1. Antineoplastics Pharmacology III Practical Sessions Cairo University
Faculty of Pharmacy
Department of Pharmacology & Toxicology
Pharmacology III
Practical Sessions
Antineoplastics

2. Cancer is a disorder of cell division (leading cause of death).
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Pharma-III Practical
What is Cancer ?
Cancer is a disorder of cell division (leading cause of death).
Cancers most commonly occur in:
breast (♀) - prostate (♂) - lung - colon - rectum
Common characteristics of neoplastic cells:
- Persistent proliferation and Immortality
-Dedifferentiation.
- Invasive growth
- Formation of metastasis
-Sustained angiogenesis.

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Antineoplastics

4. -The abnormal behavior of cancer cells results from DNA alterations.
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Cancer Etiology
-The abnormal behavior of cancer cells results
from DNA alterations.
Malignant transformation results from a
combination of activation of oncogenes and
inactivation of tumor suppressor genes.
- These genetic alterations are caused by:
Chemical carcinogens (cigarette smoking).
Pathogens (hepatitis C virus, H. pylori).
Radiation (X-rays).
Hereditary factors.
Drugs (estrogen).

5. Pathophysiology of cancer
Chemicals, viruses, radiation,etc.
Inherited mutations
Acquired mutations
Altered gene expression
Proto-oncogenes to oncogenes.
(Uncontrolled cell proliferation and dedifferentiation)
Inactivation of tumor suppressor genes.
(Decrease apoptosis)
Development of primary tumor
Invasiveness
Angiogenesis
Metastasis

6. Malignant transformation occur in three major stages:
1- initiation: DNA damage
2- promotion : multiplication
3- progression : growth and invasion

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8. Tumor staging Antineoplastics
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Tumor staging
Most commonly applied staging system for solid tumors is TNM (tumor-nodes-metastasis) classification where a numerical value is assigned to each letter to indicate size or disease extent.
TNM system
T: refers to the size of the primary tumor (0-4)
e.g. T4 (large size tumor).
N: refers to the extent of lymph nodes involvement (0-4)
e.g. N0 (no lymph node disease).
Nx(Lymph nodes not assessed).
M: refers to the presence or absence of distant metastasis (0-1)
e.g. M1 (distant metastasis).
M0 ( No distant metastasis).
Mx (distant metastasis not assessed).
T2N1M0 (moderate size tumor with limited nodal disease and no distant metastases).

9. Cancer Grading:
Tumor grade is the description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope.
Gx: Grade cannot be assessed (undetermined grade)
G1: Well differentiated (low grade)
G2: Moderately differentiated (intermediate grade)
G3: Poorly differentiated.
G4: undifferentiated (high grade)

10. Cell Cycle Antineoplastics G1 = 40% S = 39% G2 = 19% M = 2%
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Cell Cycle
G1 = 40%
S = 39%
G2 = 19%
M = 2%
Checkpoints:
P27: G1-S
P53: G2-M
Growth Fraction = GF = Proliferating cells (S or M phase) /resting cells (G0).
Cell-cycle phase specific (phase specific) drugs
Cell-cycle phase non-specific (cycle specific) drugs

11. Treatment Modalities: 1.Surgery (solid tumors).
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Pharma-III Practical
Treatment Modalities:
1.Surgery (solid tumors).
2. Radiation (solid tumors).
3. Drug therapy:
-Disseminated cancers (leukemias, lymphomas & widespread metastases.
-Some localized tumors e.g. testicular carcinoma.
-Adjuvant to surgery & radiation.

12. - Cure e.g. Hodgkin̕ s disease - Prophylaxis of recurrence
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Goals of therapy:
- Cure e.g. Hodgkin̕ s disease
- Prophylaxis of recurrence
- Prolong survival
- Palliation of symptoms
Outcome of therapy depends on:
-General health of patient
-Responsiveness of cancer type (size, location, grade, etc.).
-Drug resistance.

13. Drug Selection Antineoplastics
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Drug Selection
Combination therapy is more effective than single drug therapy
- Maximal cell kill
- ↓ Injury to normal cells.
- Slow/prevent development of drug resistant
Criteria of drug selection for combination therapy
- Different MOAs (act at diff. cell-cycle stages)
- Different toxicities (↓overlapping toxicities)
- Each drug effective by itself

14. Cell-Cycle Drug Effects
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Cell-Cycle Drug Effects
Cell-cycle phase-specific drugs:
Must be present for an extended time → given by infusions or in frequent small doses.
G1-phase specific: Asparaginase (Enzyme).
S-phase specific: Methotrexate, Fluorouracil, Mercaptopurine (Antimetabolites).
G2-phase specific: Bleomycin (Antitumor antibiotic)
M-phase specific: Vinca alkaloids (Vincristine, Vinblastine) (Mitotic inhibitors).

15. 2. Cell-cycle phase non-specific drugs (cycle-specific):
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2. Cell-cycle phase non-specific drugs (cycle-specific):
Act during any phase including G0. More toxic to proliferating cells than G0 cells.
cyclophosphamide. Carmustine: Alkylating agents.
Cisplatin, Carboplatin: Platinium compds.
Doxorubicin: Antitumor antibiotics.

16. Toxicity to malignant tissues & normal tissues with↑ growth fraction
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Toxicity to malignant tissues & normal tissues with↑ growth fraction
(bone marrow – GIT epithelium – hair follicles – sperm-forming cells)
Myelosuppression “most common”
Neutropenia, Thrombocytopenia, Anemia.
GIT Toxicities
Nausea & Vomiting
GI mucosal irritation (stomatitis, diarrhea)
Dermatologic Disorders:
Alopecia, Extravasation, Photosensitivity.
Infertility
Tumor Lysis Syndrome (TLS):
Massive cell death & DNA degradation → hyperuricemia → renal injury

17. Unique toxicities Antineoplastics Cardiotoxicity: Doxorubicin
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Unique toxicities
Cardiotoxicity: Doxorubicin
B. Nephrotoxicity: Cisplatin & Methotrexate.
C. Pulmonary Toxicity: Bleomycin.
D. Hepatotoxicity: Asparaginase
E. Hemorrhagic cystitis: Cyclophosphamide → acrolein
F. Neurotoxicity: Vincristine, Cisplatin.

18. Rescue Drugs Antineoplastics
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Rescue Drugs
Combat chemotherapy-induced toxicity
Filgrastim: (granulocyte colony-stimulating factor)
↓ duration and depth of neutropenia after chemotherapy
Allopurinol: (↓xanthine oxidase)
Management of hyperuricemia
Glucocorticoids & others…
(dexamethasone + ondansetron - rantidine? - strong anti-emetic)
Glucocorticoids & Antihistaminics
↓ hypersensitivity

19. Rescue Drugs Antineoplastics
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Rescue Drugs
Mesna: treatment of acrolein induced hemorrhagic cystitis
Leucovorin or folinic acid :
reduces toxicity of methotrexate to normal cells.

20. ERA & PRA Estrogen Receptor Assay Antineoplastics
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ERA & PRA
Estrogen Receptor Assay
Progesterone Receptor Assay
Lab test done to find out if cancer cells have estrogen (progesterone) receptors
Cells with ERs need E to grow while cells with PRs need P to grow.
ER+  growth of cancer cells is E-dependant
ER¯  growth of cancer cells is E-independent

21. Tumor markers Antineoplastics
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Tumor markers
Tumor markers are substances found in blood, urine and tissues, produced by tumor cells or by other body cells in response to cancer or certain benign conditions.
An elevated level of a tumor marker can indicate cancer; however, there can also be other causes of the elevation.
Tumor marker levels are checked at the time of diagnosis; before, during, and after therapy; and then periodically to monitor for recurrence.

22. Tumor Marker Associated Tumor
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Tumor Marker
Associated Tumor
CEA
Carcinoembryonic Antigen
GIT, BREAST, LUNG CANCERS
CA-125
Cancer Antigen-125
OVARIAN CANCER
PSA
Prostate Specific Antigen
PROSTATE CANCER
β-HCG
Human Chorionic Gonadropin
TESTICULAR CANCER
AFP
Alpha-fetoprotein
LIVER CANCER Tg
Thyroglobulin
THYROID CANCER

23. Antineoplastics If a man has ↑ PSA level  Search for PC
Pharma-III Practical
If a man has ↑ PSA level
 Search for PC
If a person has ↑ β-HCG level
 Search for testicular cancer
If a person has ↑ AFP level
 Search for liver cancer

24.  No distant metastasis Nx means…  Lymph nodes not assessed
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M0 means…
 No distant metastasis
Nx means…
 Lymph nodes not assessed
Mx means….
 Distant metastasis not assessed