anticancer

Anticancer drugs

Introduction
Cancer treatment employs 1- Surgery 2- Radiotherapy 3- Cytotoxic chemotherapy 4- Endocrine chemotherapy 5- Immunotherapy 6- Biological (targeted) Therapy

Principles of cancer chemotherapy

A- Treatment strategies 1- Goal of treatment 2- Indication for treatment 3- Tumor susceptibility and the goal of treatment a- Cell-cycle specificity of drugs b- Tumor growth rate

B- Treatment regimens and scheduling

1- Log kill 2- Pharmacological sanctuaries 3- Treatment protocols a- Combinations of drugs b- Advantage of drug combinations c- Treatment protocols

C- Problems associated with chemotherapy

1- Resistance 2- Multidrug resistance 3- Toxicity a- Common adverse effects b- Minimizing adverse effects 4- Treatment-induced tumors

Individual anticancer drugs

1- Antimetabolite A- Methotrexate B- 6-mercaptopurine C- 6-thioguanine D- Fludarabine E- 5-fluoruracil F- Cytarabine

Individual anticancer drugs continued

2- Antibiotics A- Dactinomycin B- Doxorubicin and daunorubicin C- Bleomycin

Individual anticancer drugs continued

3- Alkylating agents A- Mechlorethamine B- Cyclophosphamide and ifosfamide C- Nitrosoureas

Individual anticancer drugs continued

4- Microtubule inhibiters A- Vincristine and vinblastine

Individual anticancer drugs continued

4- Steroid hormone and antagonists A- prednisolone B- Tamoxifen C- Aromatase inhibitors 1- Aminoglutethimide 2- Anastazole D- Progestins

Individual anticancer drugs continued

E- Leuprlide and goserelin F- Estrogens G- Flutamide and nilutamide

Individual anticancer drugs continued

5- Monoclonal antibodies A- Trastumab B- Rituximab C- Bevacizumab


Individual anticancer drugs continued
6- Other chemotherapeutic agents A- Platinium coordination complexes Cisplatin Carbplatin B- procarbazine C- L-asparginase D- Interferons

1- Antimetabolites

They interfere with the availability of normal pure and pyrimidine nucleotide precursors either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis

1- Antimetabolites – continued A- Methotrexate Mechanism of action It is structurally related to folic acid, and act as an antagonist of that vitamin by inhibiting dihydrofolate reductase - the enzyme that converts folic acid to its active , coenzme form, tetrahydrofolic acid

1- Antimetabolites – continued A- Methotrexate Therapeutic uses MTX is used in combination with other drugs against cancer such as lymphocytic leukema, breast cancer, and head and neck carcenoma. MTX in a single dose used against certain inflammatory diseases as Sever psoriasis Rheumatoid arthritis Crohn disease

1- Antimetabolites – continued A- Methotrexate Adverse effects Common adverse effects Nausea, vomiting and diarrhea Stomitis, mylosupression, erythemia,rash Renal damage Hepatic function

Methotrexate

Higher affinity for enz than does FH2Add’l H or ionic bond forms Depletion FH4 in cell  depl’n dTMP  “thymine-less death”  Inhib’n DNA synth Uptake through folate transport systemResistance through decr’d uptakeMetabolites (polyglutamate deriv’s) retained for weeks, months

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1- Antimetabolites B- 6-mercaptopurine
Azathioprine is converted to 6-mercaptopurine to produce its effects


1- Antimetabolites B- 6-mercaptopurine
Mechanism of action 1-Nucleotide formation It must penetrate target cells and be converted to its nucleotide analog. 2- Inhibition of purine synthesis It blocks the first step of purine synthesis 3- Incorporation into nucleic acids It is incorporated in the DNA and RNA lead to non-functional nucleic acid

1- Antimetabolites B- 6-mercaptopurine

Main uses Acute lymphocytic leukemia Adverse effects Bone marrow depression, anorexia, hepatotoxocity

1- Antimetabolites C- 5- Fluorouracil

It is a pyridine analogue It has a stable fluorine atom instead of hydrogen atom at 5- position of the uracil ring Depriving the cell of one of the essential precursor for DNA synthesis

1- Antimetabolites – contC- 5- Fluorouracil Mechanism of action It enters the cell through a carrier mediated transport system and is converted to deoxynucleotide (5-FdUMP) 5- FdUMP acts as a pseudosubstrate which compete with deoxynucleotide monophosphate for thymidylate synthase. DNA synthsis decreases due to lack of thymidine

1- Antimetabolites – contC- 5- Fluorouracil Main uses Slow growing solid tumor (colorectal, breast, overian, pancreatic, gastric carcinoma) Adverse effects Sever ulceration of the oral and GI mucosa, bone marrow depression

2-AntibioticsA- Dactinomycin

The antitumor antibiotics act on DNA and also inhibit topoisomerase I and II produce free radical play a major role in their cytotoxicity. Mechanism of action The drug intercalates into the miner grooves of the double helex between guanine-cytosine base pairs of DNA, forming a stable dactinomycin-DNA complex.

2-AntibioticsA- Dactinomycin

Clinical uses Wilms tumor Gestational choriocarcinoma Adverse effects Bone marrow depression is the major limiting toxicity



2- AntibioticsDoxoroubicin and daunorubicin
They are classified as anthracycline antibiotics Mechanism of action 1- Intercalation in the DNA 2- Binding to cell membrane 3- Generation of Oxygen radicals Uses Breast cancer, lung cancer, acute lymphoctic leukemia, lym.phoma

2- AntibioticsDoxoroubicin and daunorubicin

Adverse effects Irreversible, dose-dependent cardiotoxicity apparently a result of the generation of free radicals and lipid peroxidation Increased skin pigmentation is also seen

2- AntibioticsBleomycin

Mechanism of action A DNA-bleomycin-Fe2+ complex appears to undergo oxidation to bleomycin-Fe3+. The liberated electron react with oxygen to form superoxide or hydroxyl radical which attack DNA. Uses Testicular cancer-cure, lymphoma-not curative

3- AntibioticsBleomycin

Adverse effects Pulmonary toxicity, Hypertrophic skin, hyperpigmentation

3- Alkalyting agents

They bind covalently to nucleophilic groups on various cell constituants. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cell. Alkylating agents so not discriminate between cycling and resting cells.

3- Alkalyting agentsA- cyclophosphamide and Ifosfamide

They are very closely related to mustard agents. They can be taken orally



3- Alkalyting agentsA- cyclophosphamide and Ifosfamide
Mechanism of action They are biotranformed to hydroxylated intermediates by cytochrome p450 system. The intermediate undergo break down to form the active compounds, phosphoramide mustard and acrolein. Phosphoramide mustard react with DNA.

3- Alkalyting agentsA- cyclophosphamide and Ifosfamide

Clinical uses Broad spectum as a single or as a part of the regimens to treat wide variety of neoplastic diseases Non-neoplastic disease such as nephrotic syndrome and intractable rheumatoid arthrits

3- Alkalyting agentsA- cyclophosphamide and Ifosfamide

Adverse effects Bone marrow depression especially leukocytosis Hemorrhagic cystitis which can lead to fibrosis of the bladder

4- Microtubule inhibitorsVincrestine and vinblastine

These drugs are referred as vinica alkaloids, since they are derived from the plant vinica rosea. Although they are similar in structure but they are different in therapeutic use.

4- Microtubule inhibitorsVincrestine and vinblastine

Mechanism of action They are both cell cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. The result dysfunctional spindle apparatus

4- Microtubule inhibitorsVincrestine and vinblastine

Uses Acute lymphocytic leukemia Hodgkin and non- hodgkin lymphomas Adverse effects Phlebitis and cellulitis, if the drugs extravasate during injection Peripheral neuropathy

5- Steroid hormone and their antagonists

1- Hormone-responsive 2- Hormone-dependent 3- Both

5- Steroid hormone and their antagonists

A- Prednisone uses: Lymphocytic leukemia, Hodgkin and non- hodgkin lymphomas B- Tamoxifen Selective estrogen receptor modulator Uses: Breast cancer in patients with positive estrogen receptors

5- Steroid hormone and their antagonists

C- Progestins Megestrol Uses: Hormone responsive breast cancer and endometrial neoplasm However. Aromatase inhibitors are replasing it in therapy

5- Steroid hormone and their antagonists

D- Leuprolide and goserelin They are synthetic nonapeptide analogs of gonadotropin releasing hormone (GnRH). They occupy GnRH receptor in the pituitary and lead to its desensitization and consequently inhibition of release of LH and FSH. Thus both androgen and estrogen are reduced. Uses: Prostate cancer Adverse effects: Impotence, hot flashes

5- Steroid hormone and their antagonists

E- Flutamide, nilutamide They are non steroidal antiandrogens. They compete with the natural hormone for binding to androgen receptor and prevent its translocation into the nucleus

5- Steroid hormone and their antagonists

Flutamide blocks the inhibitory effect of testosterone on gonadotrophin secretion causing increase in LH and testosterone secretion. Therefore, it should always administer with leuprolide or gasorelin which can desensitize the hypothalamus pituitary axis uses: Prostate cancer Adverse effects: Gynecomastia, GI disturbance, liver failure

5- Steroid hormone and their antagonists

F- Aromatase inhibitors The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen which take place in the liver, fat and muscle and breast tissue, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. Aminoglutethimide Uses: Metastatic breast cancer in postmenopausal women Adverse effects: inhibition of hydrocortisone synthesis

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Antitumor Agents Working through Cell Signalling

6- Monoclonal antibodies

They are created from B lymphocytes (from immunized mice or hamster) fused with immortal B lymphocyte tumor cells. The resulting hybrid cells can be individually cloned and each clone will produce antibodies directed against single antigen type. Recombinant technology has led to the creation of humanized antibodies overcome the immunologic problems observed in mouse antibodies

6- Monoclonal antibodies

Trastuzumab Uses In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor-receptor protein 2 (Her 2) Adverse effects Congestive heart failure is the most serious toxicity, fever, chill, nausea, vomiting

Trastuzumab“Humanized” mouse monoclonal AbBinds HER2Membr prot structurally similar to EGFRHas integral tyr kinase activityImpt in breast cancer cellsMay also induce p21 and p27 Cell cycle inhibitors http://www.gene.com/gene/products/information/oncology/herceptin/images/moa.jpg

7- Other chemotherapeutic agents

Platinium coordination complex Cisplatin, Oxaliplatin and carboplatin Uses: solid tumor, bladder carcinoma, Testicular carcinoma, ovarian carcinoma

7- Other chemotherapeutic agents

Interferons Recommbent DNA techniques in bacteria produce interferons including interferon-α-2α and -2β that are employed in treating neoplastic diseases

Interferons

After binding interferon, a series of complex intracellular reactions take place including enzyme synthesis, suppression of proliferation activation of macrophage and increased cytotoxity of lymphocyte. Uses Hairy cell leukemia, melanoma, and follicular lymphoma.

Treatment of breast cancer للاطلاع فقط Cyclophosphamide 500 mg/m2 + 5-fluorouracil 500 mg/m2 + doxrubicin 50 mg/m2 Every 21 days for 6 cycles Then followed after the treatment Tamoxifen (20 mg/day) is given for estrogen positive patients for 5 years


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