CHEMO Flashcards
An anticancer agent that acts on tumor stem cells when they are traversing the cell
cycle and when they are in the resting phase.
Cell cycle-nonspecific (CCNS) Drug
An anticancer agents that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G0 phase.
Cell cycle-specific (CCS) Drug
The proportion of cells in a tumor population that are actively dividing
Growth fraction
A drug that suppresses the formation of mature blood cells such as erythrocytes,
leukocytes, and platelets. This effect is also known as “bone marrow suppression.”
Myelosuppressant
A mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells.
Oncogene
Act with first-order kinetics. A given dose kills a constant proportion of a cell population rather than a constant number of cells.
Cytotoxic Drugs
Proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic
function.
Log-Kill Hypothesis
There is an inverse relationship between tumor cell number and curability.
Hematologic malignancies
Most do not grow in an exponential manner; rather, the growth fraction of the tumor decreases with time owing to blood supply limitations and other factors.
Solid tumors
The response to chemotherapy depends on where the tumor is in its growth curve.
Drug-sensitive solid tumors
Changes in drug sensitivity and increased synthesis of target enzyme, dihydrofolate reductase
Methotrexate
Increased activity of enzymes capable of inactivating anticancer drugs
Purine and pyrimidine antimetabolites
- Drug therapy as primary treatment
- Many hematologic cancers
- Advanced solid tumors for which no alternative treatment exists
- Curative in a small number of patients with advanced metastatic disease (eg. lymphoma, acute myelogenous leukemia, choriocarcinoma, and several childhood
cancers) - In many cases the goals of therapy are:
> Palliation of cancer symptoms
> Improved quality of life
> Increased time to tumor progression
Primary Induction Chemotherapy
- Use of chemotherapy in patients who present with localized cancer for which alternative local therapy, such as surgery, exist.
- Goal:
> To render the local therapy more effective
Neoadjuvant chemotherapy
- Used in the treatment of many solid tumors
- Chemotherapy serves as an important adjuvant to local treatment procedures such as surgery or radiation.
- Goals:
> To reduce the risk of local and systemic recurrence
> To improve disease-free and overall survival
Adjuvant Chemotherapy
Benefits of Combination Therapy
- Increases log-kill markedly
- Synergistic effects in some cases
- Often cytotoxic to a heterogeneous population of cancer cells
- May prevent development of resistant clones
- Dexrazoxane
- Inhibits free radical formation
- Affords protection against the cardiac toxicity of these agents
Anthracyclines (eg. doxorubicin)
- Leucoverin
- Form of tetrahydrofolate that is accumulated more readily by normal than by neoplastic cells.
- Results in rescue of the normal cells.
Methotrexate
- Mercaptoethanesulfonate (mesna)
- “Traps” acrolein released by cyclophosphamide
- Thus reduces incidence of hemorrhagic cystitis
Cyclophosphamide
- are CCNS drugs.
- Form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine.
- Leads to cross-linking of bases, abnormal base-pairing, and DNA strand breakage.
Alkylating Agents
- Hepatic cytochrome P450-mediated biotransformation is needed for antitumor
activity. - One of the breakdown products is acrolein.
- Expected adverse effect includes GI distress, myelosupression, and alopecia
Cyclophosphamide
Clinical Use of Cyclophosphamide
- leeukemia
- Non-Hodgkin’s Lymphoma
- Breast and Ovarian cancers
- Neuroblastoma
Cyclophosphamide Toxicity
- hemorrhagic cystitis from formation of acrolein
- cardiac dysfunction
- Pulmonary toxicity
- Syndrome of inappropriate antidiuretic hormone (ADH) secretion
- Spontaneously converts in the body to a reactive cytotoxic product
- Best known for use in: Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma
- common toxic effects includes GI distress, myelosupression, alopecia, and sterility
Mechlorethamine
- Used intravenously
- The drugs distribute to most tissues and are cleared in an unchanged form by the kidney
Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)
- commonly used for testicular carcinoma and cancers of the bladder, lung, and ovary
- used in advanced colon cancer
- Cisplatin & Carboplatin
- Oxaliplatin:
Cisplatin Toxicity
- GI distress
- Mild hematotoxicity
- Neurotoxic (peripheral neuritis and acoustic nerve damage)
- Nephrotoxic - may be reduced by use of mannitol with forced hydration
Carboplatin Toxicity
Oxaliplatin Toxicity
- Less nephrotoxic than cisplatin
- Less likely to cause tinnitus and hearing loss
- Greater myelosuppressant actions
- Dose-limiting neurotoxicity
- A reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA strand scission.
- Orally active
- Penetrates into most tissues, including the CSF
- Eliminated via hepatic metabolism
- Use. for Hodgkin’s Lymphoma, Non-Hodgkin’s Lymphoma, Brain tumors
Procarbazine
Procarbazine Toxicity
- Myelosuppressant
- GI irritation
- CNS dysfunction
- Peripheral neuropathy
- Skin reactions
- Inhibits many enzymes in including monoamine oxidase and and those involved in hepatic drug metabolism.
- Disulfiram-like reactions have occurred with ethanol
- Leuokemogenic
Sometimes used in chronic myelogenous leukemia
- Causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation
Busulfan
- Other alkylating drugs that is highly lipid-soluble and used in brain tumors
- Hodgkin’s Lymphoma. Causes alopecia, skin rash, GI distress, myelosuppression,
phototoxicity, and a flu-like syndrome
- Carmustine & Lomustine
- Dacarbazine
- Structurally similar to endogenous compounds
- Antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), or pyrimidines (fluorouracil, cytarabine, gemcitabine).
- CCS drugs acting primarily in the S phase of the cell cycle.
- Cytotoxic effects on neoplastic cells
- Immunosuppressant
Antimetabolites
- Inhibitor of dihydrofolate reductase
- This leads to decreased synthesis of thymidylate, purine nucleotides, and amino acids and thus interferes with nucleic acid and protein metabolism.
- The formation of polyglutamate derivatives of methotrexate appears to be important for cytotoxic actions.
- Decreased drug accumulation
- Changes in drug sensitivity or activity of dihydrofolate reductase
- Decreased formation of polyglutamates
Methotrexate
Clinical Use of Methotrexate:
- Effective in:
- Solid tumors
- other uses
Effective in:
- Choriocarcinoma
- Acute leukemias
- Non-Hodgkin’s and Primary
- CNS lymphomas
Solid tumors:
- breast cancer,
- head and neck cancer, and
- bladder cancer
Other uses:
- rheumatoid arthritis
- psoriasis &
- ectopic pregnancy
Methotrexate Toxicity
Common:
Leocovarin Rescue:
Long Term Use:
Common
- bone marrow suppression
- Toxic effects on the skin and GI mucosa (mucositis)
Leucovarin Rescue
- toxic effect of methotrexate on normal cells may be reduced by administration of folinic acid (leucovorin).
Long-Term Use
- Hepatotoxicity
- Pulmonary infiltrates and fibrosis
- Purine antimetabolites
- Activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic
nucleotides that inhibit several enzymes involved in purine metabolism. - Decreased activity of HGPRTase
- Increase production of alkaline phosphotases that inactivate the toxic nucleotides
- Low oral bioavailability because of first-pass metabolism by hepatic enzymes
Mercaptopurine (6-MP) and Thioguanin (6-TG)
Main Clinical Use of Mercaptopurine (6-MP) and Thioguanin (6-TG)
- Acute leukemias
- Chronic myelocytic leukemia
