© Assoc. Prof. Ivan Lambev ANTICANCER DRUGS Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

Possible causes of cancer  Physical agents (radiation, GSM or injury)  Chemicals (carcinogens, including smoking)  Hereditary factors  Effectiveness of immune system (virus infections: Ca collum uteri)  Stress, > BMI, some drugs

 Uncontrolled proliferation  Can be invasive  Can metastasize  Lack of function (lack of differentiation) Characteristics of cancer cells

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

ANTICANCER TREATMENT  surgery  radiotherapy (irradiation)  chemotherapy  modificators of biological response  sustain therapy

I.CLASSICAL ANTICANCER DRUGS  Alkylating agents (alkylators)  Antimetabolites  Mitotic inhibitors  Cytotoxic antibiotics  Hormones and hormone antagonists  Enzymes etc.

Mechanism of action and clinical use The majority of antineoplastic agents inhibit process of DNA synthesis within the cancer cells. Resting cells (those in the G o phase) are resistant to many anticancer drugs.

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

Precursors Purine Pyrimidine Ribonucleotides Deoxiribonucleotides DNA RNA Proteins Methotrexate Mercaptopurine Hydroxyurea Alkylators Cis-platin Antibiotics Sex sterioids Nitrosureas Mitotic inhibitors Asparagine Asparaginase

The sensitivity of a cancer to treatment depends on the growth fraction  that is the fraction of cells undergoing mitosis at any time.

The fraction of cell division in 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.

However, metastases from colonic 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.

Different forms of cancer differ in their sensitivity to chemothe- rapy. The most responsive are rapidly proliferating tumors:  lymphomas  leukemias  chorioncarcinoma  testicular carcinoma

Solid tumors show a poor response:  colorectal carcinomas  adrenocortical carcinomas  squamous cell bronchial carcinomas

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

Treatment of cancer Solid tumors – surgery or irradiation, plus CHEMOTHERAPY “Non-solid tumors” – CHEMOTHERAPY Metastases – CHEMOTHERAPY

Myelotoxicity (decreased of leuco- cytes produce resistance to infection) Hair loss Adverse effects of anticancer agents Limited selectivity (selectivity resides in damage to dividing cells). As a result general adverse effects are:

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

Resistance to cytotoxic drugs (primary or acquired) Increased rate of synthesis of target enzyme (dihydrofolate reductase and methotrexate) Increased repair of DNA (alkyllating agents) Insufficient activation of prodrug – cytarabine (does not undergo phosphorylation) Multi Drug Resistans – increasing action of membrane efflux system (P170, P190) etc.

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

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

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

The important functional groups is the dichlor-ethyl-amine side-chain: RNRN CH 2 CH 2 Cl The dichlorethylamine chains are highly reactive and produce alkylating groups which bind covalently to sites within DNA such as N7 of guanine.

Chlorambucil Cyclophosphamide First alkyl- lators are:

Cyclophosphamide and Chlorambucil are commonly used for Hodgkin’s and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia. Cyclophosphamide is also used for immunosupression in non-malignant disorders (severe rheumatoid disorders, myasthenia gravis, multiple sclerosis). Busulfan: in chronic myeloid leukemia.

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

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

Cis-platin binds to DNA and proteins. It has made a significant impact on treatment of testicular teratoma and ovarian tumors. It has a long t 1/2 (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.

A number of useful chemothera- peutic agents have produced by simple modifications to the structures of normal purine and pyrimidine bases.  Antimetabolites – produce lethal synthesis

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

Gemcitabine inhibits DNA polymerase and impairs DNA synthesis. Its is suitable for treatment of chronic lymphocytic leukemia in patients who have not responded to alkylating agent regimen. b) Analogues of purine Mercaptopurine (6-MP): in childhood acute leukemia. Thioguanine (6-TG): in childhood acute leukemia. Azathioprine suppresses T-lymphocytes: used in organ transplantation and rheumatoid arthritis

c) Folic acid antagonists 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 dihyd- rofolic acid which has to be reduced by dihydrifolate reductase back. Methotrexate inhibits dihydrofolate reductase and blocks purine and thymidylate synthesis.

Folic acid Methotrexate

Methotrexate is given for treatment of: acute lymphoblastic leukemia non-Hodgkin’s lymphomas chorionepithelioma non-malignant disorders (such as psoriasis).

Adverse effects of methotrexate Vasculitis Arachnoiditis Pharyngitis, pneumonitis Cystitis Vomiting Hepatotoxicity Renal dysfunction PRC: D

 Mitotic inhibitors  Vinca alkaloids  Podophyllin derivatives  Taxans (taxoids) They have cycle and phase specific action on the cell division.

Vinca alkaloids are complex natural chemicals isolated from the periwinkle plant (Vinca rosea). Vinblastine Vincristine, Vinorelbine þThey bind to tubulin and produce metaphase arrest. þThey use for acute leukemia.

Vinblastine Vincristine

Podophyllin derivatives May apple (Podophyllum peltatum  India, USA) Epipodophyllotoxin Etoposide Podophyllin

Etoposide Inhibits mitosis Acts in late S- or early G 2 -phases Treatment of lymphoma; lung, testicular, bladder and prostate carcinoma

Taxans (toxoids) Docetaxel in breast cancer Paclitaxel Inhibit the depolymerization of tubulin and block mitosis.

 Cytotoxic antibiotics Inhibit DNA replication.

Daunorubicin Idarubicin Doxorubicin Epirubicin

Mitomycin – in cancer of bladder (locally) Other antibiotics Bleomycin in: – tetsicular carcinoma – melanomas, sarcomas – squamous cell carcinomas

 Hormones and hormone antagonists Some cancer arise from cell lines with steroid 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.

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

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

Estrogens suppress prostate cancer cells both locally and metastases, and provide symptomatic improv- ment. Gynecomastia is a common side-effect. Fosfestrol (Honvan ® ) Polyestradiol phosphate

Progestins suppress endometrial cancer cells and lung secondaris: Gestonorone Medroxyprogesterone

Androgens are used in treating of carcinoma ovarii and uteri Drostanolon Testosterone

Androgen antagonists suppress prostate cancer cells. Unwanted effects include: gynecomastia, decreased spermatogenesis, decreased libido. Cyproterone Flutamide

Cyproterone (Androcur ® ) p.o. i.m.  antiaphrodisiacum too 

Inhibitors of alpha-reductase (e.g. Finasteride) Alfa-reductase converts testosterone in more active dihydrotestosterone. Finasteride is useful orally in the treatment of benign prostatatic hyperplasia. Unlabeled use: Adjuvant monotherapy after radical prostatectomy in the treatment of prostatic cancer.

Estrogen antagonists (e.g. Tamoxifen  p.o.) suppress breast cancer cells. Transisomer of Tamoxifen binds competitively to estrogen receptors. Adverse effects include hot flushes and amenorrhoea in premenopausal women and vaginal bleeding in postmenopausal women.

Aromatase inhibitors Aminoglutethimide (p.o.) Formestane (i.m.) - 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).

Aromatase is also present 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.

Gonadotropin 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 dec- rease in testosterone (in man) or estrogens (in women).

Gonadotropin releasing hormone agonists: Goserelin  3.6 mg/30 days s.c. Leuprolide - palliative treatment of advanced prostatic carcinoma - endometriosis Indications:

 Enzymes (Asparaginase and other inhibitors of protein synthesis) Asparaginase removes circulating asparagine which essential for cancer cells. It has been given by i.v. infusion in acute lymphoblastic leukemia. It causes sever toxicity to liver and pancreas, anaphylactic reactions too.

The immune system probably contributes to the final removal of residual malignant cells, and most cytotoxic anticancer agents compromise immunoresponsiveness. Many modificators of biological response act really as immunostimulants. II. MODIFICATORS OF BIOLOGICAL RESPONSE

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

Aldesleukin (IL-2) Produced by T-lymphocytes which activate cytotoxic killer cells. Received by recombinant DNA technology. IL-2 has been given by i.v. infusion in patients with metastatic renal carcinoma. It can produce hypotension, edema, flue- like symptoms, vomiting, anaemia.

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

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

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

 Blockers of cell transduction signalling a) Antiangiogenic drugs (used in colorectal cancer)

TRASTUZUMAB ( Herceptin ® ): i.v. inf. RITUXIMAB ( MabThera ® ) – NHL b) Monoclonal antibodies – blockers of receptors for growth factors

c) Inhibitors of tyrosinekinase Imatinib (Glivec ® ) – – for oral treatment of chronic myeloid leukemias

 Vaccines BCG Immunotherapeuticum ® – locally in bladder cancer Silgard ® : Ca colli utrei (HPV – type 16 и 18)  Immune stimulation Levamisole (out of date) Polyerga ® (improves quality of life)

III. SUSTAIN THERAPY IN ONCOLOGY Analgesics Antiemetics Antiemetics Bisphosphonate derivatives Etc.

Cisplatin Carmustine Cyclophosphamide Mitomycin C L-Asparginase Fluorouracil Methotrexate Etoposide Vincristine Emetogenic activity Ondansetron (Zofran ® )

Bisphosphonate derivatives - inhibit bone resorption via action on osteoclasts Alendronate Clodronate Ibandronate Pamidronate Hypercalcemia, associated with malignancy Osteolytic bone lesions in multiple myeloma or metastatic breast cancer