Introduction Malignant disease accounts for a high proportion of deaths in industrialised countries. The treatment of anticancer drug is to give palliation, induce remission and if possible, cure. Introduction Cancer occurs after normal cells have been transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes. Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties. These changes lead to uncontrolled cell division and many result in the invasion of previously unaffected organs a process called metastasis. Treatment options of cancer: Surgery: before 1955 Radiotherapy: 1955~1965 Chemotherapy: after 1965 Immunotherapy and Gene therapy According to chemical structure and resource of the drug; According to biochemistry mechanisms of anticancer action; According to the cycle or phase specificity of the drug According to chemical structure and resource of the drug: Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts，Hormones， ImmunotherapyRadiotherapeutic Agents, Cytoprotective Agents, Antineoplastic Platinum Compounds According to biochemistry mechanisms of anticancer action: Block nucleic acid biosynthesis Direct influence the structure and function of DNA Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis According to the cycle or phase specificity of the drug: Cell cycle nonspecific agents (CCNSA) Cell cycle specific agents (CCSA) The cycle of cell replication includes: G1（Gap1, period S（DNA synthesis） before S）phase phase G2（Gap2,period M（Mitosis）phase after S）phase The Basic Concept of Cell Generation Cycle The G1 phase is the period when newly created cell is born. The period of time the cell remains in the G1 phase depends upon the type of cell (tumor cell or normal cell).Cells can be born in proliferated or non-proliferated state. If the cell is a proliferating cell,it will move quickly to S or synthesis phase. In this period, DNA replicates and two copies of DNA are present in the cell. The next phase is G2 phase and cells are prepared for final cell cycle M phase or Mitosis. There are two major control points in cell cycle, G1/S phase, the cell replicates and G2 / M phase, the cell divides. G1 / S phase is important in understanding cancer and cancer treatment. Tumor cells can be classified as proliferating cells and non-proliferating cells. The ratio of proliferating cells in the whole tumor tissue is called growth fraction (GF). Proliferating cell group GF＝ Total tumor cell group The faster the tumor cells proliferate, the bigger the GF is and the higher the sensitivity of tumor to a drug is. Generally, in the early stage, the GF of a tumor is bigger and the effect of a drug on the tumor is better CCNSA：drugs that are active throughout the cell cycle. CCSA: drugs that act during a specific phase of the cell cycle. Cell Cycle Nonspecific Agents (CCNSA) drugs that are active throughout the cell cycle Alkylating Agents Platinum Compounds Antibiotics Cell Cycle Specific Agents (CCSA) drugs that act during a specific phase of the cell cycle S Phase Specific Drug: Antimetabolites, Topoisomerase Inhibitors M Phase Specific Drug: Vinca Alkaloids, Taxanes G2 Phase Specific Drug: Bleomycin One of the frightening developments of World War I was the introduction of chemical warfare. These compounds were known as the nitrogen mustard gases. The nitrogen mustards were observed to inhibit cell growth, especially of bone marrow. Shortly after the war, these compounds were investigated and shown to inhibit the growth of cancer cells. Alkylating Agents Alkylating agents were one of the earliest classes of drugs used to treat cancer, beginning in the 1940’s. The biggest weakness of most cancer cells is that they are very sensitive to DNA damage. Alkylating agents work by reacting with the proteins that bond together to form the very delicate double helix structure of a DNA molecule, adding an alkyl group to some or all of them. This prevents the proteins from linking up as they should, causing breakage of the DNA strands and eventually, the death of the cancer cell. Alkylating Agents This phenomenon is essentially a mutation that takes away the cancer cell’s ability to multiply. While there are many different classes of alkylating agents, they all work by this same chemical mechanism. Alkylating agents are highly electrophilic compounds which react with nucleophiles to form a strong covalent bond. It acts by transfer of alkyl group to biologically important constituents such as amino, sulfhydryl or phosphate group whose function is then impaired. Alkylating Agents Alkylating agents are known to react with DNA, RNA and protein They act by alkylating N - 7 position of guanine in DNA, which results in the formation of apurinic site. The alkylating agent appears to be most effective in G1 or S phase. nu – H + alkyl - Y alkyl – nu + H+ +Y+ Nucleophile of Alkylating biopolymer agent Alkylating Agents The five major categories of alkylating agents are Nitrogen mustard Alkyl sulfonates Ethylenimines Methylmelamine Methyl hydrazines Nitrosourea Imidazo tetrazines Resistance to alkylating agents has several causes: Membrane transport may be decreased. The drug may be bound by glutathione (GSH) via GSH-S-transferase or metallothioneins in the cytoplasm and inactivated. The drug may be metabolized to inactive species. Myelosuppression is the dose-limiting adverse effect for alkylating agents. Nausea and vomiting are common as are teratogenesis and gonadal atrophy, although in the latter cases these are variable, according to the drug, its schedule, and route of administration. Treatment also carries a major risk of leukemogenesis and carcinogenesis. O O (ClCH2 CH2)2N P H2O HN 2-[Bis (2-chloroethyl) amino] tetrahydro - 2H -1,3,2- oxazo - phosphorin -2- oxide monohydrate Use: It is used against multiple myeloma, chronic lymphocytic leukemia and acute leukemia of children Block nucleic acid (DNA, RNA) biosynthesis Directly destroy DNA and inhibit DNA reproduction Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis Antimetabolites: • Folic Acid Antagonist: inhibit dihydrofolate reductase (methotrexate) • Pyrimidine Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine) • Purine Antagonist: inhibit interconversion of purine nucleotide (mercaptopurine) • Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea) A. Fluorouracil (5FU – CBC, Flocil) O F HN O N H 5-Fluoro - 2, 4- (1H, 3H) pyrimidindione. O O CF 3OF HN Fluoroxy tri F fluoro methane HN O Fluorination N O H N H Uracil Fluorouracil Use: It is effective in palliative management of carcinoma of the breast, colon, pancreas, rectum and stomach in patient who cannot be cured by surgery. It is also used in the treatment of skin and basal cell carcinomas. S H N N N H2N N H 2-Amino-7H-purin-6-thiol It is a guanine analogue, belongs to the family of drugs called antimatabolites. Its act by integrated into DNA and RNA, which result in the inhibition of synthesis and metabolism of purine nucleotides. Antitubulin: Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when a cell starts to divide itself into two new cells. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division vinca alkaloids and taxanes; Interfere the function of ribosome: harringtonines； Influence amino acid supply: L-asparaginase Bind tubulin, destroy spindle to produce mitotic arrest. In the 1950's a biochemical difference in metabolism related to the amino acid asparagine was found. Normal cells apparently can synthesize asparagine while leukemia cells cannot. If leukemia cells are deprived of asparagine, they will eventually die If the enzyme L-asparaginase is given to humans, various types of leukemias can be controlled. Tumor cells, more specifically lymphatic tumor cells, require huge amounts of asparagines to keep up with their rapid, malignant growth. L-asparaginase is an enzyme that destroys asparagine external to the cell. Normal cells are able to make all the asparagine they need internally whereas tumor cells become depleted rapidly and die. Bind with DNA to block RNA production. doxorubicin Alkylating Agent: mechlorethamine, cyclophosphamide and thiotepa Platinum: cis-platinium Antibiotic: bleomycin and mitomycin C Topoismerase inhibitor: camptothecine and podophyllotoxin These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth. Estrogens and estrogen antagonistic drug Androgens and androgen antagonistic drug Progestogen drug Glucocorticoid drug gonadotropin-releasing hormone inhibitor: leuprolide, goserelin aromatase inhibitor: aminoglutethimide, anastrazole General Characteristics： ¾ Antimetabolites are S phase-specific drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis. ¾ Myelosuppression is the dose-limiting toxicity for all drugs in this class. Folic acid Antagonists:MTX Purine Antagonists:6MP 6TG Pyrimidine Antagonists：5FU araC HU Methotrexate （MTX） Mechanism of Action： ¾ The structures of MTX and folic acid are similar. MTX is actively