3. Characteristics of Cancer Cells
• The problem:
– Cancer cells divide rapidly (cell cycle is
accelerated)
– They are “immortal”
– Cell-cell communication is altered
– uncontrolled proliferation
– invasiveness
– Ability to metastasise
6. • After completion of mitosis, the resulting
daughter cells have two options:
• (1) they can either enter G1 & repeat the cycle or
• (2) they can go into G0 and not participate in the cell
cycle.
• The ratio of proliferating cells to cells in G0, is called
the growth fraction.
• A tissue with a large percentage of proliferating cells
& few cells in G0 has a high growth fraction.
•
• Conversely, a tissue composed of mostly of cells in G0
has a low growth fraction.
7.
8. Chemotherapeutic Agents
• Cell Cycle Specific Drugs:
• Antimetabolites
• Bleomycin peptide antibiotics
• Vinca alkaloids
Effective for high
growth-fractionmalignancies, such
as hematologic
cancers.
• Cell Cycle non-Specific Drugs:
• Alkylating agents
• Antibiotics (Dactinomycin)
• Cisplatin
Effective for both
low-growth (solid
tumors) and high
growth fraction
malignancies
9. Log kill hypothesis
• According to the log-kill hypothesis, chemotherapeutic
agents kill a constant fraction of cells (first order
kinetics), rather than a specific number of cells, after
each dose
1. Solid cancer tumors - generally have a low growth
fraction thus respond poorly to chemotherapy & in most
cases need to be removed by surgery
2. Disseminated cancers- generally have a high growth
fraction & generally respond well to chemotherapy
12. Role of Chemotherapy in Cancer
Treatment
(1) Metastatic Cancer: Palliative or
Curative Chemotherapy
(2) Adjuvant Chemotherapy:
to eradicate or control micro-metastasis
(3) Neo-adjuvant Chemotherapy:
to make Surgery of RT possible
to alleviate surgical damage
to eradicate micro-metastasis
(4) Hematological Malignancies:
Primary Treatment
14. Chemotherapeutic Agents
1. Alkylating agents:
Cyclophosphamaide
Carboplatin
Cisplatin
Oxaliplatin
Dacarbazine
• Major interaction: Alkylation of DNA
• Binds to nucleophilic groups on various cell
constituents. Including DNA
• These drugs react with
carboxyl, sulfhydryl, amino, hydroxyl, and
phosphate groups of cellular constituents.
• Primary DNA alkylation site: N7 position of guanine
(other sites as well)
• Major Toxicity: bone marrow suppression
15. Chemotherapeutic Agents
2. Antimetabolites:
5-Fluoro Uracil
Gemcitabine
Cyterabine
Methotrexate
•Structurally related to normal compounds that exist
within the cell.
•Interfere with the availability of normal purine or
pyrimidine nucleotide precursors, either by inhibiting
their synthesis or by competing with them in DNA or
RNA synthesis.
•Their maximal cytotoxic effects are in S-phase and
therefore are cell-cycle specific.
16. Chemotherapeutic Agents
Vinca Alkaloids
Vincristine
Vinblastine
Vinorelbine
Taxanes
Paclitaxel
Docetaxel
3. Microtubule Inhibitors:
• These are plant-derived substances .
• Cause cytotoxicity by affecting the equilibrium
between the polymerized and depolymerized
forms of the microtubules.
• Vinca alkaloids inhibit microtubule
polymerization and increase microtubule
disassembly. The mitotic spindle apparatus is
disrupted, and segregation of chromosomes in
metaphase is arrested.
17. Chemotherapeutic Agents
4. Antineoplastic Antibiotics:
Bleomycin
Doxorubicin
Dactinomycin
Daunorubicin
• Interacts with DNA, leading to disruption of
DNA function.
• Also Inhibit topoisomerases (I and II) and
produce free radicals.
• Cell-cycle nonspecific.
• Eg: Actinomycin D binds with double-stranded
DNA and blocks the action of RNA
polymerase, which prevents DNA transcription.
18. Chemotherapeutic Agents
5. Hormonal Agents:
Prednisone
Tamoxifen
Estrogens
Flutamide
Nilutamide
Bicalutamide
• Commonly involves the use of glucocorticoids.
•
Direct antitumor effects are related to their
lympholytic properties;.
• Glucocorticoids can inhibit mitosis, RNA
synthesis, and protein synthesis in sensitive
lymphocytes.
•
Considered cell-cycle nonspecific .
• Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
glucocorticoids.
19. Chemotherapeutic Agents
6. Monoclonal Antibodies:
Rituximab
Trastuzumab
Cetuximab
Bevacizumab
• Antibodies that are made in the lab rather than by
a person's own immune system.
• Directed at specific targets and often have fewer
adverse effects.
• Designed to recognise and find specific
abnormal proteins on cancer cells.
• Each monoclonal antibody recognizes one
particular protein.
20. Chemotherapeutic Agents
• Three types of monoclonal A-bodies:
Rituximab
Trastuzumab
Cetuximab
Bevacizumab
1. Trigger the immune system to attack and kill cancer
cells. E.g. Rituximab (Mabthera)
2. Stop cancer cells from taking up proteins
E.g. Trastuzumab (Herceptin).
3. Carry cancer drugs or radiation to directly to cancer
cells These are called conjugated MABs.
E.g. Ibritumomab (Zevalin)
27. Interactions with METHOTREXATE
• Aspirin, Cotrimoxazole, Penicillin, Nsaids
(Indomethacin, Ketoprofen);
Inhibition Of Tubular Secretion Of Methotrexate
:
Prolonged Excretion Of Methotrexate And
Enhanced Toxicity.
28. Interactions with 6-MERCAPTOPURINE
• 6-mercaptopurine (6-MP) or azathioprine with
ALLOPURINOL.
• 6-MP (or azathioprine) toxicity
(thrombocytopenia, granulocytopenia) is
enhanced and may be fatal.
• The dose of 6-MP or azathioprine should be
decreased to one-third to one-fourth the
normal amount when allopurinol is used
concurrently
29. Interactions with PHENYTOIN
• The initial decrease in phenytoin
concentration shortly after receiving various
chemotherapeutic agents and dose increase
leads to phenytoin toxicity.
• Phenytoin should have blood concentrations
measured 24-72 hours after receiving
chemotherapy and adjust the dose
accordingly.
30.
31. ADR of Antineoplastic Drugs in Humans
Tissue
Undesirable Effects
Bone marrow
Leukopenia and resulting infections
Immunosuppression
Thrombocytopenia
Anemia
GI tract
Oral or intestinal ulceration
Diarrhea
Hair follicles
Alopecia
Gonads
Menstrual irregularities, including premature
menarche; impaired spermatogenesis
Wounds
Impaired healing
Fetus
Teratogenesis (especially during first trimester)
33. Prevention or Management of Drug
Induced toxicities
• The toxicities of some anticancer drugs
can be well anticipated and hence be
prevented by giving proper medications
E.g.
• mesna is given to prevent hemorrhagic
cystitis by cyclophosphamide
• Dexrazoxane, is used to reduce the risk of
anthracycline-induced cardiomyopathy