Transcript File

Pharmacology – IV
PHL-425
Chapter 2:
CANCER CHEMOTHERAPY:
The basic Concepts
By:
Dr. Abdulaziz Bin Saeedan
Ph.D.
Department of Pharmacology
E mail: [email protected]
Pathogenesis of Neoplasia
 DNA is altered via mutagens including chemical carcinogens,
viruses, and radiation. This mutations is inherted by at least
one cell division (initiation).
 This mutation mainly lead to activation of proto-oncogene
into oncogenes (leading to uncontrolled cell proliferation)
and/or inactivation of tumor suppressor genes (leading to
resistance to apoptosis.)
 Once the cell reproduction process is altered, other factors
(epigenetic factors ) indirectly allow and promote these cells
to proliferate unchecked (promotion)
 These promoters can be (hormones, co- carcinogens,
immunosuppressant…which themselves are non
carcinogenic).
• Initiation - point at which an irreversible alteration, usually
genetic, is introduced into a target cell.
Initiation:
(1) is essentially irreversible
(2) caused only by carcinogenic compounds
(3) occurs rapidly after carcinogen exposure
(4) alone does not result in tumor formation
• Promotion is the process whereby an initiated tissue or
organ develop focal proliferations and it requires the
presence of continuous stimulation.
Promotion:
(1) reversible
(2) acts only after exposure to an initiating agent
(3) requires repeated administration of a promoter
(4) is not carcinogenic in itself
Etiolopathology
50.2 Rang
Apoptosis
 Programmed cell death
 Cascade of proteases
initiate process
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
The Goal of Cancer Treatments
 Curative
 Total irradication of cancer cells
 Curable cancers include testicular tumors
 Palliative
 Alleviation of symptoms
 Avoidance of life-threatening toxicity
 Increased survival and improved quality of life
 Adjuvant therapy
 Attempt to eradicate microscopic cancer after surgery
 e.g. breast cancer & colorectal cancer
Rx Modalities (Cancer Treatments)
1.
2.
3.
4.
5.
6.
Surgery
Radiotherapy
Chemotherapy
Endocrine therapy (hormonal therapy)
Immunotherapy
Targeted therapy or molecularly targeted
therapy: blocks the growth of cancer cells by interfering with
specific targeted molecules needed for carcinogenesis and tumor
growth, rather than interfering with all rapidly dividing cells
- Small molecule inhibitors: Tyrosine kinase inhibitors
(e.g imatinib)
- Genetic material (RNA or DNA)
Major approaches to therapy of
cancers
Cell Cycle =
Growth, Division
18_01_cell_cycle.jpg
Cancer Chemotherapy
 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.
 Growth fraction - at any particular time some cells are going
through the cell cycle whereas other cells are resting.
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.
Cell Cycle Specific (CCS) & Cell Cycle NonSpecific Agents (CCNS)
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.
In other words, at a given dose, in a given tumor the
drug will kill a constant % of cells, regardless the
tumor size
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
Log kill hypothesis:
LOG kill hypothesis
 The example shows the




effects of tumor burden,
scheduling, initiation/duration
of treatment on patient
survival.
The tumor burden in an
untreated patient would
progress along the path
described by the RED LINE
–
The tumor is detected (using
conventional techniques)
when the tumor burden
reaches 109 cells
The patient is symptomatic
at 1010-1011 cells
Dies at 1012 cells.
Cancer Chemotherapy
 Combinations of agents with differing toxicities &
mechanisms of action are often employed to
overcome the limited cell kill of individual anti cancer
agents. Each drug selected should be effective alone
3 advantages of combination therapy:
 1. Suppression of drug resistance - less chance of a cell
developing resistance to 2 drugs than to 1 drug.
 2. Increased cancer cell kill - administration of drugs with
different mechanisms of action.
 3. Reduced injury to normal cells - by using a combination of
drugs that do not have overlapping toxicities, we can achieve
a greater anticancer effect than we could by using any one
agent alone.
Resistance to Cytotoxic Drugs

Increased expression of
MDR-1 gene for a cell
surface P-glycoprotein

MDR-1 gene is involved
with drug efflux

Drugs that reverse MDR :
verapamil, quinidine,
cyclosporine

MDR increases resistance
to natural drug products including the anthracyclines, vinca
alkaloids, and epipodophyllotoxins
Modes of Resistance to Anticancer
Drugs
Mechanism
Drugs or Drug Groups
Change in sensitivity or ↓ binding Etoposide, methotrexate, vinca
affinity of target enzymes or
alkaloids, estrogen & androgen
receptors
receptors
Decreased drug accumulation via
↑ expression of glycoprotein
transporters, or ↓ permeability
Methotrexate, alkylating agents,
dactinomycin
Formation of drug-inactivating
enzymes
Purine & pyrimidine antimetabolites
Production of reactive chemicals
that “trap” the anticancer drug
Alkylators, bleomycin, cisplatin.
doxorubicin
Increased nucleic acid repair
mechanisms
Alkylating agents, cisplatin
Reduced activation of pro-drugs
Purine & pyrimidine antimetabolites
General problems with anticancer
drugs
 Most of them are antiproliferative, i.e. they
damage DNA and so initiate apoptosis.
 They also affect rapidly dividing normal cells.
 This leads to toxicity which are usually severe.
 To greater or lesser extent the following
toxicities are exhibits by all anticancer drugs.
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)
Distinctive Toxicities of Some Anticancer Drugs
Toxicity
Drug(s)
Renal
Cisplatin,* methotrexate
Hepatic
6-MP, busulfan, cyclophosphamide
Pulmonary
Bleomycin,* busulfan, procarbazine
Cardiac
Doxorubicin, daunorubicin
Neurologic
Vincristine,* cisplatin, paclitaxel
Immunosuppressive
Cyclophosphamide, cytarabine,
dactinomycin, methotrexate
Other
Cyclophosphamide (hemorrhagic cystitis);
procarbazine (leukemia); asparaginase*
(pancreatitis)
Chemotherapeutic agents are much more toxic to tissues that
have a high growth fraction than to tissues that have a low growth
fraction.
 Proliferating cells are
especially sensitive to
chemotherapy because
cytotoxic drugs usually
act by disrupting DNA
synthesis or mitosis,
cellular activities that only
proliferating cells carry
out.
 Unfortunately, toxicity to
the anticancer agents is
to any rapidly dividing
cells. (e.g. bone marrow,
hair follicles, sperm
forming cells).
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 (How? it reacts
with the drug metabolite)
 Dexrazoxane, is used to reduce the risk of
anthracycline-induced cardiomyopathy
Anti-cancer drugs
Classification
Cell Cycle–Specific (CCS) Agents
Cell Cycle–Nonspecific (CCNS)
Agents
Antimetabolites (S phase)
Alkylating agents
Capecitabine
Altretamine
Cladribine
Bendamustine
Clofarabine
Busulfan
Cytarabine (ara-C)
Carmustine
Fludarabine
Chlorambucil
5-Fluorouracil (5-FU)
Cyclophosphamide
Gemcitabine
Dacarbazine
6-Mercaptopurine (6-MP)
Lomustine
Methotrexate (MTX)
Mechlorethamine
6-Thioguanine (6-TG)
Melphalan
Epipodophyllotoxin (topoisomerase II
inhibitor) (G1–S phase)
Etoposide
Taxanes (M phase)
Temozolomide
Thiotepa
Anthracyclines
Daunorubicin
Albumin-bound paclitaxel
Doxorubicin
Docetaxel
Epirubicin
Paclitaxel
Idarubicin
Vinca alkaloids (M phase)
Vinblastine
Mitoxantrone
Antitumor antibiotics
Vincristine
Dactinomycin
Vinorelbine
Mitomycin
Antimicrotubule inhibitor (M phase)
Ixabepilone
Antitumor antibiotics (G2–M phase)
Camptothecins (topoisomerase I
inhibitors)
Irinotecan
Topotecan
Platinum analogs
Bleomycin
Carboplatin
Cisplatin
Targeted agents
Monoclonal antibodies
bevacizumab humanized monoclonal antibody with a circulatory system target
(VEGF-A)
cetuximab
monoclonal antibody with a tumor target (EGFR)
ipilimumab
fully human antibody with an immune system target (CTLA-4)
Small molecules
bortezomib small molecule proteasome inhibitor
imatinib
small molecule tyrosine kinase inhibitor
seliciclib
small molecule cyclin-dependent kinase inhibitor
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