MM 24-26 Cancer Drugs

Question 1

Adjuvant therapy

Answer 1

Chemotherapy used in patients with tumor removed, but who are still at risk of metastasis.

Question 2

Nonadjuvant therapy

Answer 2

Chemo treatment given to local therapy-to shrink tumor before therapy.

Question 3

Classical cytotoxic drugs

Answer 3

Affect only the cell division process.

Question 4

Classes of cytotoxic drugs

Answer 4

Antimetabolites
Alkylating agents
Cytotoxic antibiotics
Plant alkaloids/microtubule inhibitors

Question 5

Antimetabolates

Answer 5

Act to block or subvert metabolic pathways in the synthesis of DNA.

• Folate antagonist
• Nucleic acid synthesis inhibitors

Question 6

Folate inhibitors

Answer 6

Folates are essential for the synthesis of purine nucleotides (A/G), needed for DNA synthesis and cell division.

Methotraxate

Question 7

Methotraxate

Answer 7

Folate antagonist. Structurally similar but 1000x higher affinity for enzyme DFHR. Arrests cell cycle in S phase.

Folinic Acid must be given 24 hours after methotrexate to rescue bone marrow and GI mucosa.

Question 8

Folinic Acid

Answer 8

Folinic Acid must be given 24 hours after methotrexate to rescue bone marrow and GI mucosa.

Healthy cell seem better able to use folinic acid to compete with methotrexate.

Question 9

Nucleic Acid inhibitors

Answer 9

Analogs of Purines/Pyrimidines. Form a false DNA/RNA that are unable to replicate/transcribe.

Pyrimidine: Have thiol group. 
    6-thioguanine
    6-mercaptopurine
Purines:
    5-fluorouracil

Question 10

5-fluorouracil

Answer 10

Widely used, especially for colorectal cancer. Antimetabolite. Uracil analog.

5-FU inhibits Thymidylate inhibitor, an enzyme used to make thymidine monophosphate (dTMP), which is subsequently phosphorylated to dTTP for use in DNA synthesis and repair.

Question 11

Alkylating agents

Answer 11

Bonds covalently within DNA forming crosslinks between bases, thereby inhibiting synthesis during S phase and interfering with transcription. Guanine is particularly susceptible.

There is no targeting here. Tumor cells just perform more DNA synthesis than normal cells. So people become immune suppressed, because blood cells should reproduce frequently.

Eg. Cisplatin

Question 12

Cisplatin

Answer 12

An alkylating agent. Causes DNA to crosslink, causing apoptosis.

Question 13

Cytotoxic antibiotics

Answer 13

Substances of microbial origin that prevent DNA cell division. Flat molecules that intercalate between the DNA strands.

Eg Anthracyclines and Doxorubicin

Question 14

Anthracyclines and Doxorubicin

Answer 14

Cytoxic antibiotics. Used to treat leukemias, lymphomas, and solid tumors.

Prevent DNA uncoiling by stabilizing Topoisomerase II complex.

Adverse effect: produces O2 free radicals.

Question 15

Plant Alkaloids/microtubule inhibitors

Answer 15

Of plant origin. Act on microtubule dynamics.

Eg. Vinca alkaloids and taxanes

Question 16

Vinca alkaloids

Answer 16

Plant alkaloids/microtubule inhibitor.

Binds to tubule and prevent its polymerization into microtubules. Prevent spindle formation and arrest metaphase.

Vincristine and vinblastine

Question 17

Taxanes

Answer 17

Plant alkaloids/microtubule inhibitor. Derivatives of tree bark.

Promote microtubule growth and prevent their disassembly during anaphase.

Paclitaxel (tree bark)
Daclitaxel (derivative of paclitaxel)

Question 18

Drug resistance

Answer 18

Resistance is the most common reason for failed drug therapy. The resistance may exist upon initial administration (primary) or be acquired. Can be the result of adaptation or mutation.

Resistance may be the result of:

• Increased target enzyme production (methotrexate).
• Use by cells of alternative pathway (anti metabolites)
• Repair of DNA interference (alkylating agents)
• Reduced activation of drug (5-FU)
• Decreased amount of drug taken up by the cell (methotrexate).

Question 19

Multidrug resistance

Answer 19

Multidrug resistance often comes from the increased expression of transporters that pump drugs out of the cell.

P-glycoprotein 1, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette transporters (ABCs) is an important protein of the cell membrane that pumps many foreign substances out of cells.

Question 20

Limitations to cytotoxic chemotherapy

Answer 20

• Resistance
• Non specific to cancer cells
• Toxic effects on body (marrow)
• Target cell proliferation but not invasion of metastasis.
• Total elimination may not be possible.

Question 21

Hormone therapy

Answer 21

Some tumors in hormone sensitive tissue (breasts, testis) can be dependent on the presence of hormones. This can be determined by the number of hormone receptors on the tumor cells, examined by biopsy.

Hormone dependent cells can fought using hormones with opposing actions, hormone antagonists, or agents that inhibit synthesis of the hormone.

Question 22

Tamoxifen

Answer 22

It is a Selective Estrogen Receptor Modulater (SERM) that is a competitive antagonist to the Estrogen receptor. In breast it is a full antagonist and in other tissues (uterus, bone) it is partial.

Mechanism:
Tamoxifen is first metabolized to its active form (4 hydroxytamoxifen) by CYT P450. Then, like estrogen, it enters the cell by passive diffusion, after which it binds to the estrogen receptor (ER). The ER can still bind to DNA at the estrogen response element (ERE) but is prevented a conformational change that recruits cofactors, thereby inhibiting ER dependent gene transcription of oncogenes (EGFR2/HER2).

Adverse effects: Hot flashes, DVT, PE, Irregular menstruation,

Question 23

HER2/EGFR2

Answer 23

HER2 (Aka EGFR2) is a member of the Human Epidermal growth factor Receptor family (tyrosine kinase receptors). It plays a role in signal transduction for proliferation. Over expression leads to overactivity, causing uncontrolled growth. It is common in breast cancer and is the target for estrogen/anti-antiestrogen transcription factors, as well as target therapy.

Question 24

Tamoxifen and ER

Answer 24

The ER consists of 2 transcriptionally active domains, AF1 and AF2. Tamoxifem completely blocks AF2 but not AF1. However, in breast tissue, AF2 activity is dominant so Tamoxifen is a full antagonist. Other tissues, however, are more dependent one AF1 (bone, uterus) and so Tamoxifen is only a partial antagonist.

Question 25

Aromatase inhibitors - 2 types

Answer 25

Prevents the synthesis of hormones in cancers that are hormone receptor positive.

Aromatase is a CYT P450 that is responsible for the aromatization of androgens into estrogens. Some drugs will irreversibly inhibit Aromatase enzyme as a steroid analogue and others will competitively bind to Aromatase active site as a non steroidal inhibitor.

Exemenstan, Anastrozole

Question 26

Targeted Therapy

Answer 26

Therapies designed to target mechanisms specific to cancer cells. Less toxic. For example, they may block cell proliferation receptor (HER2, VEGFR) or BCR/ABL

Limitations:

• Generally result in stopping cancer growth rather than regression.
• Cost
• End stage disease not likely to respond.

Question 27

Transtuzumab (Herceptin)

Answer 27

Target therapy that blocks HER2, blocking the proliferation of certain cancer cells.

Question 28

Imatinib

Answer 28

Targeted Therapy, selective tyrosine kinase receptor. Blocks ATP binding to BCR/ABL, inhibiting its phosphorylation activity.

BCR/ABL from Philadelphia chromosome in chronic myeloid leukemia.

Question 29

Drugs ending in -tinib

Answer 29

Selective tyrosine kinase inhibitors (target therapy). For example, they inhibit EGFR/HER, VEGFRs, BRC/ABL.

Question 30

Angiogenesis inhibition

Answer 30

Targeted therapy that inhibit the growth of new blood vessels by either blocking signaling cascades or endothelial cell proliferation.

Eg. anti-VEGF blocks binding of VEGF to VEGFR.

Question 31

Other therapy strategies

Answer 31

• Promote apoptosis.
• Regulate gene expression
• Target cancer stem cells
• Immunotherapy
• Signal transduction inhibitors
• Gene therapy

Question 32

Drugs ending in -mab

Answer 32

Monoclonal AntiBodies.

Question 33

Precision medicine

Answer 33

Use of assays to asses underlying condition. And then select the most appropriate treatment for each patient based on knowledge about the underlying molecular abnormalities.

Question 34

Companion Diagnostics (CDx)

Answer 34

Tests paired to specific drugs. CDx is required for all drugs that work on a specific target that is present in some, but not all patients with a certain cancer/disease. Tests show which patients could be helped/harmed.