anti cancer Flashcards
what is cancer
Cancer cells use the same nutrients and metabolic
process as normal host cells.
- Cancer cells are altered host cells:
shorter cell cycle (accelerated)
excessive proliferation
higher activity of nucleic acid and protein synthesis
altered cell-cell communication
invasive (disrupt normal healthy tissues)
migration to distant sites - metastasis
how do we treat cancer
• Surgery
• Radiation – usually followed up with
• Chemotherapy – then this
• Biological – newer Ab therapies
what are the principles of cancer chemo
• Causes a lethal cytotoxic event or apoptosis in the
cancer that can arrest the progression of tumor
growth.
• Generally directed toward DNA or against metabolic
sites essential to cell replication (e.g. the availability
purines and pyrimidines required for synthesis of DNA
and RNA).
• Ideally, these anticancer drugs should interfere only
with cellular processes that are unique to malignant
cells.
• Unfortunately, most anticancer drugs do not
specifically recognize neoplastic cells but, rather, affect
both normal and abnormal cells.
• Most all these drugs will have a steep-dose curve for
both therapeutic and toxic effect
what are the goals of chemo
– The ultimate goal of chemotherapy is a cure (long-term,
disease-free survival). This requires the eradication of every
neoplastic cell.
– If a cure is not attainable, then the goal becomes control of the
disease (stop the cancer from enlarging and spreading) to
extend survival and maintain the best quality of life.
– Treating cancer as a chronic disease
– In either case the neoplastic cell burden is reduced by surgery
and/or radiation followed by chemotherapy, immunotherapy,
using biological modifiers or using a combination of these
modalities. Figure 37.3
– In advanced stages of cancer, the likelihood of controlling the
cancer is difficult and the goal is palliation (alleviation of
symptoms and avoidance of life-threatening toxicity).
when do we start chemo
– Neoplasms are disseminated and are not amenable to surgery.
– Also used as a supplemental treatment to attack micrometastases
following surgery and radiation treatment, (adjuvant
chemotherapy).
– Prior to the surgical procedure in an attempt to shrink the cancer
(neoadjuvant chemotherapy)
– Also given in low doses to assist in prolonging a remission
(maintenance chemotherapy).
what are the chemo regimens
• Drug combination is more successful than single drug treatment
in most cancers.
• Cytotoxic agents with different toxicities, and with different
molecular sites and mechanisms of action, are usually combined
at full doses
• This results in higher response rate and/or potentiated cytotoxic
effects and nonoverlapping host toxicities.
• The advantages of combinations:
– Provide maximal cell killing within the range of tolerated
toxicity
– Effective against a broader range of cell lines in the
heterogeneous tumor population
– May delay or prevent the development of resistant cell lines
• Many cancer treatment protocols have been developed and
applicable to a specific neoplastic state.
• e.g. POMP is used for the treatment of acute lymphocytic
leukemia—
• consists of prednisone, oncovin(vincristine), methotrexate, and
purinethol (mercaptopurine).
• Therapy is scheduled approximately 21 days apart to allow
recovery of the patient’s immune system.
• Drugs are usually administered based on body surface area to
tailor the dosage to each patient
when is the tumor most susceptible against chemo
The fraction of tumor cells that are in the replicative cycle (“growth fraction”)
influences their susceptibility to anticancer agents.
– Rapidly dividing cells are generally more sensitive to anticancer drugs,
whereas slowly proliferating cells are less sensitive to chemotherapy.
– In general, nonproliferating cells (those in the G0 phase) usually survive
the toxic effects of many of these agents.
A- Cell cycle specificity of drugs:
- Normal and tumor cells go through growth cycle( fig.37.5) but differ in
the number of cells in various stages in the cycle
a. Cell-cycle specific drugs:
- are effective only against replicating cells (that is, those cells that are cycling).
b. Cell-cycle non-specific drugs:
- used for replicating and non-replicating cells but with greater toxicity in
cycling cells
what is the log kill phenomenon
• Destruction of cancer cells follows first-order kinetics (a given dose of drug for a
defined time period destroys a constant fraction of cells regardless the absolute
number of cells, this is called LOG KILL or fraction kill).
• For example: A diagnosis of leukemia is generally made when there are about
109
leukemic cells.
• Consequently, if treatment leads to a 99.999% kill, then 0.001% of 109 cells (or
104 cells) would remain. This is defined as a five-log kill (reduction of 105 cells or
100,000-fold reduction). At this point, the patient will become asymptomatic; that
is, the patient is in remission.
what are the pharmacological sanctuaries of chemo
Some tumors find sanctuary in tissues such as CNS, where transport constraints
prevent certain anti-cancers from entering.
• Therefore, a patient may require irradiation or intrathecal administration of drugs
to eliminate the tumor at that site.
how does resistance happen against chemo
Resistance to chemotherapy:
– Inherited resistance (for example, melanoma is resistant
to most anticancer drugs)
– Acquired resistance by mutation, particularly after
prolonged administration of suboptimal drug doses.
– Minimized by short-term, intensive, intermittent therapy
with combinations of drugs is advised to be taken.
Multidrug resistance:
• Transmembrane P-glycoprotein is
responsible for this ( ATP-dependent
pump of drugs out of the cell
• Cross-resistance following use of
structurally unrelated agents also
occurs
• Note: P-glycoprotein is normally
expressed at low levels in most
tissues , higher levels in kidney, liver
GIT
what are the side effects of chemo
• Therapy affects normal cells undergoing rapid proliferation (buccal mucosa, bone
marrow, GI mucosa, and hair).
• a. Common adverse effects:
• Most of chemotherapeutic drugs have a narrow TI
• Severe vomiting (use antiemetic), stomatitis, bone marrow suppression, and alopecia.
• The duration of side effects varies widely (e.g. alopecia is transient, but the cardiac,
pulmonary, and bladder toxicities are irreversible.
give examples on anti metabolites?
methotrexate (folate)
5-fluroracil(pyrimidine)
6-mercaptopurine (purine)
give examples in antibiotics used in chemo
dactinomycin
daunorubicin
bleomycin
mitomycin C
give examples on alkylating agents
mechlorethamine
cyclophosphamide
give examples on microtubular inhibitors
1) Vincristine
vinblastine
2) Paclitaxel
give examples on monoclonal antibodies
1) Trastuzumab
2) Rituximab
give examples on steroids and their antagonists
1) Prednisone
2) Tamoxifen
3) Raloxifene
4)flutamide
what are anti metabolites
• Structurally related to normal compounds that
exist within the cell.
• They generally 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.
• Maximal cytotoxic effects are in S-phase, DNA
replication (cell-cycle specific).
what is the MOA for methotrexate
MOA: Structurally related to folic acid and acts as an inhibitor of dihydrofolate
reductase (DHFR)—the enzyme that converts DHF to its active form, tetrahydrofolic acid
(THF). MTX is specific for the S phase of the cell cycle.
• MTX enters the cell by active transport processes that normally mediate the entry of
folate. Figure 37.9
• The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural
substrate, dihydrofolate (DHF) or by administration of leucovorin( folinic acid), which
bypasses the blocked enzyme and replenishes the folate pool.
how is resistance against methotrexate is formed
• Non proliferating cells are resistant to MTX
• Amplification (production of additional copies) of the gene that codes for DHFR,
resulting in increased levels of this enzyme.
• The enzyme affinity for MTX is diminished.
• Reduced influx of MTX.