一、general information antineoplastic agents 二、some selected antineoplastic agents 三、cancer diseases

PART I general information

Characteristics of cancer cells 1 Persistent cell proliferation 2 Invasive growth 3 Metastases

Central nervous system cancers Categorized of cancer cancers that begin in the tissues of the brain and spinal cord. cells of the immune system that affects antibodies- spreads through lymphatic system. White blood cells and their precursor cells such as the bone marrow cells, causes large numbers of abnormal blood cells to be produced and enter the blood. Carcinoma Sarcoma Leukemia Lymphoma Myeloma Central nervous system cancers bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. B-cells that produce antibodies- spreads through lymphatic system. skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas. 7 7

Benign Types of Tumors Malignant

what is the cause of cancer? Causes of Cancer: 1. 30 % is due to smoking: lung, mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, and kidney cancers. 2. Lifestyle – diet, alcohol consumption, reproductive behavior, sexual behavior, exposure to sunlight, etc. 3. At least 15% are related to viruses, e.g. cervical cancer caused by human papillomavirus.

surgery radiotherapy

chemotherapy

Cancer Treatment Surgery Radiation 3.Chemotherapy 30% of patients without metastasis Respond to surgery and radiation. Surgery Radiation 3.Chemotherapy If diagnosed at early stage, close to 50% cancer could be cured. 50% patients will undergo chemotherapy, to remove micrometastasis. However, chemotherapy is able to cure only about 10-15% of all cancer patients. 14 14

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classification of anticancer drugs Mechanisms of action and classification of anticancer drugs methotrexate、 fluorouracil、 mercaptopurine、 hydroxycarbamide and cytarabine. (1) Drugs that interfere with the synthesis of DNA and RNA

alkylating agents、 bleomycin、 mitomycin and cisplatin (2) Drugs that damage the structure and function of DNA alkylating agents、 bleomycin、 mitomycin and cisplatin

vinblastine and vincrestine. (3) Drugs that bind to double-stranded DNA to inhibit DNA-dependent RNA synthesis vinblastine and vincrestine. dactinomycin、 daunorubicin and doxorubicin. (4) Drugs that interfere with proteins synthesis

sex hormones and adre­nocortical hormones (5) Drugs that affect the balance of hormone levels

GF ﹦ proliferating cells cancer cells resting cells total cells

G1 Phase: synthesizes material needed to duplicate DNA Cell cycle G0 Phase: resting stage G1 Phase: synthesizes material needed to duplicate DNA S Phase: duplicates DNA G2 Phase: premitotic phase M Phase: mitosis occurs Cell returns to G0 phase

CCSD： CCNSD： such as antimetabolites and vinblastine such as alkylating agents and antibiotics

                                        

Cell cycle specificity of Anti-Neoplastic Agents Vincristine, Vinblastine Paclitaxel, Docetaxel Cyclophosphamide Bleomycin Actinomycin D M G resting G G Hydrocortisone 2 1 G0 = resting phase G1 = pre-replicative phase G2 = post-replicative phase S = DNA synthesis M = mitosis or cell division S Actinomycin D Purine antagonists 5-Fluorouracil Methotrexate Cytosine arabinoside Cyclophosphamide Methotrexate 5-Fluorouracil 6-Mercaptopurine Cytosine arabinoside 6-Thioguanine Daunomycin 26 26

Pharmacology of Antineoplastic Agents PART II Pharmacology of Antineoplastic Agents 27 27

the aim of anticancer drugs: 1.cure or prolonged remission 2. Palliation 3.Adjuvant chemotherapy

Basic pharmacol-ogy of anticancer drugs 1、Alkylating agents Basic pharmacol-ogy of anticancer drugs 2、Antimetabolites (structural analogs) 3、 Natural products 4、Antitumor antibiotics 5、Hormonal agent

Alkylating Agents (Covalent DNA binding drugs) The first class of chemotherapy agents used. They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. Cell-cycle nonspecific effect Alkylating agents are also mutagenic and carcinogenic 31 31

phosphoramide mustard DNA alkylating crosslink DNAs Cyclophosphamide aldophosphamide phosphoramide mustard DNA alkylating crosslink DNAs inhibition of DNA synthesis mechanism

It is given orally as well as intravenously with efficacy. Cyclophosphamide Cyclophosphamide is an alkylating agent. It is a widely used as a DNA crosslinking and cytotoxic chemotherapeutic agent. They crosslink DNAs resulting in inhibition of DNA synthesis It is given orally as well as intravenously with efficacy. 33 33

Aldophosphamide are delivered to the dividing normal and tumor cells. Cyclophosphamide It is inactive in parent form, and must be activated to cytotoxic form by liver CYT450 liver microsomal system to Aldophosphamide. Aldophosphamide are delivered to the dividing normal and tumor cells. Aldophosphamide is converted into acrolein and phosphoramide mustard. 34 34

Clinical Applications: Cyclophosphamide Clinical Applications: Breast Cancer Ovarian Cancer Non-Hodgkin’s Lymphoma Chronic Lymphocytic Leukemia (CLL) Soft tissue sarcoma Neuroblastoma Wilms’ tumor Rhabdomyosarcoma 35 35

Major Side effects Nausea and vomiting Decrease in PBL count Cyclophosphamide Major Side effects Nausea and vomiting Decrease in PBL count Depression of blood cell counts Bleeding 36 36

Major Side effects 4.Alopecia (hair loss) 5.Skin pigmentation Cyclophosphamide Major Side effects 4.Alopecia (hair loss) 5.Skin pigmentation 6.Pulmonary fibrosis 37 37

Similar to cyclophosphamide Application Germ cell cancer, Ifosphamide Mechanisms of Action Similar to cyclophosphamide Application Germ cell cancer, Cervical carcinoma, Lung cancer Hodgkins and non-Hodgkins lymphoma Sarcomas 38 38

Ifosphamide Major Side Effects Similar to cyclophosphamide, toxicity of ifosphamide is haemorrhagic cystitis. TO prevent the same mesna is routinely given with it. 39 39

Melphalan It is very effective in multiple myeloma and has been used in advanced ovarian cancer.

Melphalan Infections,diarrhoea and pancreatitis are the complications. Side effecs: Bone marrow depression is the most important toxicity, Infections,diarrhoea and pancreatitis are the complications.

It inhibits dihydrofolate reductase Methotrexate(MTX) It inhibits dihydrofolate reductase dihydrofolate tetrahydrofolic acid nucleic acid and protein metabolism 43

Methotrexate(MTX) Methotrexate has cell cycle specific action—kills cells in S phase;primarily inhibits DNA synthesis,but also affects RNA and protein synthsis. 44

MTX has been used in the management of acute childhood leukemia and choriocarcinoma. Methotrexate is also used in treatment of rheumatoid arthritis and psoriasis. 45

Intrathecal administration of MTX can be used for treatment of meningeal leukemia and carcinomatosis, and for prevention of leukemia meningitis. 46

Desquamation and bleeding may occur . The main toxicity on bone marrow—low doeses given repeatedly cause megaloblastic anaemia，but high does produce pancytopenia. Desquamation and bleeding may occur . 47

How would reduce methotrexate toxicity in overdoes or high-does? leucovorin rescue 48

Mercaptopurine (6-MP) : They are converted in the body to 6-thioinosinic acid that in turn inhibits the enzymes of purine metabolism. 49

Mercaptopurine is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine , is used as an immunosuppressive agent. 50

The principal adverse effects of mercaptopurine are bone marrow depression and toxicities in gastrointestinal tract. Jaundice and hepatic damage may also be encountered. 51

Fluorouracil(5-FU) It is converted in the body to the corresponding nucleotide 5-fluoro-2-deoxy-uridine monophosphate，which inhibits thymidylate synthase and blocks the conversion of dexxyuridilic acid to deoxythymidylic acid

It has been particularly used for many solid tumours—breast, colon, urinary bladder, liver, etc. 53

Topical application in cutaneous basal cell carcinoma has yielded gratifying results. The earlist untoward symptoms of fluorouracil are anorexia and nausea . 54

Vinca rosea

VINCA ALKALOIDS These are mitotic inhibitors, by binding tubulin and inhibiting the polymerization and assembly of microtubules ,cause disruption of mitotic spindle and interfere with cytoskeletal function. 57

It has clinical activity in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer.

Toxicity includes nausea vomiting, bone marrow suppression,　and alopecia.

Vincristine Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children 60

Vincristine The main dose-limiting toxicity is neurotoxicity.

Taxus chinensis

Paclitaxel The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization.

Paclitaxel Paclitaxel has significant activity in a wide variety of solid tumors, including ovarian, advanced breast, nonsmall cell and small cell lung, head and neck, esophageal, prostate, and bladder cancer and AIDS-related Kaposi’s sarcoma. 64

Camptotheca acuminate tree

Camptothecins They inhibit the activity of topoisomerase1. the key enzyme responsible for cutting and religating single DNA strands. 66

Dactinomycin It binds tightly to double stranded DNA through intercalation between adjacent guanine-cytosine base pairs and inhibits all forms of DNA-dependent RNA synthesis. 68

Dactinomycin is mainly used to treat pediatric tumors such as Wilms’tumor,　rhabdomyosarcoma,　and Ewing’s sarcoma.

Its adverse effects are vomiting, stomatitis, diarrhea, erythema and desquamation of skin, alopecia and bone marrow depression. 70

Bleomycin It acts by binding to DNA,　which results in singlestrand and double-strand breaks following free radical formation,　and inhibition of DNA biosynthesis.　 71

It is highly effective in testicular tumour and squamous cell carcinoma of skin, oral cavity, head and neck, genitourinary tract and esophagus; also useful in Hodgkin’s lymphoma. 72

Hormones Corticosteroids have been useful in the treatment of acute leukemia,　lymphoma,　multiple myeloma,　and other hematologic malignancies as well as in advanced breast cancer. 74

Estrogen &AndRogen Inhibitors Estrogens produce symptomatic relief in carcinoma prostate. 75

The antiestrogen tamoxifen has proved to be extremely useful for the treatment of both early-stage and metastatic breast cancer. 76

PART Ⅲ cancer dieases

Acute lymphoblastic leukemia (ALL) With the advent of the folic acid antagonists. the length of survival was greatly increased. corticosteroids corticosteroids corticosteroids corticosteroids corticosteroids vincristine vincristine vincristine vincristine daunorubicin daunorubicin daunorubicin daunorubicin daunorubicin mercaptopurine mercaptopurine Cyclophosphamide Cyclophosphamide Cyclophosphamide 79

Acute lymphoblastic leukemia (ALL) Intrathecal therapy with methotrexate should therefore be considered as a standard component of the induction regimen for children with ALL. 80

Prostate cancer Bilateral orchiectomy or estrogen therapy in the form of diethylstilbestrol were previously used as first-line therapy. Hormonal treatment reduces symptoms-especially bone pain------in 70-80% of patients and may cause a significant reduction in the PSA level. 81

Prostate cancer Second-line hormonal therapies include aminoglutethimide plus hydrocortisone, the antifungal agent ketoconazole plus hydrocortisone, or hydrocortisone alone. 82

GASTROINTESTINAL CANCERS Colorectal adenocarcinoma is the most common type of gastrointestinal tumor. Patients presenting with high-risk stage II disease and stage III disease with involvement of regional lymph nodes are candidates for adjuvant chemorherapy with fluorouracil plus leucovorin.

GASTROINTESTINAL CANCERS Treatmem with this combination regimen reduces the recurrence rate after surgery by 35% in these patients.

topoisomerase I inhibitor（ irinotecan） cisplatin-based topoisomerase I inhibitor（ irinotecan） taxanes, paclitaxel or docetaxel response rates in the range of 40-50% are now being reported.

LUNG CANCER Non-small cell lung cancer (NSCLC) makes up about 75-80% of all cases of lung cancer, while small cell lung cancer (SCLC) makes up the remaining 20--25%.

LUNG CANCER Patients with small cell lung cancer (the most aggressive type) show the best responses to platinum-based combination regimens, including cisplatin and etoposide or cisplatin and irinotecan.

LUNG CANCER The topoisomerase I inhibitor topotecan is used as second-line monotherapy in patients who have failed a platinum-based regimen.

Patienrs with stage I disease appear to OVARIAN CANCER Patienrs with stage I disease appear to benefit from whole-abdomen radiotherapy and may receive additional benefit from combination chemotherapy with cisplatin and cyclophosphamide.

carboplatin plus paclitaxel OVARIAN CANCER carboplatin plus paclitaxel cisplatin plus paclitaxel however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice.

BRAIN CANCER Carmustine can be used a single agent, or lomustine can be used in combination with procarbazine and vincristine.

BRAIN CANCER the nonclassic alkylating agent temozolomide has activity in the setting of recurrent disease.

IN CHEMOTHERAPY OF CANCER GENERAL PRINCIPLES IN CHEMOTHERAPY OF CANCER

1、A single clonogenic malignant cell is capable of producing progeny that can kill the host. 2、combined modality approach

3、complete remission should be the goal of cancer chemotherapy 4、Synergistic combinations and rational sequences are devised