13 - Cancer Chemotherapy Flashcards

Question

Drugs to Treat Cancer

Answer 1

Anti-cancer drugs can be broken down into 2 classes: 1. Cytotoxic agents 2. Hormonal and other agents

Answer 2

1) Alkylating agents 2) Platinum compounds 3) Antimetabolites 4) Antitumour antibiotics 5) Mitotic inhibitors

Answer 3

- Cytotoxic drugs can be separated into either cell cycle phase specific or cell cycle phase non-specific drugs. Cell cycle phase specific drugs → only effective if the cancer cell is in a specific phase of the cell cycle → ex. mitotic inhibitors are only effective when cancer cells are undergoing mitosis → Phase specific drugs are only effective in cells that are actively part of the cell cycle and are ineffective for cells that are in Go. Cell cycle phase non-specific drugs → act during any stage of the cell cycle including Go → Although phase non-specific drugs are effective at any stage of the cell cycle, they are more toxic to cells that are proliferating than to cells in Go → still much more effective at targeting proliferating cells

Answer 4

- Are highly reactive chemicals that transfer an alkyl group to cell components (primarily DNA). - They form cross-bridges between nitrogen atoms on guanine nucleotides that make up our DNA. - The result of treatment with alkylating agents is miscoding, breaking of DNA, and inhibition of DNA replication. - Alkylating agents are cell-cycle phase non-specific: they are effective during ANY phase of the cell cycle. Cyclophosphamide - the most widely used drug in this class. - prodrug and must be converted to its active form by the liver → For this reason its onset of effect is often delayed. - Common uses for cyclophosphamide: → Hodgkins disease → solid tumours of the head, neck, ovary and breast

Answer 5

- Are drugs with platinum in their chemical structure. - Act by cross-linking DNA and inhibiting DNA replication. - They cross-link DNA by binding to guanine nucleotides (similar to alkylating agents) - Are cell-cycle phase non-specific: act at ANY phase of cell cycle Cisplatin → most widely used platinum compound → used in the treatment of metastatic ovarian/ testicular cancers and advanced bladder cancer → extremely nephrotoxic, ototoxic (toxic to the ear and may cause deafness) and emetogenic (causes nausea and vomiting)

Answer 6

- Are structurally similar to natural compounds the body uses to: a) synthesize cellular constituents or b) incorporate into DNA - They act by inhibiting particular enzymes or by preventing DNA replication. - Antimetabolites are phase specific and most (although not all) act during S-phase. Antimetabolites can be further classified into 3 subclasses: 1) Folic acid Analogs → block the conversion of folate to its active form (which is required for DNA synthesis) 2) Purine Analogs → purines are used to make DNA and RNA → Purine analogs inhibit the synthesis of DNA and RNA. 3) Pyrimidine Analogs → pyrimidines are used to make DNA and RNA. → Pyrimidine analogs inhibit the synthesis of DNA and RNA.

Answer 7

1. Folate is enzmaytically converted into tetrahydrofolate - required cofactor for synthesis of pyrimidines (uracil, thymine, cytosine) 2) Pyrimidines are needed for synthesis of nucleotides 3) Nucleotides are needed for DNA and RNA synthesis - Antimetabolite drugs act at different sits of this cycle Folate analogs - block conversion of folate into active form tetrahydrofolate - causes decrease purine and pyrimidine synthesis - decreases DNA synthesis Purine Analogs - block conversion of purine to nucleotides Pyrimidine Analogs - block conversion of pyrimidines to nucleotides NET EFFECT: decreased DNA synthesis which causes cancer cell death

Answer 8

- Kill cancer cells by intercalating DNA → they move between the bases of DNA and bind to DNA → This causes a change in the structure of DNA and altered DNA structure is unable to be used as a template by DNA polymerase = DNA synthesis is inhibited. - Antitumour antibiotics are very poorly absorbed and are given intravenously

Answer 9

- Are a type of antitumour antibiotic. Can cause: 1. severe bone marrow suppression 2. are cardiotoxic (toxic to the heart)

Answer 10

- Act during the cell cycle to inhibit mitosis and prevent cell division → are cell cycle phase specific → vinca alkaloids and taxanes act at different parts of cell cycle - Are separated into 2 different subclasses: vinca alkaloids and taxanes. 1) Vinca Alkaloids → act during Metaphase of mitosis → Block the process of mitosis during metaphase. → are derived from the periwinkle plant → They block metaphase by binding to the protein tubulin - a major component of the microtubule → disrupts the organization of microtubules during cell division and leads to inappropriate distribution of chromosomes and eventually cell death. 2) Taxanes → Act in the late G2 phase of the cell cycle, just prior to mitosis. → Taxanes stabilize microtubule bundles and therefore prevent cell division

Answer 11

1) Glucocorticoids 2) Drugs for Prostate Cancer 3) Drugs for Breast Cancer

Answer 12

- used as an adjunct to other chemotherapeutic agents in cancers that are derived from lymphoid tissue. - Are beneficial because they are directly toxic to lymphoid tissue. Side effects from long term use include: → osteoporosis → adrenal insufficiency → susceptibility to infection → GI ulceration → electrolyte disturbance → growth retardation. - Can also be helpful in management of complications of other chemotherapy drugs including reduction in nausea and vomiting, reduction of pain, and improved appetite

Answer 13

- Prostate tissue (normal and neoplastic) is androgen dependent, so the primary goal in the treatment of prostate cancer is androgen (i.e. testosterone) deprivation. Androgen deprivation can be achieved by: 1. Gonadotropin Releasing Hormone (GnRH) agonist or surgically by castration. → GnRH agonists cause a transient increase in testosterone production in the testes, so cancer symptoms may increase at the start of therapy. → Over time, testosterone synthesis and release is decreased (due to negative feedback and increased receptor sensitization) 2. Androgen Receptor Antagonists → Used in combination with a GnRH agonist or castration. → Act by blocking androgen receptors in tumour cells → GnRH causes release of testosterone from the testes. →Testosterone “feeds” prostate cancer cells but also acts by negative feedback to inhibit further GnRH release. →GnRH agonists cause a transient increase in testosterone but then cause decreased GnRH activity through desensitization and negative feedback. →The net effect is decreased testosterone synthesis and release (listen to slide)

Answer 14

- Breast cancer is the most common cancer affecting women. - Estrogen causes breast tumour cells to proliferate. - Depriving breast cancer cells of estrogen is the primary treatment of breast cancer. - estrogen receptor antagonism is used as an adjunct to surgery and radiation therapy. Treatment of breast cancer can be divided into 3 classes: 1) The anti-estrogens 2) Aromatase inhibitors 3) Trastuzumab

Answer 15

– block estrogen receptors -The most commonly prescribed drug for breast cancer (specifically tamoxifen) - Tamoxifen is a partial estrogen receptor agonist; it minimally activates the estrogen receptor but also blocks endogenous estrogen from binding to its receptor - Net effect of tamoxifen is blocking the binding of endogenous estrogen to the estrogen receptor (w minimal activation) - breast cancer cells estrogen dependent - estrogen binds to intracellular receptor and this complex binds to DNA and increases transcription which allows breast cancer tumour cell to proliferate - tamoxifen blocks the binding of estrogen to its receptors and decreases proliferation of breast cancer cells - tamoxifen is only effective in cells containing an estrogen receptor

Answer 16

Aromatization: the process of converting androgens into estrogen. - Aromatase inhibitors inhibit the conversion of androgens to estrogens = decrease the amount of estrogen available to breast cancer cells. - aromatase inhibitors do not block synthesis of estrogen from ovaries, so aromatase inhibitors are only useful in postmenopausal women (who don't have estrogen synthesis in ovaries)

Answer 17

- Some patients with breast cancer have an increased number of human epidermal growth factor receptor 2 (HER2). - HER2 is a transmembrane receptor that helps regulate cell growth. - Tumours with increased HER2 have especially aggressive tumour growth

Answer 18

- Trastuzumab is a monoclonal antibody that binds to HER2 and prevents cell proliferation. - As trastuzumab is an antibody, it must be administered IV (as antibodies are degraded in the stomach and poorly absorbed). - most prominent adverse event: cardiotoxicity - most breast cancer cells only contain small # of HER2 receptors which send signals to nucleus to grow and divide - abnormal breast cancer cells have abundant HER2 receptors = too many receptors send signals to grow/divide = cell grows too quickly -trastuzumab binds to HER2 receptors, stops the signal from getting to nucleus = stops proliferation of cell

Answer 19

- Protein kinases are enzymes that phosphorylate proteins on specific amino acid residues (i.e. tyrosine). - Activity of tyrosine kinases can activate gene transcription and/or DNA synthesis - Increased activity of tyrosine kinases has been observed in many cancers - tyrosine kinases phosphorylates substrate molecule which results in tumour cell able to proliferate - a target blocks phosphporalation and does not allow the tumour to proliferate

Answer 20

1. Is the prototype tyrosine kinase inhibitor. 2. Effective in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumours (GIST). 3. Causes complete inhibition of cellular proliferation and cell death via apoptosis (programmed cell death). 4. Primary toxicities include nausea, vomiting, edema, and muscle cramps.