Cancer Chemotherapy #1 - Chapter 54

An anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in the resting phase

An anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G-0 or resting phase

The proportion of cells in a tumor population that are actively dividing

• A concept used in cancer chemotherapy to
• mean that anticancer drugs kill a fixed proportion of a tumor cell population, not a fixed number of tumor cells.

• For example, a 1-log-kill will decrease a tumor cell population by one order of
• magnitude

•i.e. 90% of the cells will be eradicated

• A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.
• Myelosuppression is a side effect of some cancer treatments. When myelosuppression is severe, it is called myeloablation.

Oncogenes are genes that are responsible for the conversion of normal cells into cancer cells.

The administration of endogenous metabolites to counteract the effects of anti-cancer drugs on normal cells.  A strategy for ameliorating the toxic effects of anticancer drugs. 

• For example, high doses of methotrexate are given for 36-48 hours,
• –Leucovorin (tetrahydrofolate) which is accumulated preferentially by normal cells is then administered,
• –This results in the rescue of normal cells since leucovorin bypasses the dihydrofolate reductase step of folate synthesis.

A blister agent, or vesicant, is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severe chemical burns, resulting in painful water blisters on the bodies of those affected

Vesicants cause blistering and other tissue injury that may be severe and can lead to tissue necrosis (tissue death).

New growth

Tumor

Malignant tumors

• Cells that have undergone malignant
• transformation express signs of immaturity such as the expression of fetal antigens.

They may show chromosomal abnormalities

They may have altered metabolic pathways

• 1   one or more mutations in its DNA which can be inherited or acquired
• 2  Activation of proto-oncogenes to oncogenes
• 3  Inactivation of tumor suppressor genes

• The multiplication of normal cells involves division of the stem cells in a particular tissue to give rise to daughter cells. 
• These daughter cells differentiate to become mature cells.
• Cancer cells show a reverse process

•  Dedifferentiation

•  Uncontrolled proliferation

•  Invasiveness

•  The ability to metastasize

•  Cancer cells and normal cells are so similar in many respects that it is difficult to find areas of selective toxicity

Metastases are secondary tumors that are released from the primary tumor

METASTASIS

carcinogen

• Chemicals,
• radiation,
• viruses

Tumor suppressor

p53 tumor suppressor

selective toxicity

CCNS

They form reactive molecular species that alkylate nucleophillic groups on DNA bases, particularly the N-7 position of guanine.

–This  leads to cross-linking of bases, abnormal base pairing, and strand breakage. 

•Cyclophosphamide

•Mechlorethamine

•Mephalan

•Chlorambucil

•Thiotepa

•Busulfan

Tumor resistance to these drugs occurs through:

•  - increased DNA repair,
•  - decreased drug permeability,
•  - or the production of trapping agents such as thiols.

sulfur-hydrogen bond

• Non-Hodgkin’s lymphoma,
• breast and ovarian cancer,
• and neuroblastoma

Hepatic transformation is needed for antitumor activity.

• GI distress,
• myelosuppression,
• alopecia,
• hemorrhagic cystitis,
• cardiac dysfunction,
• lung toxicity,
• and SIADH

Syndrome of Inappropriate Antidiuretic Hormone secretion is characterized by excessive release of antidiuretic hormone from the posterior pituitary gland or another source.

hyponatremia as a result of an excess of water rather than a deficiency of sodium.

• High lipophilicity that facilitates CNS entry,
• used intravenously

• Hodgkin’s disease,
• melanoma,
• multiple myeloma,
• brain cancer,
• mycosis fungoides

• GI distress,
• myelosuppression,
• CNS dysfunction

• Procarbazine,
• Dacarbazine,
• Bendamustine

• Hodgkin’s and non-Hodgkin’slymphoma,
• brain tumors

Forms a metabolic that is an MAO inhibitor

Higher risk of secondary cancer (acute leukemia) than with other alkylating agents.

• malignant melanoma,
• Hodgkin’s lymphoma,
• sarcomas,
• and neuroblastoma

myelosuppression

It is a potent vesicant

• CLL,
• Hodgkin’s and non-Hodgkin’s lymphoma,
• multiple myeloma,
• and breast cancer

Has only partial cross resistance with other alkylating agents.

• Cisplatin (Platinol),
• Carboplatin,
• Oxaliplatin

Platinol

• Testicular,
• bladder,
• ovary,
• uterine,
• head and neck cancers

• GI distress,
• myelosuppression,
• neurotoxicity,
• (peripheral neuropathy and acoustic nerve),
• renal damage

• Used intravenously,
• widely distributed and cleared,
• unchanged by the kidneys

•Second generation platinum analog

•Less renal and GI toxicity than Cisplatin

• •Does not require pretreatment hydration
• and is therefore less cumbersome to administer

•Third generation platinum analog

•No cross resistance with Cisplatin and Carboplatin

•Useful for colorectal cancer

•Neurotoxicity is the primary dose-limiting toxicity.

endogenous compounds

Antagonists of

•  - folic acid(methotrexate),
•  - purines (mercaptopurine),
•   - or pyrimidines (fluorouracil).

the S phase

They have immunosuppressant actions

• Methotrexate
• Mercaptopurine (6-MP)
• Fluorouracil (5-FU)
• Capecitabine (prodrug of 5-FU)

• Both oral and IV administration afford good tissue distribution except to the CNS.
• Excreted unchanged by the kidneys.
• Adequate hydration is required to prevent crystallization in renal tubules

• •Substrate for and inhibitor of dihydrofolate reductase.
• •This interferes with nucleic acid and protein synthesis.

• •Tumor cell resistance mechanisms include decreased drug accumulation, changes in dihydrofolate reductase, increased formation of dihydrofolate reductase, and
• decreased formation of cytotoxic metabolites of methotrexate

• Acute lymphoblastic leukemia,
• choriocarcinoma,
• head and neck cancer,
• testicular cancer,
• osteogenic sarcoma,
• rheumatoid arthritis,
• psoriasis,
• and it is also used as an abortifacient

Purine antimetabolite which is activated by hypoxanthine-guanine phospho-ribosyltranferase (HGPRTase) to toxic nucleotides that inhibit several enzymes involved in purine metabolism.

A Prodrug

• decreased activity of HGPRTase,
• or increased inactivation of the toxic nucleotide

Low oral bioavailability due to first pass metabolism. 

The metabolism of mercaptopurine is inhibited by allopurinol.

Childhood acute leukemia

• Bone marrow suppression,
• and hepatic dysfunction

Transformed to 5-FdUMP which inhibits thymidylate synthase and leads to “thymineless” death of cells.

• Decreased activation of 5-FU,
• increased thymidylate synthase activity,
• and reduced drug sensitivity of this enzyme

• Given IV,
• widely distributed including the CSF,
• Elimination is by metabolism.

• Breast,
• colon,
• rectum,
• stomach,
• and pancreas,
• topically used for skin cancer

• GI distress,
• myelosuppression,
• and alopecia

• A prodrug which is ultimately converted to 5-FU inside the cell.
• Given orally
• Less toxic than IV 5-FU

Widely used in the treatment of metastatic breast cancer.

• diarrhea,
• hand-foot syndrome

hand-foot syndrome – swelling, redness, and pain  of hands and feet