
3. Cell cycle analysis
3.1 Introduction
3.2 Materials and methods
3.3 Results
3.4 Discussion
CHAPTER 4
4. Mixed lymphocyte cultures
4.1 Introduction
4.2 Materials and methods
4.3 Results
4.4 Discussion
CHAPTER 5
5. In vivo toxicity
5.1 Introduction
5.2 Materials and methods
5.3 Results
5.4 Discussion
Chapter 6
6.1 Conclusion
REFERENCES
