Chapter 48

Chapter 48 Anti-neoplastic Drugs Guofang

Wang

(Pharmacology Department , Jining Medical College)

overview Cancer is the most common cause of death in the world. At present, about 50% of patients with cancer can be cured, with chemotherapy contributing to cure 10% -15% of patients.

Cancer etiology extrinsic factor chemical factor (lung cancer: Asbestos, smoking) Physical factor (leukemia: ionising radiation) Virus (cancer of liver: hepatovirus; nasopharyngeal carcinoma: EB virus )

endogenous factor immune state, genetic constitution (Multiple polyps, colon carcinoma)

Objectives • list the types of anti-neoplastic drugs;

• understand the effects, pharmacological mechanisms, and clinical applications of major anti-neoplastic drugs • understand the major mechanisms underlying drug resistance; •List major adverse effects of anti-neoplastic drugs

cell cycle

• Tumor cells are composed of cycling cells and resting cells (G0 phase). • A cell cycle consists of four phases: (1) the presynthetic phase (G1); (2) the synthesis of DNA phase (S); (3) the postsynthetic phase (G2); (4) mitosis (M) phase. This cycle kinetics is relevant to the drugs’ mode of action, indication, scheduling of CCS or CCNS .

(CCS) drugs and (CCNS) drugs. Anticancer drugs that are only capable of inhibiting cell replication during one phase of the cell cycle are called cell-cycle specific (CCS) drugs. For example, antimetabolites specificly affect DNA synthesis, thus acting on the cell in S phase. Anticancer drugs, such as alkylating agents that act against cancer cells at any phase of the cell cycle, including G0 cells, are called cell cycle non-specific (CCNS) drugs.

CCS drugs are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are in the growth fraction. CCNS drugs are particularly usefully in low growth fraction solid tumors as well as in high growth fraction tumors.

Resistance

Resistance 1.Decreased intracellular levels of cytotoxic agents • Decrease in intracellular levels of cytotoxic agents is one of the most common mechanisms of drug resistance. result from decreased drug influx due to a defective carrier-mediated transport system. Enhanced drug efflux may also lower intracellular levels of drugs.

MDR （ multi-drug resistance) to antineoplastic agents due to overexpression of the Pglycoprotein drug efflux pump is an important example of this mechanism.

Resistance 2. Repair of Drug-induced Injury • Cells possess a variety of mechanisms for repairing drug-induced damage. The repair mechanisms may account for cellular resistance to certain anticancer drugs. • alkylating agents-caused DNA cross-link could be removed in the cellular repair processes.

Resistance 3. Free radical scavenging mechanism • Free radical scavenging systems can protect cells from the effects of ionizing radiation and drugs that generate oxygen free radicals intracellularly. • Doxorubicin-resistance

Resistance 4. Increased production of target enzymes • Cells may circumvent drug-induced injury by increased production of target enzymes. • exposure of cells to MTX or 5-FU stimulates production of dihydrofolate reductase or thymidylate synthase, respectively, resulting in drug resistance.

Resistance 5. Inactivate the activation of drug • Many antimetabolites and some alkylating agents are administered as prodrugs, which must be converted to their cytotoxic forms by the targeted tumor or by other tissues. • Resistance to these drugs can be attributed to decreased conversion of these analogues to their cytotoxic nucleoside and nucleotide derivatives by the relevant enzymes.

Toxicity

Anticancer drugs target

proliferating cells - I • Anticancer drugs are not magic bullets. Ideally they should target only the cancer cells. However, they target proliferating cells whether normal or neoplastic. proliferating cells - II • Normal cells of the hair follicles, bone marrow and intestinal epithelium are rapidly dividing and are especially sensitive to anti-neoplastic drugs. This results in the toxic side effects to most anticancer drugs.

Toxicity Common toxicity Myelosuppression (except hormone, Bleomycin, LAsparaginase alimentary tract toxicity( severe vomiting , stomatitis) Alopecie

Specific toxicity Cyclophosphamide: hemorrhagic cystitis Doxorubicin: cardiotoxicity Bleomycin: pulmonary fibrosis

Classification of drugs Classification according to structure and sources (a) alkylating agents; (b) antimetabolites; (c) antibiotics; (d) alkaloids; (e) hormones; (f) miscellanous agents:Platinum

Classification according to the mechanism of action • agents affecting synthesis of nucleic acids • agents directly affecting structure and function of DNA • agents interrupting transcription and RNA synthesis • agents affecting protein synthesis • agents affecting hormone balances.

Biochemical mechanisms

Biochemical mechanisms 1.Inhibition of the synthesis of nucleic acids

Antimetabolites such as Methotrexate (MTX) and Flurouracil (5-FU) inhibit enzymes in the purine or pyrimidine biosynthetic pathways or DNA polymerases. Such drugs are referred to as S phase-specific since they are cytotoxic during the S phase of the cell cycle.

Biochemical mechanisms 2. Interference of DNA structure and function Some agents bind to DNA and inhibit DNA replication. alkylating agents cause alkylation of nucleophilic sites within the DNA double helix, thereby prevent the use of DNA as a template for further DNA and RNA synthesis ， leading to inhibition of DNA replication and cell death.

Biochemical mechanisms 3. Inhibition of RNA synthesis Some agents are non-covalently bound to DNA and distorts the shape of DNA double helix, resulting in inhibition of RNA synthesis. This mechanism is characteristic of many antitumor antibiotics such as dactinomycin, doxorubicin .

Biochemical mechanisms 4. Inhibition of protein synthesis The Vinca alkaloids, vincristine and vinblastine exert their cytotoxic effects by binding to specific sites on tubulin, inhibiting assembly of tubulin into microtubules 5. Hormone-related mechanisms Antiestrogens are effective for breast cancers that contain the estrogen receptor. Antiandrogens are important in the treatment of prostate cancer.

Individual agents

Agents affecting synthesis of nucleic acids (antimetabolites) 1. folic acid antagonist: MTX (methotrexate) 2. Purine antagonists: 6-MP (6-mercaptopurine), 6-TG (6-thioguanine) 3. Pyrimidine antagonists: 5-FU (5-fluorouracil), Ara-C (cytarabine), gemcitabine

Antimetabolites are similar to necessary substances such as folic acid , purine and pyridine in chemical structure. These agents compete the action site on an essential enzyme and inhibit nucleic acid synthesis. Agents of this group mainly affect S phase cells. All antimetabolites undergo intracellular activation.

Methotrexate (MTX) Mechanism of action of MTX MTX, similar to dihydrofolate in structure, inhibits dihydrofolate reductase activity, resulting in tetrahydrofolate (FH4) deficiency and disorder in DNA synthesis in cancer cells.

Clinical uses of MTX • acute childhood leukemia and choriocarcinoma. • be used for prevention of leukemic meningitis by intrathecal administration • used for treatment of meningeal leukemia and carcinomatosis. Adverse effects of MTX • myelosupression, alopecia and gastrointestinal reactions. • Leucovorin may be administered to counteract the myelosuppression of MTX.

Flurouracil (5-FU) Mechanism of action of 5-FU • 5-FU is intracellularly converted to the active monophosphate 5F-dUMP, which inhibits thymidylate synthase, inhibiting the formation of dTMP from dUMP and resulting in disorder in DNA synthesis. • the drug may be cytotoxic after incorporation into RNA, causing disorder in protein synthesis.

Clinical uses of 5-FU • gastrointestinal cancers and breast cancer. • carcinoma of the ovary, cervix, chorion, urinary bladder and prostate. Adverse effect of 5-FU • gastrointestinal tract such as anorexia and nausea • Myelosuppression • Alopecia, pigmentation.

Mercaptopurine (6-MP) Mechanism of action of 6-MP 6-MP is aminated to thioguanine monophosphate (TIMP), which is the active inhibitor of purine nucleotide synthesis.

clinical uses of 6-MP 6-MP is of use in the maintainance therapy of acute lymphoblastic leukemia. Adverse effect of 6-MP Bone marrow depression and toxicities in gastrointestinal tract are major adverse effects of 6-MP. Jaundice, hepatic damage may also be encountered.

Cytarabine (Ara-C) Mechanism of action of Ara-C Ara-C also requires phosphorylation to active nucleotide diphosphate or triphosphate forms (Ara-CDP or Ara-CTP) and incorporation into DNA, resulting in inhibition of DNA polymerase and exerting a cytotoxic effect.

Clinical uses of Ara-C acute leukemia in both children and adults. relapses of acute lymphocytic leukemia adverse effect of Ara-C Severe myelosuppression and gastrointestinal reactions are frequently occurred.

Agents directly affecting structure and function of DNA

Agents directly affecting structure and function of DNA •Alkylating Agents •Platinum Antitumor Compounds •Antibiotics •Topoisomerase inhibitors

Ⅰ. Alkylating agents Mechanism of action • react with electron-rich atoms in biologic molecules to form covalent bonds. • transfer their alkyl groups to various cellular constituents such as DNA, RNA or proteins. • Alkylation of DNA results in DNA interactions, which damage the structure and function of DNA, leading to cell death.

Alkylating agents • Although alkylating agents are not cell cycle-specific,

cells are most susceptible to alkylation in late G1 and S phases of the cell cycle and express block in G2. • Drug resistance: – Increased capability to repair DNA lesions – Decreased permeability of the cell to the drug – Increased production of glutathione • In general, if a tumor is resistant to one alkylating agent, it will be relatively resistant to other agents of this class.

Nitrogen Mustard • Nitrogen mustard is the earliest used and most reactive alkylating agents. • Nitrogen mustard has been replaced by other alkylating agents.

Cyclophosphamide (CTX) Mechanism of action • CTX undergoes activation by cytochrome P450 mediated microsomal oxidation in the liver to produce aldophosphamide • Aldophosphamide spontaneously decomposes to produce reactive phosphoramide mustard.

Clinical uses of CTX • treatment of lymphomas. • multiple myeloma and chronic lymphocytic leukemia. • treatment of carcinomas of the lung, breast, cervix and ovary . adverse reactions of CTX • Toxicities include myelosuppression, nausea,vomiting, and hair loss with a specific adverse effect of hemorrhagic cystitis.

Busulfan •

Busulfan

is used in the treatment of chronic

myelocytic leukemia. • myelosuppression and gastrointestinal upset. Thiotepa (TSPA) •Thiotepa is used particularly in the treatment of carcinomas of the ovary and breast. It is also used in carcinomas of liver and bladder .

Carmustine (BCNU) • BCNU causes alkylation of DNA ， RNA and protein molecules. • BCNU is now mainly employed in the treatment of malignant astrocytomas and metastatic tumors of the brain because of its ability to cross the blood-brain barrier. • The toxicities to bone marrow and gastrointestinal tract may occur.

Ⅱ. Platinum Antitumor Compounds The platinum antitumor agents are complexes of platinum with ligands. They can form strong bonds with covalent characteristics, resulting in DNA intercalation.

Cisplatin (DDP) After the chloride ligands of DDP are displaced, the platinum compounds react with DNA and interfere with DNA replication and cell division. • DDP is a CCNS drug and has a broad spectrum of activity. It is useful for testicular carcinoma, cancers of bladder, lung and ovary.

Adverse reactions of DDP • gastrointestinal distress, myelosupression, ototoxicity and mild hepatotoxicity. •

Neurotoxicity and nephrotoxicity.

Ⅲ. antibiotics

• Mitomycin C (MMC) • Bleomycin (BLM)

Mitomycin C (MMC) •

Mitomycin C is a natural product. It exerts its cytotoxic effect through the cross-linking of DNA.

•

MMC is a CCNS drug, and mainly used in the treatment of cancers of breast and the gastrointestinal tract; lung cancer, leukemia and chronic myelocytic leukemia.

• severe myelosupression ， gastrointestinal distress, hepatotoxicity and nephrotoxicity may occur.

Bleomycin (BLM) • BLM is a mixture of glycopeptides. It can generate free radicals, which bind to DNA and cause strand breaks resulting in inhibition of DNA synthesis. • BLM is a CCNS drug , G2 phase. BLM is commonly used in the treatment of squamous cell carcinomas, lymphomas and testicular cancer. • The toxicities of BLM include hypersensitivity, alopecia and pulmonary dysfunction. no myelosuppression

Ⅳ. Topoisomerase inhibitors Camptothecins Etoposide (VP-16) and teniposide (VM-26)

Camptothecins Mechanism of Camptothecins Camptothecins target the nuclear enzyme topoisomerase I, causing damage of DNA structure and function. Clinical uses of Camptothecins • advanced ovarian and small cell lung cancer and choriocarcinoma. • treatment of hematological malignancy, colorectal and gastric cancer.

Etoposide (VP-16) and teniposide (VM-26) Mechanism of Camptothecins topoisomerase Ⅱ, causing damage of DNA structure and function. Clinical uses of Camptothecins lung cancer and testicular cancer, Hodgkin’s and non-Hodgkin’s lymphomas. myelosuppression and gastrointestinal distress.

Agents interrupting transcription and RNA synthesis

Agents interrupting transcription and RNA synthesis Dactinomycin (DACT) Doxorubicin (ADM) Daunorubicin (DNR) Some microbial products have antitumor effects. They interact with DNA or RNA, leading to disruption of DNA function.

Dactinomycin (DACT) Mechanism of action of DACT • DACT can bind to double-helical DNA, intercalates between the adjacent guanine-cytosine base pairs of DNA, causing inhibition of DNA-dependant RNA polymerase and the transcription of DNA to RNA.

Clinical uses of Dactinomycin • rhabdomyosarcoma and Wilm’s tumor in children. • choriocarcinoma, Hodgkin’s disease . Adverse reaction of Dactinomycin gastrointestinal distress, Myelosuppression and alopecia

Doxorubicin (ADM) • ADM can intercalate with DNA between base pairs, inhibiting the transcription and DNA replication.

Clinical uses of Doxorubicin

•ADM is effective against many kinds of tumors, such as leukemia, lymphoma, and cancers of breast, ovary, stomach, liver and bladder. Adverse reaction of Doxorubicin •ADM may cause severe cardiac toxicity and myelosuppression. Gastrointestinal distress, pigmentation and alopecia may also occur.

Daunorubicin (DNR) The effect and clinical uses of DNR are similar to those of ADM. Myelosuppression, gastrointestinal distress and cardiac toxicities are the major adverse reactions.

Agents inhibiting protein synthesis

Agents inhibiting protein synthesis Microtubule inhibitors • Vinblastine and Vincristine • Paclitaxel Harringtonine and Homoharringtonine L-asparaginase

Microtubule inhibitors The mitotic spindle is part of a larger intracellular skeleton that is essential for the internal movements occurring in the cytoplasm of all eukaryotic cells. the mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells formed when a eukaryotic cell divides. Several plant derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules, thereby causing cytotoxicity.

Plant alkaloids Microtubule inhibitors • Disrupt mitotic spindle by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules. – Cycle-specific, phase-specific, block mitosis in metaphase •Vincristine and vinblastine •Paclitaxel

vinca rosea western yew and european yew

Vinblastine and Vincristine Mechanism of action Vinblastine (VLB) and Vincristine (VCR) are CCS agents (M phase cells specific). The two agents are spindle poisons, which block the formation of mitotic spindle by preventing the assembly of tubulin dimmers into microtubules.

Clinical uses of VLB and VCR • Vinblastine is effective against Hodgkin’s disease, nonHodgkin’s lymphomas, breast cancer, and testicular carcinoma. •Vincristine is used for acute leukemia and lymphomas, Wilm’s tumor and choriocarcinoma. Adverse reactions of VLB and VCR • VLB and VCR may cause myelosuppression, neurotoxicity, gastrointestinal distress and hair loss VCR being more neurotoxic.

Paclitaxel Mechanism of action of Paclitaxel Paclitaxel exhibits unique pharmacological actions as an inhibitor of mitosis. It promotes microtubule formation and inhibits the microtubule disassembly, producing bundles of microtubules with aberrant structures and thus causes arrest in mitosis.

Clinical uses of Paclitaxel cancers of ovary and advanced breast ， carcinomas of small cell or no small cell lung, head and neck, esophageal, and bladder. Adverse reactions of Paclitaxel myelosuppression, neurotoxicity and cardiac toxicity.

Harringtonine and Homoharringtonine

• Harringtonine and Homoharringtonine interrupt • •

the function of ribosome, resulting in inhibition of protein synthesis. acute myelocytic leukemia. chronic myelocytic leukemia and lymphoma.

• myelosuppression, gastrointestinal distress and hair loss may be encountered.

L-asparaginase

• L-asparaginase can deprive L- asparagine • •

leading to cell death. It is commonly used for the therapy of lymphoblastic leukemia. Common toxicity of L-asparaginase is gastrointestinal distress.

Hormones and related agents • Glucocorticoids • Sex hormones

Glucocorticoids Prednisone • Prednisone is the most commonly used glucocorticoid in cancer therapy. It can inhibit the growth of lymphocytes and cause the lysis of them. • acute and chronic lymphocytic leukemia, Hodgkin’s disease and other lymphomas

Sex hormones Estrogen Diethylstilbestrol is commonly used for prostatic cancer. Androgens Androgens, e.g., methyltestosterone has anti-estrogen effect and are used in breast cancer therapy.

camptotheca acuminata tree

Mayapple

Cephalotaxus 　 fortunei

Vinca rosea

Question 1. What’s first-line antituberculous drugs? 2. Please describe the mechanisms of action , pharmacoligical effects, major adverse reactions of first-line antituberculous drugs. 3. what’s CCS and CCNS drugs? please give examples. 4. List possible mechanisms of action of cancer chemotherapitics and please give examples.

Thanks For Your Attention !!!