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Features of cancer cells different from most normal cells (5)
- •Constant DNA synthesis (Alkylating agents, anti-tumor antibiotics)
- •High metabolic rate (Antimetabolites)
- •Continuous cell division –mitosis (Microtubule-targeting agents)
- •Fast growth – need new blood supply (Anti-angiogenic drugs)
- •Some tumors depend on hormones
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Cell cycle specific chemotherapeutic agents that are S phase specific
- Attack cell during DNA synthesis
- E.g., antimetabolites (purines, pyrimidines)
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Cell cycle specific chemotherapeutic agents that are M phase specific
- Attack cell at mitosis
- E.g., taxol, vincas
- (MTV)
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Use Body Surface Area (BSA) (sq root((weight * height)/3600)) due to?
- Better correlation between THERAPEUTIC and TOXIC doses between patients and between species
- Correlates well with cardiac output (Important with cardiotoxic drugs like the anthracyclines)
- Affects HEPATIC AND RENAL ELIMINATION of drugs
-
Chemotherapeutic agents are Typically cycled every month, why?
Due to side-effects of drugs
-
Criteria for combination chemotherapy:
- Should be active alone against the tumor of interest
- Should act by different mechanisms of action
- Should have different dose-limiting toxicities (DLTs)
- Should have different mechanisms of resistance
- Should include cell cycle specific and non-specific agents
-
added to methotrexate treatment to rescue normal cells; agents having different toxicities
leucovorin
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Classification of Chemotherapeutic Agents:ALKYLATING AGENTS these work by what method?
- Mechanism: Bind covalently to the DNA molecule
- Attack ANY dividing cell
-
ALKYLATING AGENTS stop cell growth by Inhibit DNA synthesis (S phase)
Physically prevent DNA synthesis enzymes (polymerase) from passing adduct
-
alkylating agents that Can be removed by the cell DNA repair enzymes
Monoadducts: easier to fix than crosslinks
-
Classification of drugs that work by;
Mechanism: most act by ALKYLATION or INTERCALATION
BOTH mechanisms → inhibition of DNA synthesis
ANTITUMOR ANTIBIOTICS
-
ANTITUMOR ANTIBIOTICS
CLASSES:
ANTHRACYCLINES: intercalators (2 of them)
- epirubicin
- Doxorubicin
- bleomycin
-
Bleomycin
- Generates reactive oxygen species (Superoxide (O2-•) and hydroxy radical (OH•))
- Results in DNA strand breaks (Similar to radiation, RANDOM breaks)
-
Antimetabolites (
- Block the biosynthesis or use of normal cellular metabolites (“materials for building DNA”)
- Decrease DNA synthesis
- MOA of inhibiting DNA synthesis:
- ØRemove critical proteins in DNA replication
- ØBeing “false substrates” for DNA synthetic enzymes
-
class of antimetabolites that is a FOLIC ACID analogue
methotrexate (also used to block immune cells for arthritis)
-
class of antimetabolites that is a PYRIMIDINE analogues (3)
- fluorouracil (5-FU) (false substrates)
- gemcitabine
- capecitabine
-
class of antimetabolites that is a PURINE analogues
6-mercaptopurine
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class of antimetabolites that are PLANT ALKALOIDS; VINCAS
- vincristine
- vinblastine
- (Isolated from the periwinkle bush
- Mechanism: arrest cell division by preventing the formation of the mitotic spindle)
- cause diarhea
- Block M phase
-
class of antimetabolites that are PLANT ALKALOIDS; CAMPTOTHECINS
and method of action
- MOA: inhibit topoisomerase I - an enzyme responsible for unwinding DNA during synthesis Inhibition of topo I causes DNA strand breaks
- Block M phase
-
class of antimetabolites that are PLANT ALKALOIDS; EPIPODOPHYLLOTOXINS
and method of action
- MOA: inhibit topoisomerase II → DNA strand breaks
- enzyme responsible for unwinding DNA during synthesis
-
class of antimetabolites that are PLANT ALKALOIDS; TAXENES
and method of action
MOA: stabilize microtubules → block cell division
-
Enzyme that removes a vital amino acid (asparagine) critical to the growth of some tumor cells
- ASPARAGINASE
- PEGASPARAGINASE
-
Antihelmitic drug that non-specifically stimulates immune system
Used as adjunct agent in colon cancer
Levamisole
-
biological response modifier
PCOL: vaccine against bovine bacteria that non-specifically enhances the immune system to remove tumor cells
Treats bladder cancer
Bacillus Calmette-Guerin (BCG):
-
MOST COMMON DOSE-LIMITING TOXICITY
DOSE and AGENT related
causes neutropenia
MYELOSUPPRESSION (bone marrow suppression):
-
decreased neutrophils
Measured by the absolute neutrophil count (ANC)
↑ infection incidence
TREATMENT: Growth factors (immunotherapy lecture)
neutropenia
-
Most common types of myelosuppression
- ERYTHROPENIA (↓ RBCs)
- THROMBOCYTOPENIA (↓ platelets)
- TREATMENT:
- Epoetin-α (immunotherapy lecture)
- Blood tranfusions
- ANEMIA
-
↓Hb secondary to RBC loss
ANEMIA
-
Time course of Myelosuppresion (why chemo is cycled)
Many agents: onset of suppression at 7 days, nadir at 10-14 days , back to normal by 28 days
-
Localized tissue damage if drug is administered outside a vein
EXTRAVASATION NECROSIS
-
TREATMENTS for extravasation necrosis for VINCAS and OTHER AGENTS
- VINCAS: heat and hyaluronidase
- OTHER AGENTS: neutralizing solution - sodium thiosulfate for mechlorethamine
-
GI TOXICITIES of chemo
- NAUSEA AND VOMITING (Probably the most UPSETTING to a patient)
- COMMON WITH: cisplatin
-
Treatment of GI TOXICITIES of chemo
- 5HT3 antagonists (ondansetron, granisetron, etc.) - work in CNS to decrease emetogenic potential of agents - very effective
- 5HT3 = Serotonin in CNS
-
irritation of mucus membranes
5-FU and methotrexate are most common
Can lead to cachexia and infection
STOMATITIS
-
common with topotecan and irinotecan
DIARRHEA
-
Bleomycin - drug is inactivated by an enzyme (bleomycin hydrolase) - absent in lungs causes what toxicity
Mitomycin and nitrogen mustards also cause this also
pulmonary toxicity
-
Platinum analogues, cisplatin - direct renal cell death
Amifostine: sulfhydryl containing drug that detoxifies free radicals that can lead to renal cell death
RENAL TOXICITY
-
Type of toxicity causing Numbness, trouble walking, loss of reflexes
Common with vincristine
Neurotoxicity
-
Type of Toxicity that is Common with the ANTHRACYCLINES
Damage extent proportional to total cumulative dose
MOA: ↑↑reactive oxygen species in the myocardium
Requires Iron
Dexrazoxane: Chelates iron - ↓↓↓ ROS decreasing this toxicity
CARDIOVASCULAR TOXICITY
-
Bladder toxicity associated with cyclophosphamide and ifosfamide
Due to a breakdown product of the drug, acrolein
MESNA: drug that binds to acrolein and inactivates it
HEMORRHAGIC CYSTITIS
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