Assoc. Prof. Ivan Lambev E-mail: [email protected] ANTICANCER
DRUGS Medical University of Sofia, Faculty of Medicine Department
of Pharmacology and Toxicology
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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
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Uncontrolled proliferation Can be invasive Can metastasize Lack
of function (lack of differentiation) Characteristics of cancer
cells
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Normal cells Growth is controlled by growth factors and growth
inhibitory factors Cancer cells Inactivation of tumor-suppressor
genes Activation of proto-oncogenes
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ANTICANCER TREATMENT surgery radiotherapy (irradiation)
chemotherapy modificators of biological response sustain
therapy
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I.CLASSICAL ANTICANCER DRUGS Alkylating agents (alkylators)
Antimetabolites Mitotic inhibitors Cytotoxic antibiotics Hormones
and hormone antagonists Enzymes etc.
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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.
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Action of cytotoxic agents on the cell cycle Cycle non-specific
Alkylators Antibiotics Phase specific Antimetabolites Mitotic
inhibitors
The sensitivity of a cancer to treatment depends on the growth
fraction that is the fraction of cells undergoing mitosis at any
time.
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The fraction of cell division in Burkitts 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.
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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.
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Different forms of cancer differ in their sensitivity to
chemothe- rapy. The most responsive are rapidly proliferating
tumors: lymphomas leukemias chorioncarcinoma testicular
carcinoma
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Solid tumors show a poor response: colorectal carcinomas
adrenocortical carcinomas squamous cell bronchial carcinomas
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An intermediate response is shown by other cancers, for
example: bladder head and neck ot cell bronchogenic carcinoma
sex-related cancers of breast, ovary, endometrium, prostate
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Treatment of cancer Solid tumors surgery or irradiation, plus
CHEMOTHERAPY Non-solid tumors CHEMOTHERAPY Metastases
CHEMOTHERAPY
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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:
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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
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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.
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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
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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.
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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.
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The important functional groups is the dichlor-ethyl-amine
side-chain: RNRN 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.
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Chlorambucil Cyclophosphamide First alkyl- lators are:
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Cyclophosphamide and Chlorambucil are commonly used for
Hodgkins and non-Hodgkins 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.
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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.
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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 Hodgkins
lymphoma.
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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.
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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
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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
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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
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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.
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Folic acid Methotrexate
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Methotrexate is given for treatment of: acute lymphoblastic
leukemia non-Hodgkins lymphomas chorionepithelioma non-malignant
disorders (such as psoriasis).
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Adverse effects of methotrexate Vasculitis Arachnoiditis
Pharyngitis, pneumonitis Cystitis Vomiting Hepatotoxicity Renal
dysfunction PRC: D
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Mitotic inhibitors Vinca alkaloids Podophyllin derivatives
Taxans (taxoids) They have cycle and phase specific action on the
cell division.
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Vinca alkaloids are complex natural chemicals isolated from the
periwinkle plant (Vinca rosea). Vinblastine Vincristine,
Vinorelbine They bind to tubulin and produce metaphase arrest. They
use for acute leukemia.
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Vinblastine Vincristine
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Podophyllin derivatives May apple (Podophyllum peltatum India,
USA) Epipodophyllotoxin Etoposide Podophyllin
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Etoposide Inhibits mitosis Acts in late S- or early G 2 -phases
Treatment of lymphoma; lung, testicular, bladder and prostate
carcinoma
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Taxans (toxoids) Docetaxel in breast cancer Paclitaxel Inhibit
the depolymerization of tubulin and block mitosis.
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Cytotoxic antibiotics Inhibit DNA replication.
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Daunorubicin Idarubicin Doxorubicin Epirubicin
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Mitomycin in cancer of bladder (locally) Other antibiotics
Bleomycin in: tetsicular carcinoma melanomas, sarcomas squamous
cell carcinomas
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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.
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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.
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Glucocorticoids are also helpful in reducing oedema around a
tumor. They have antiemetic activity too. Hydrocortisone,
Prednisone Dexamethasone, Prednisolone
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Estrogens suppress prostate cancer cells both locally and
metastases, and provide symptomatic improv- ment. Gynecomastia is a
common side-effect. Fosfestrol (Honvan ) Polyestradiol
phosphate
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Progestins suppress endometrial cancer cells and lung
secondaris: Gestonorone Medroxyprogesterone
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Androgens are used in treating of carcinoma ovarii and uteri
Drostanolon Testosterone
Cyproterone (Androcur ) p.o. i.m. antiaphrodisiacum too
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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.
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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.
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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).
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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.
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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).
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Gonadotropin releasing hormone agonists: Goserelin 3.6 mg/30
days s.c. Leuprolide - palliative treatment of advanced prostatic
carcinoma - endometriosis Indications:
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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.
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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
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Cytokines peptide regulators of inflam- matory and immune
reactions. Interleukins, interferons, colony-stimulating factors,
tumour necrosis factors...
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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.
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Interferon alfa-2b (Intron A) in: chronic hepatitis, hairy cell
leukemia AIDS-related Kaposis 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.
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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.
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Molgramostim (Recombinant Human Granulocyte- Macrophage
Colony-Stimulating Factor rHuGM-CSF) Filgrastim (Recombinant Human
Granulocyte Colony-Stimulating Factor rHuG-CSF)
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Blockers of cell transduction signalling a) Antiangiogenic
drugs (used in colorectal cancer)
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TRASTUZUMAB ( Herceptin ): i.v. inf. RITUXIMAB ( MabThera ) NHL
b) Monoclonal antibodies blockers of receptors for growth
factors
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c) Inhibitors of tyrosinekinase Imatinib (Glivec ) for oral
treatment of chronic myeloid leukemias
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Vaccines BCG Immunotherapeuticum locally in bladder cancer
Silgard : Ca colli utrei (HPV type 16 18) Immune stimulation
Levamisole (out of date) Polyerga (improves quality of life)
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III. SUSTAIN THERAPY IN ONCOLOGY Analgesics Antiemetics
Antiemetics Bisphosphonate derivatives Etc.
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