Malignant disease accounts for a high proportion Malignant disease in industrialised countries. of deaths of anticancer drug is to give The treatment cure . and if possible, palliation, induce remission

Introduction „ „ Cancertransformed occurs into neoplastictheir cells after genetic through material alterationcertain and of genes. normal theNeoplastic abnormal expression cells of abnormalities cells and haveproperties. the These been usuallydivision loss changes and of lead manyunaffected organs exhibit result to their a in process uncontrolled differentiated the called cell metastasis. invasion chromosomal of previously

Introduction ƒ ƒ Treatment options of cancer:

ƒ Surgery: before 1955 ƒ Radiotherapy: 1955~1965 ƒ Chemotherapy: after 1965 ƒ 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. ƒ Tumor cells can be classified as proliferating cells and non-proliferating cells. ƒ The ratio of proliferating cells in the whole tumor tissue is called growth fraction (GF).

Proliferating cell group GF＝ Total tumor cell group ƒ The faster the tumor cells proliferate, the bigger the GF is and the higher the sensitivity of tumor to a drug is. ƒ 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

ƒ 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 tocauses: alkylating agentsMembrane transport may be decreased. has several The drug may be bound by glutathione (GSH) via GSH-S-transferase or metallothioneins in the cytoplasm and inactivated. drug may be metabolized to inactive The species. ‹ ‹ ‹ ƒ Myelosuppression is the dose-limiting adverse effect for alkylating agents. ƒ 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. ƒ 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 ƒ Block nucleic acid (DNA, RNA) biosynthesis ƒ Directly destroy DNA and inhibit DNA reproduction ƒ Interfere transcription and block RNA synthesis ƒ Interfere protein synthesis and function ƒ 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. ƒ 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;

ƒ Interfere the function of ribosome: harringtonines；

ƒ 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.

ƒ Bind with DNA to block RNA production. doxorubicin ƒ Alkylating Agent: mechlorethamine, cyclophosphamide and thiotepa ƒ Platinum: cis-platinium ƒ Antibiotic: bleomycin and mitomycin C ƒ 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. ƒ Estrogens and estrogen antagonistic drug ƒ Androgens and androgen antagonistic drug ƒ Progestogen drug ƒ Glucocorticoid drug ƒ gonadotropin-releasing hormone inhibitor: leuprolide, goserelin ƒ 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 ：

MTX ）

（ The structures of MTX and folic acid are similar. MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase, the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis.

Methotrexate Mechanism of Action ¾ ）

MTX

（ ： The use of MTX in the treatment of choriocarinoma, a trophoblastic tumor, was the first demonstration of curative chemotherapy. is especially effective for treating acute It lymphocytic leukemia and for treating the of a wide range tumors. meningeal metastases

Methotrexate Indications ƒ ƒ ）

MTX ：

（ MTX is myelosuppressive, producing severe myelosuppressive, MTX is aplasia, and leukopenia, bone marrow thrombocytopenia. gastrointestinal This agent may produce severe disturbances. Renal toxicity may occur because of precipitation metabolite of MTX. (crystalluria) of the 7-OH

Methotrexate Adverse Effects ‹ ‹ ‹ ）

6-MP

（ purine base synthesis, although their exact mechanisms of action are still uncertain. primarily for the used Mercaptopurine is acute with in patients maintenance of remission lymphocytic leukemia and is given in combination with purpose. MTX for this Well tolerate. Myelosuppression is generally mild with may cause thioguanine.Long-term mercaptopurine use hepatotoxicity. The drugs are believed to act similarly inhibit The drugs are believed ƒ ƒ ƒ 6-Mercapapurine Indications: Adverse Effects: ： Fluorouracil is an analogue of thymine in which the an analogue of thymine Fluorouracil is methyl group is replaced by a fluorine atom. It has 5-FdUMP and two active metabolites: 5-FdUTP. 5- and prevents FdUMP inhibits thymidylate synthetases of thymidine, a major building block the synthesis of DNA. 5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function.

5-Fluorouracil (5-FU) Mechanism of Action ƒ ： Fluorouracil is exclusively used to treat is exclusively Fluorouracil solid tumors, especially breast, colorectal, cell and gastric tumors squamous tumors of the head and neck.

5-Fluorouracil (5-FU) Indications ƒ ： Fluorouracil may cause nausea and vomiting, and oral gastrointestinal myelosuppression, ulceration. Nausea and vomitting are usually mild. With fluorouracil, myelosuppression is more problematic after bolus injections, whereas mucosal damage is dose-limiting with continuous infusions.

5-Fluorouracil (5-FU) Adverse Effects ƒ ƒ : ： Cytarabine has a narrow clinical spectrum and is primarily used in combination with daunorubicin or thioguanine for the treatment of acute nonlymphocytic leukemia. High dosesheart, of and other cytarabine organs. can damage the liver, Indications ƒ ƒ Cytarabine Adverse Effects Classification of Antibiotics: ƒ Adriamycin (Anthracyaline Antibiotics) ƒ Mitomycin C ƒ Bleomycin ƒ Actinomycin D ： Adriamycin and Daunorubicin are tetracycline rings Adriamycin and Daunorubicin are with the sugar daunosamine. They are DNA intercalating agents that block of DNA the synthesis and RNA. S phase primarily toxic during the agents are These of cell cycle. These agents imparts a red tinge to the urine. Adramycin is used to treat acute leukemias, lymphoma, and a number of solid tumors.

Adriamycin and Daunorubicin Properties: ƒ ƒ ƒ ƒ Mitomycin C is an antineoplastic antibiotic that is Mitomycin C alkylates DNA and thereby causes strand breakage and inhibition of DNA synthesis. It is primarily used in combination with vinvristine as salvage therapy for breast cancer. Mitomycinmyelosuppression producesplatelets that and delays leukocytes. preferentially and affects prolonged Mechanism: ƒ ƒ ƒ Mitomycin C: Indications: Adverse Effects: Actinomycin D intercalates DNA and thereby DNA Actinomycin D intercalates prevents DNA transcription and messenger RNA synthesis. The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and of the treatment such as Wilms’ tumor and Ewing’s pediatric tumors, sarcoma.

Actinomycin D: ƒ ƒ The drug has its greatest effect on neoplastic The drug has its greatest cell replication of the G2 phase cell in the cycle.Although bleomycin intercalates DNA, the major cytotoxicity is believed to result from radical formation and DNA ironcatalyzed free strand breakage. It is useful in Hodgkin’s and non-Hodgkin’s lymphomas, testicular cancer, and several other solid tumors. Bleomycin producesThe very little mostpulmonary and myelosuppression. serious mucocutaneous reactions. toxicities of Bleomycin are Mechanism: ƒ ƒ ƒ Bleomycin: Indications: Adverse Effects: ƒ Tubulin-Binding Agents Vinca Alkaloids: The cellular mechanism of action of vinca alkaloids is the prevention of microtubule assembly, causing cells to arrest in the late G2 phase by preventing formation of mitotic filaments for nuclear and cell division. ƒ Tubulin-Binding Agents ƒ Vinca alkaloids: Vinblastine,vincristin, vindesine and vinorelbine are all alkaloids derived from the periwinkle plant (Vinca rosea). Indications: ƒ Vinblastine is used in combination with Bleomycin and Cisplatin for metastatic testicular tumors. ƒ Vincristine is used in combination with prednisone to induce remission in childhood leukemia. ƒ Vinorelbine is used to treat non-small-cell lung cancer and breast cancer. ƒ Tubulin-Binding Agents ƒ Paclitaxel: Taxanes enhance all aspects of tubulin polymerization, an action that is the opposite to that of vinca alkaloids, but they are also cytotoxic, emphasizing the dynamic importance of tubulin polymerization as a target for cytotoxic drugs. Paclitaxel, Taxotere ƒ Interfere the Function of Ribosome: ƒ Cephalotaxus Alkaloids : Harringtonine Homoharringtonine Cisplatin binds to guanine in DNA and RNA, and the interaction is stabilized by hydrogen bonding. The molecular mechanism of action is unwinding and shortening the DNA helix.

Cisplatin: Mechanism of Action: ƒ Cisplatin has efficacy against a wide range of neoplasms. It is given intravenously as a first- line drug for testicular, ovarian, and bladder of cancer, and it is also useful in the treatment melanoma and a number of other soild tumors. little Cisplatin produces relatively nausea, myelosuppression but can cause severe vomiting, and nephrotoxicity. Indications: ƒ ƒ Cisplatin: Adverse Effect: Carboplatin has a similar spectrum of activity, but it is approved only as a second-line drug for ovarian cancer.

Carboplatin: Indication: ƒ ƒ Several types of hormone-dependent cancer (especially breast, prostate, and endometrial cancer) respond to treatment with their corresponding hormone antagonists. ƒ Estrogen antagonists are primarily used in the treatment of breast cancer, whereas androgen antagonists are used in the treatment of prostate cancer. Corticosteroids are particularly useful in treating lymphocytic leukemias and lymphomas. Estrogens: ƒ Estrogens inhibit the effects of endogenous androgens and androgen-dependent metastatic prostatic carcinoma. Diethylstilbestrol is usually the agent of choice. ƒ Cardiac and cerebrovascular complications and carcinoma of the male breast are potential adverse effects. Progenstins: ƒ Progestins are useful in the management of endometrial carcinoma and back-up therapy for metastatic hormone-dependent breast cancer. Antiestrogen: Tamoxifen ƒ Tamoxifen is the drug of choice in postmenopausal women with or recovering from metastatic breast cancer. It is most effective in patients who have estrogen receptor-positive tumors. ƒ Tamoxifen is also used as adjunvctive therapy to oophorectomy to leuprolide or goserelin in premenopausal women with estrogen receptor- positive tumors. Androgens: ƒ Androgen activity in breast cancer is similar to that of estrogens, perhaps for the same mechanistic reasons. ƒ Virilizing effects and hepatic toxicity make them unacceptable to most patients. ƒ Fluoxymesterone is the most widely used agent. ƒ Danazol has use in hematology in aplastic anemia and congenital anemias. Glucocorticoids: ƒ They are integral components of curative therapy for acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s disease. ƒ Glucocorticoids have essential roles in the prevention of allergic reaction, emesis control, relief of intracranial hypertension or spinal cord compression in neurologic complications, and pain relief. ƒ Drug Resistance ƒ Drug Toxicity ‹ De novo Resistance ƒ Acquired Resistance ƒ Multidrug Resistance (MDR) De novo resistance: z De novo resistance can be de novo genetic (i.e. the cells are initially inherently resistant), or can arise because drugs are unable to reach the target cells because of permeability barriers such as the blood-brain barrier. Acquired Resistance: ƒ Acquired drug resistance may result from genomic mutations, such as the induction or deletion of enzymes involved in drug inactivation or drug activation, respectively. Multidrug Resistance (MDR): ƒ P-glycoprotein transports many naturally occurring drugs out of neoplastic cells, and its induction may lead to multidrug resistance. ƒ As scientific understanding of the mechanisms of drug resistance increases, new treatments may be developed to counteract resistance. ƒ The most common toxicities of antineoplastic drugs result from inhibition of cell replication in the bone marrow, gastrointestinal epithelium, and hair follicles. Many antineoplastic drugs also stimulate the chemoreceptor trigger zone in the medulla and thereby elicit nausea and vomiting. Immunosuppressive Agents: ƒ Act to suppress immune mechanisms and are used to treat autoimmune diseases or to prevent graft rejection following tissue transplantation. ƒ Ciclosporin, Tacrolimus, adrenocortical hormones, antimetabolites, alkylating agent, antilymphocyte globulin, Mycophenolate Mofetil Thanks!