1. Anticancer drugs

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

3. 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

4. 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

5. C- Problems associated with chemotherapy
1- Resistance
2- Multidrug resistance
3- Toxicity
a- Common adverse effects
b- Minimizing adverse effects
4- Treatment-induced tumors

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

7. Individual anticancer drugs continued
2- Antibiotics
A- Dactinomycin
B- Doxorubicin and daunorubicin
C- Bleomycin

8. Individual anticancer drugs continued
3- Alkylating agents
A- Mechlorethamine
B- Cyclophosphamide and ifosfamide
C- Nitrosoureas

9. Individual anticancer drugs continued
4- Microtubule inhibiters
A- Vincristine and vinblastine

10. Individual anticancer drugs continued
4- Steroid hormone and antagonists
A- prednisolone
B- Tamoxifen
C- Aromatase inhibitors
1- Aminoglutethimide
2- Anastazole
D- Progestins

11. Individual anticancer drugs continued
E- Leuprlide and goserelin
F- Estrogens
G- Flutamide and nilutamide

12. Individual anticancer drugs continued
5- Monoclonal antibodies
A- Trastumab
B- Rituximab
C- Bevacizumab

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

14. 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

15. 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

16. 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

17. 1- Antimetabolites – continued A- Methotrexate
Adverse effects
Common adverse effects
Nausea, vomiting and diarrhea
Stomitis, mylosupression, erythemia,rash
Renal damage
Hepatic function

18. Methotrexate Higher affinity for enz than does FH2
Add’l H or ionic bond forms
 Depletion FH4 in cell  depl’n dTMP  “thymine-less death”
 Inhib’n DNA synth
Uptake through folate transport system
Resistance through decr’d uptake
Metabolites (polyglutamate deriv’s) retained for weeks, months

20. 50.8 Rand

21. 1- Antimetabolites B- 6-mercaptopurine
Azathioprine is converted to 6-mercaptopurine to produce its effects

22. 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

23. 1- Antimetabolites B- 6-mercaptopurine
Main uses
Acute lymphocytic leukemia
Adverse effects
Bone marrow depression, anorexia, hepatotoxocity

24. 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

25. 1- Antimetabolites – cont C- 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

26. 1- Antimetabolites – cont C- 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

27. 2-Antibiotics A- 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. le

28. 2-Antibiotics A- Dactinomycin
Clinical uses
Wilms tumor
Gestational choriocarcinoma
Adverse effects
Bone marrow depression is the major limiting toxicity

29. 2- Antibiotics Doxoroubicin 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

30. 2- Antibiotics Doxoroubicin 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

31. 2- Antibiotics Bleomycin
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

32. 3- Antibiotics Bleomycin
Adverse effects Pulmonary toxicity, Hypertrophic skin, hyperpigmentation

33. 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.

34. 3- Alkalyting agents A- cyclophosphamide and Ifosfamide
They are very closely related to mustard agents.
They can be taken orally

35. 3- Alkalyting agents A- 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.

36. 3- Alkalyting agents A- 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

37. 3- Alkalyting agents A- cyclophosphamide and Ifosfamide
Adverse effects Bone marrow depression especially leukocytosis Hemorrhagic cystitis which can lead to fibrosis of the bladder

38. 4- Microtubule inhibitors Vincrestine 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.

39. 4- Microtubule inhibitors Vincrestine 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

40. 4- Microtubule inhibitors Vincrestine and vinblastine
Uses Acute lymphocytic leukemia Hodgkin and non- hodgkin lymphomas Adverse effects Phlebitis and cellulitis, if the drugs extravasate during injection Peripheral neuropathy

41. 5- Steroid hormone and their antagonists
1- Hormone-responsive
2- Hormone-dependent
3- Both

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. Antitumor Agents Working through Cell Signalling
Rang 50.1

49. 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

50. 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

51. Trastuzumab “Humanized” mouse monoclonal Ab Binds HER2
Membr prot structurally similar to EGFR
Has integral tyr kinase activity
Impt in breast cancer cells
May also induce p21 and p27
Cell cycle inhibitors

52. 7- Other chemotherapeutic agents
Platinium coordination complex
Cisplatin, Oxaliplatin and carboplatin
Uses: solid tumor, bladder carcinoma,
Testicular carcinoma, ovarian carcinoma

53. 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

54. 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.

55. 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

56. Thank you