Principles of Chemotherapy Flashcards
Primary Chemotherapy
Chemotherapy indicated when neoplasms are disseminated and not amenable to surgery
Adjuvant Chemotherapy
Chemotherapy used to attack micro metastases following surgery and radiation
Neoadjuvant Chemotherapy
Chemotherapy given before surgery to shrink the cancer
Log Kill Phenomenon
Destruction of cancer cells by drugs follows 1st order kinetics: a given dose of drug destroys a constant fraction of cells
Eg: Diagnosis of leukaemia made when there are 10^9 leukaemia cells. If treatment leads to 99.999% kill (a 5-log kill), there would still be 10^4 tutor cells remaining in the body
Combination Chemotherapy
Treatment with agents of differing toxicities and mechanisms of action is the standard approach for treatment of many tumor types
Advantages of Combination Chemotherapy
- Several combination of drugs produce true synergism
- Drug combinations provide maximal cell kill within range of tolerated toxicity
- Drug combinations are effective against a broad range of cell lines
- Drug combinations may slow or prevent the development of resistance cell lines
- Therapy is scheduled intermittently to allow recovery of normal tissue, such as patient’s immune system, that has been affected by the drugs, thereby reducing the risk of serious infection.
Growth fraction and susceptibility to anticancer drugs
Rapidly dividing cells = large growth fraction = more sensitive to anticancer drugs
Slow-growing tumors = small growth fraction = often unresponsive to cytotoxic drugs
Cell-cycle specific drugs
Exert their action on cell transversing the cell cycle.
Most effective in hematologic malignancies and the rumours in which large proportion of cells are in the growth fraction
Antimetabolites - S-phase Bleomycin: G2-M phase Microtubule Inhibitors: M phase Epipodophyllotoxins: G1-S phase Camptothecins: G2-M phase
Cell-cycle nonspecific drugs
Can kill tutor cells whether they are cycling or resting in the G0 compartment (but cycling cells are more sensitive)
Are useful in low growth fraction solid tumors as well as in high growth fraction tumors
Primary Resistance
No response to the drug on the first exposure
Acquired Resistance
Single drug resistance: Due to increased expression of one or more genes by the tumor cell. Specific to a single drug.
Multi-drug resistance (MDR): Resistance emergences to several different drugs after exposure to a single agent
MOA of Multidrug Resistance
Mainly due to over expression of membrane efflux pumps that pump anticancer drugs out of the cell
P-glycoprotein is the most important –> ATP-dependent efflux pump for xenobiotic compounds.
- Does not transport alkylating agents, antimetabolites or cisplatin
- Can confer MDR to: Dozorubicin, daunorubicin, vincristine, vinblastine, etoposide, tenoposide
Why do anticancer drugs cause toxicity?
Chemotherapeutic agents have a narrow therapeutic window - dose of drug needed to achieve adequate tutor cell kill often causes toxicity to normal tissues
Therapy aimed at killing rapidly proliferating cells affects normal cells undergoing rapid proliferation. Ex: buccal mucosa, bone marrow, GI mucosa and hair cells
Common adverse effects
Sever vomiting
Stomatitis
Bone marrow suppression
Alopecia
Dugs that cause high myelosuppression
Cytrabine Alkylating agents Doxorubicin Daunorubicin Vinblastine
Drugs that cause medium myelosupperession
Carboplatin
Methotrexate
5-FU
Drugs that cause low myelosuppression
Bleomycin
Vincristine
Asparaginase
Doxorubicin - main toxicity
Cardiotoxicity
Cyclophosphamide - main toxicity
Hemorrhagic cystitis
Bleomycin - main toxicity
Pulmonary fibrosis
Vincristine - main toxicity
Peripheral neuropathy
Paclitaxel - main toxicity
Peripheral neuropathy
5HT3 receptor blockers
Used to manage chemotherapy induced emesis (nausea and vomiting)
NK-1 inhibitors
Used to manage chemotherapy induced emesis (nausea and vomiting)
Filgrastim
Prevention and treatment of chemotherapy induced neutropenia
Sargramostim
Prevention and treatment of chemotherapy induced neutropenia
Leucovorin
Rescues bone marrow from methotrexate
Mesna
Reduces hemorrhagic cystitis caused by cyclophosphamide
Dexrazoxane
Reduces anthracycline-induced cardiotoxicity
Amifostine
Reduces renal toxicity caused by cisplatin
Treatment induced tumors
Most anticancer drugs are mutagens
Neoplasms may arise 10 or more years after the original cancer was cured
Especially a problem after therapy with alkylating agents –> induce DNA damage which can lead to new mutations
