1 ANTICANCER DRUGS Assoc. Prof. Ivan Lambev

3 Characteristics of cancer cells Uncontrolled proliferationCan be invasive Can metastasize Lack of function (lack of differentiation)

4 Normal cells Cancer cells Growth is controlled by growth factorsand growth inhibitory factors Cancer cells Inactivation of tumor-suppressor genes Activation of proto-oncogenes

5 ANTICANCER TREATMENT  surgery  radiotherapy (irradiation) chemotherapy  supportive therapies NB! NB!

6 mitosis at any time. The sensitivity of a cancer to treatmentdepends on the growth fraction – that is the fraction of cells undergoing mitosis at any time.

7 The fraction of cell divisionin Burkitt’s lymphoma is 100% and this tumor is very sensitive. In contrast the growth fraction represents less than 5% of cells in a carcinoma of the colon and this explains its resistance to chemotherapy.

8 However, metastases fromcolonic carcinoma, deposited in the liver and elsewhere initially, have a high growth fraction and are sensitive to chemotherapy, which is frequently given following surgical removal of primary tumor.

9 Different forms of cancer differin their sensitivity to chemothe- rapy. The most responsive are rapidly proliferating tumors: lymphomas leukemias choriocarcinoma testicular carcinoma

10 Solid tumors show a poor response: colorectal carcinomasadrenocortical carcinomas squamous cell bronchial carcinomas

11 An intermediate response is shown by other cancers:bladder head and neck oаt cell bronchogenic carcinoma sex-related cancers of the breast, ovary, endometrium, prostate

12 surgery or irradiation, plus CHEMOTHERAPY “Non-solid tumors” – Metastases –

13 Adverse effects Most of the anticancer agents havea limited selectivity and damage all dividing cells. As a result general adverse effects are: Myelotoxicity (reduction of leukocytes increases susceptibility to infections) Hair loss

14 Damage to GI tract Impaired wound healing Depression of growth Nausea and vomiting Carcinogenicity (in rare cases) Reproductive toxicity (PRC: D/X) Kidney damage Hepatotoxicity

15 Resistance to cytotoxic drugs (primary or acquired) in 90% of cases– mechanisms: Increased rate of synthesis of target enzyme (dihydrofolate reductase and methotrexate) Increased repair of DNA (alkylating agents) Insufficient activation of prodrug – cytarabine (does not undergo phosphorylation) Multi Drug Resistance – increasing action of membrane efflux system (P-gp 170 and 190), etc.

16 Strategy to avoid resistanceUse 3 or 4 anticancer drugs together or in sequence, e.g. treatment of lymphomas: COP treatment (COP – acronym) – Cyclophosphamide – Oncovin® (vincristine) – Prednisolone

17 Criteria for selecting combinationsEach drug should be an active anticancer drug in its own right. Each drug should have a different mechanism of action and target site within the cancer cell (this will increase efficacy and will reduce the resistance). Each drug should have a different site for any organ-specific toxicity.

18 The dosage of many antineoplastic drugsis carried out according to the body surface of the patient, calculated in square meters (m2) by means of nomogram according body mass in kg and height in cm. The best treatment regimens are become the "gold standard" for treatment of cancer. They are develop and annually update by world oncotherapeutic teams.

19 Prof. A. Dudov, MD, PhD President of Bulgarian Cancer Scientific Society

20

21 Anticancer (antineoplastic) drugsI. Cytotoxic drugs (cytostatics) - Alkylators - Antimetabolites - Plant-derived drugs and their analogs - Cytotoxic antibiotics - Platinum coordination complexes II. Endocrine agents - Glucocorticoids - Sex hormones and antihormones

22 III. Target drugs      - Monoclonal antibodies (MAB)      - Protein (tyrosine kinase) inhibitors      - Inhibitors of production of TNF-α IV. Inhibitors of bone resorption and metastases V. Immunomodulators - Cytokines (ILs, IFNs) - Vaccines VI. Radiotherapy VII. Cancer supportive therapies

23 CYTOTOXIC AGENTS The majority of cytotoxic agents inhibit the processof DNA synthesis within the cancer cells. Resting cells (those in the Go phase) are resistant to many anticancer drugs.

24 DeoxiribonucleotidesPrecursors Precursors Methotrexate Pyrimidine Purine Ribonucleotides Mercaptopurine Deoxiribonucleotides Alkylators Cis-platin Antibiotics DNA Asparaginase RNA Asparagine Nitrosoureas Mitotic inhibitors Proteins

25 Action of cytotoxic agentson the cell cycle Cycle non-specific Alkylators Antibiotics Phase specific Antimetabolites Mitotic inhibitors

26  Alkylating agents These drugs were developed from thesulfur mustard gases used in the 1st WW trenches and which caused bone marrow suppression in addition to respiratory toxicity. Replacement of the sulfur atom by nitrogen allowed the first alkylating agents to be obtained.

27 The important functional group is the di-(2-chlor-ethyl)-amine side chain: CH2CH2Cl R—N CH2CH2Cl The dichlorethylamine chains are highly reactive and produce alkylating groups which bind covalently to sites within the DNA such as N7 of guanine.

28

29 a) First Nitrogen mustardsalky- lators are di-(2-chlor ethyl)- amines: Nitrogen mustards Cyclophosphamide Chlorambucil

30 Cyclophosphamide and Chlorambucilare commonly used for Hodgkin’s and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia. Cyclophosphamide is also used for immunosuppression in non-malignant disorders (severe rheumatoid disorders, myasthenia gravis, multiple sclerosis).

31 Cyclophosphamide is a prodrug.One of its metabolites is acrolein. Acrolein causes bladder toxicity with haemorrhagic cystitis which can be prevented by prior treatment with Mesna. Bladder cancer may develop years after cyclophosphamide chemotherapy. Cancer

32 b) Nitrosoureas (the other alky- lators) inhibit the synthesis of DNA, RNA, and proteins. Carmustine crosses BBB. It is used for brain tumors. Carmustine and Lomustine are used for the treatment of Hodgkin’s lymphoma.

33  Antimetabolites – produce lethal synthesisA number of useful chemothera- peutic agents have been produced by simple modifications to the structures of normal purine and pyrimidine bases.

34 a) Analogues of pyrimidine5-Fluorouracil (5-FU®: i.v.) – used for the treatment of carcinoma of stomach, colon, rectum, breast, and pancreas. 5-FU Xeloda® (p.o.) – used in colorectal carcinoma. It is a prodrug of 5-FU with very high selectivity. Cytarabine: used in acute myeloid leukemias (It acts after phosphorylation)

35 5-FU blocks thymidilate synthase

37 c) Folic acid antagonistsMethotrexate, Pemetrexed, Ralitrexed Folic acid in its reduced form (THF – tetrahydrofolic acid) is essential for syn- thesis of the purine ring system. During these reactions THF is oxidized to dihydro- folic acid which has to be reduced by dihydrofolate reductase. Methotrexate inhibits dihydrofolate reductase and blocks purine and thymidine synthesis.

38 (It has immunosuppressive activity too.)Folic acid Methotrexate (It has immunosuppressive activity too.)

40 Adverse effects of methotrexateVasculitis Arachnoiditis Pharyngitis, pneumonitis Cystitis Vomiting Hepatotoxicity Renal dysfunction PRC: D

41  Plant-derived drugs and their analogsVinca alkaloids Derivatives of Podophyllotoxin Taxans etc. They have cycle and phase specific action on the cell division.

42 Vinca alkaloids are complexnatural chemicals isolated from the periwinkle plant (Vinca rosea). Vinblastine Vincristine Vinorelbine (Navelbine®) They bind to tubulin and produce metaphase arrest. They are used in acute leukemia.

43 (mitotic inhibitors)

44 Derivatives of Podophyllotoxin (epipodophyllotoxins)Podophyllum peltatum (May apple) Podophyllotoxin Epipodophyllotoxin Etoposide Teniposide

45 Etoposide Inhibits mitosis Acts in late S- or early G2-phasesUsed in treatment of lymphoma; lung, testicular, bladder and prostate cancer

46 Taxans Docetaxel – Paclitaxel Inhibit the depolymerizationof tubulin and block mitosis. Docetaxel – in breast cancer Paclitaxel (Taxus brevifolia)

47  Cytotoxic antibiotics (inhibit DNA replication)

48 Doxorubicin Daunorubicin Epirubicin Idarubicin

50  Platinum coordination complexesCis-platin binds to DNA and proteins. It has made a significant impact on the treatment of testicular teratoma and ovarian tumors. It has a long t1/2 (72 h) due to extensive protein binding and slow renal elimination. Renal toxicity is a major problem. Severe nausea and vomiting are often troublesome too. PRC: D.

51 II. Endocrine agents Some cancer arise from cell lines withsteroid receptors. Steroid hormones cause remissions in certain types of cancer. They usually do not eradicate the disease, but can alleviate symptoms for a long period and do not depress the bone marrow.

52 Glucocorticoids suppress lymphocyte mitosisand are used in combination with cytotoxic agents in treating of lymphomas, myeloma and to induce a remission in acute lymphoblastic leukemia.

53 Glucocorticoids are also helpful in reducing oedema around a tumor.They have antiemetic activity too. Hydrocortisone, Prednisone Dexamethasone, Prednisolone

54  Estrogens suppress prostate cancer both locally and metastases, and provide symptomatic improvement. Gynecomastia is a common side effect. Ethinylestradiol Polyestradiol phosphate

55  Progestagens suppress endometrial cancer cells and lung secondaries:Gestonorone Medroxyprogesterone

56 Androgens are used rarely in the treatment of carcinomaovarii and uteri Testosterone Side anabolic effect:

57  Androgen antagonistssuppress prostate cancer cells. Unwanted effects include: gynecomastia, decreased spermatogenesis, decreased libido. Bicalutamide, Cyproterone, Flutamide PSA >> 5 1 2 3

58 – anti-aphrodisiac too.p.o. i.m. Cyproterone (Androcur®) – anti-aphrodisiac too.

59  Inhibitors of alpha-reductaseAlpha-reductase converts testosterone in more active dihydrotestosterone. Finasteride is useful orally in the treatment of benign prostatatic hyperplasia.

60  Estrogen antagonistsFluvestrant, Toremifen Tamoxifen (p.o.) suppresses breast cancer cells. The trans isomer of Tamoxifen blocks competitively estrogen receptors. Adverse effects include hot flushes and amenorrhoea in premenopausal women and vaginal bleeding in postmenopausal women.

61  Aromatase inhibitorsAminoglutethimide Exemestane (Aromasin®) Formestane, Letrozole They inhibit aromatase and block conversion of androgens to estrogens. - Inhibition of aromatase reduces estrogen production in adipose tissue, skin, muscle, and liver of postmenopausal women (because ovarian aromatase is resistant to such inhibition!).

62 advanced breast carcinoma. Side effects include symptoms of estrogenAromatase is also presented in the cells of two-thirds of breast carcinomas and about 80% of these tumors are estrogen- dependent. Aromatase inhibitors are used in postmenopausal women with advanced breast carcinoma. Side effects include symptoms of estrogen withdrawal, e.g. headache, hot flushes, and lethargy; dyspepsia, nausea, alopecia, skin rash, hypotension, tachycardia.

63 Breast cancer

64 Treatment with the aromatase inhibitor letrozole reduces the occurrence of distant metastases in Ca mammae

65  Gonadotrophin releasing hormone agonists (GnRHAs)Continuous daily administration of GnRHAs results in suppression of testicular and ovarian steroido- genesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (in man) or estrogens (in women).

66 Gonadotrophin releasinghormone agonists: Leuprolide (Leuproreline) Goserelin (Zoladex®) – 3.6 mg/30 days s.c. in: – palliative treatment of advanced prostatic carcinoma – endometriosis

67 III. Target drugs They block receptors of the growthand other angiogenic factors: VEGF – vascular endothelial growth factor EGF – epidermal growth factor PDGF – platelet-derived growth factor PlGF – placental transfer growth factor TNF-α – tumor-necrosis factor alfa, etc.

68 a) Monoclonal AntiBody (MAB)BEVACIZUMAB (Avastin®) – anti-VEGF agent blocks angiogenesis and the growth of new blood vessels. It is used to treat various cancers, including colorectal, lung, and kidney cancer, etc. Avastin®

69

70 Colorectal cancer

72 b) Protein kinase inhibitorsImatinib (Glivec®): used for the oral treatment of chronic myelogenous leukemia Everolimus (Afinitor®) – mTOR inhibitor: mammalian Target Of Rapamycin) is used: in renal cancer, pancreatic neuroendocrine tumors, as an immunosuppressant to prevent rejection of organ transpalntants (including in drug-eluting coronary stents to prevent restenosis). Lapatinib, Pasopanib Sorefenib (used in renal and liver cancer)

74 IV. Inhibitors of bone resorption and metastases

75 V. IMMUNOMODIFICATORS The immune system probablycontributes to the final removal of residual malignant cells, and most cytotoxic anticancer agents compromise immune responsiveness.

76  Cytokines – Interleukins, interferons, colony-stimulating factors,peptide regulators of inflam- matory and immune reactions. Interleukins, interferons, colony-stimulating factors, tumour necrosis factors.

77 IL-2 produced by T-lymphocytes which activate cytotoxic killercells. It is received by recombinant DNA technology. IL-2 has been given by i.v. infusion in patients with metastatic renal carcinoma. IL-2 causes many ADRs.

78 Interferons (alpha, beta, gamma)are glycoproteins produced as part of the natural host defenses to virus infections. They have antiviral activity, immunoregulatory function, reduce multiplication of cancer cells. Interferon alfa-2b (Intron® A) – in: chronic hepatitis, hairy cell leukemia AIDS-related Kaposi’s sarcoma renal carcinoma

80  Vaccines Silgard® and Cervarix® are vaccines againstBCG Immunotherapeuticum – locally in bladder cancer after TUR Silgard® and Cervarix® are vaccines against certain types of cancer- causing human papillomavirus (HPV – type 6, 11, 16, and 18) Cancer

83 Prof. G. Gorchev, MD, DSc: Medical University – Pleven

84

85 VI. Radiotherapy  Radio-pharmaceuticals (radionuclides)- Irradiated with beta-rays): 131I, 32P (Sodium phosphate), 183Pal - palladium, 145Sm - samarium 89Sr (strontium)  Brahiterpiya (locally in prostate or vaginal cancer)  Photodynamic cancer therapy (irradiation with laser light, with consequent formation of free radicals): - Porfimer, Temoporfin

86 VII. CANCER SUPPORTIVE THERAPIES

87

88

89 Emetogenic activity Cisplatin Carmustine Cyclophosphamide Mitomycin CL-Asparginase Fluorouracil Methotrexate Etoposide Vincristine

90 Colony-stimulating factors (CSFs) are used in special cancertherapy centers to reduce the severity and duration of neutropenia induced by cytotoxic anticancer chemotherapy; used in aplastic anaemia; used in anaemia in AIDS too.

91 Filgrastim Molgramostim (Recombinant Human Granulocyte Colony-Stimulating Factor – rHuG-CSF) Molgramostim (Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor – rHuGM-CSF)

92

93 “BURNOUT” syndrome

94