Anticancer Drugs

Question 1

What are two causes of cancer?

Answer 1

• Oncogenes (upregulated or deregulated in cancer)

- Tumor suppressor genes (downregulated or absent in cancer)

Question 2

What is carcinoma and sarcoma?

Answer 2

Carcinoma: epithelial cancer (eg. breast cancer)

Sarcoma: connective tissue cancer (eg. fibrosarcoma)

Question 3

List the stages of cancer

Answer 3

Stage 0: not detectable

Stages I-III: size and spread increases

Stage IV: metastasis

Question 4

Cancer can be treated with surgery, radiation and chemotherapy.

Describe three types of chemotherapy targets.

Answer 4

• Target the cell cycle: antineoplastics
• Target proliferation pathways (newer anticancers)
• Target cancer specific molecules (targeted anticancer agents)

Question 5

List four classes of antineoplastic agents

Answer 5

• Alkylating and platinum agents
• Antimetabolites
• Topoisomerase inhibitors and antibiotics
• Vinca alkaloids and taxanes

Question 6

Describe the action of alkylating antineoplastic agents

Name an alkylating agent and its MOA

Answer 6

Covalently bind to DNA and inhibit synthesis and function leading to cell death.

Not cell cycle specific.

Cyclophosphamide has a bis(chloroethyl)amine group that is activated in the liver to form phosphoramide mustard, which binds with DNA, causing cross links between strands, and sometimes lipids and proteins to kill cells.

Question 7

Describe a platinum containing antineoplastic agent.

Answer 7

Cisplatin

Does not contain an alkyl group like alkylating agents.

Causes inter and intra DNA strand cross-links in cells (similar to alkylating agents)

Question 8

Describe the mechanism of antimetabolites as anticancer agents

Name three

Answer 8

These mimic the actions of endogenous compounds which go into DNA synthesis (eg. folic acid and nucleotide bases) to prevent DNA synthesis.

Purine antagonist: mercaptopurine (similar to adenine)

Pyrimidine antagonist: fluorouracil (similar to uracil and thymine)

Folic acid antagonist: methotrexate (MTX, structurally similar to folic acid). Analogous to trimethoprim on bacterial cells (inhibits dihydrofolate reductase)

Question 9

At what stage of the cell cycle do antimetabolites work at?

Answer 9

The S phase (DNA synthesis)

Question 10

Describe topoisomerase I/II inhibitors as anticancer agents.

Answer 10

Eg. Topotecan (cancer) inhibits Topo I. Doxorubicin intercalates DNA, stabilizes TopoII complex and generates free radicals.

In both cases, halting the replication process signals cell death. Both are used for cancer.

Doxorubicin can cause cardiotoxicity

Antibiotics and topoisomerase inhibitors effect the G1, S and G2 stages of the cell cycle, but not the mitotic stage.

Question 11

What are vinca alkaloids? Name one.

What is the main side effect?

Answer 11

Natural products from the Rosy periwinkle (Catharanthus roseus) in madagascar.

Vincristine

Prevents microtubule formation of mitotic spindles to inhibit cellular division.

These are neurotoxic and cause abdominal pain, bone pain and constipation.

Question 12

What are taxanes? Name one.

Answer 12

Anticancer drugs which include taxol, a natural product isolated from the Pacific Yew.

Docetaxel (semi-synthetic)

Stabilizes microtubules and prevents the disassembly of mitotic spindles to inhibit cellular division.

Question 13

If antineoplastic drugs do not differentiate between cancerous and non-cancerous cells (they don’t), how are cancer cells targeted?

Answer 13

Cells with high turnover right are more susceptible to damage.

Such as in the oral cavity, GI, skin and hair and immune system.

Question 14

Why do antineoplastics cause so many adverse effects in light of their dose response curves?

Answer 14

The anticancer effect is at the top of the dose response curve (100%). This is also at about 70% for toxic effects.

This creates a very narrow therapeutic window where toxic effects cannot be avoided.

Question 15

Why are infections common complications with antineoplastics?

Answer 15

They target immune cells because of the high turnover rate of immune cells. Because of this, antibiotics and antifungals are often coadministered.

Question 16

What are four rules to follow when designing combo therapy for anticancer treatment?

Answer 16

Efficacy: Each drug must be effective alone

Toxicity: Different side effects from diff drugs

Scheduling: Match recovery intervals (shortest interval possible preferred to increase killing efficacy)

MOA: Different MOA desired to increase tumour killing efficacy and decrease possibility of resistance to a single drug.

Question 17

What is the CAV combination therapy?

Answer 17

• Cyclophosphamide
• Adriamycin (doxorubicin)
• Vincristine

Question 18

List five cancer-specific targets for anticancer drugs.

Answer 18

Cellular markers: CD-20

Blood vessel growth: VEGF

Growth and proliferation: EGF, EGFR, HER-2

Survival proteins: Bcl-2 via BCR-ABL,

Hormone sensitive growth: estrogen dependent (ER+) breast cancer,

Question 19

Describe the drugs that target CD-20 and other tumor antigens (3)

Answer 19

mAb conjugated radioactive isotopes targets radioactivity to tissues expressing antigen, prevents damage to neighbouring tissue like tradition radiation treatment.

Rituximab: mAb flags malignant B-cells for destruction

Tositumomab: mAb conjugated with radioactive iodine, kills CD-20 positive cells and adjacent cells.

Sipuleucel-T: “cancer vaccine.” Virus expresses tumor antigen (eg. CD-20), made from patient’s blood.

Question 20

How can angiogenesis in tumours be suppressed?

Answer 20

Targeting and inhibiting VEGFR (Vascular endothelial growth factor) tyrosine kinases.

Bevacizumab: mAb targeted against VEGF binds the ligand to make it unavailable to receptor.

Sorafenib: Binds to intracellular VEGFR domain to prevent initiation of signal.

Question 21

How can growth and proliferation of tumors be specifically targeted?

Which two receptors are targeted?

Answer 21

By targeting epidermal growth factor (EFG), which many cancer cells secrete.

EGFR and HER-2 (human epidermal growth factor receptor 2, commonly upregulated in breast cancer).

Both of these are tyrosine kinase receptors, and they dimerize upon ligand binding. Phosphorylation of tyrosine residues initiates intracellular signalling cascades to promote cell growth and proliferation.

Question 22

List drugs against EGF signaling. (3)

Answer 22

Trastuzumab: Targets HER-2 with mAbs against EGFR. First line therapy in HER-2 positive breast cancer. Targets cell for destruction and reduces intracellular signalling of proliferation.

Trastuzumab emtansine (T-DM1): Contains Trastuzumab and a antimicrotubule agent. Cytotoxic drug enters cells and inhibits microtubule assembly (like vincristine).

Gefitinib: Small molecule TK inhibitor that binds to intracellular domain of EGFR

Question 23

Why must mAb conjugated drugs be given with IV?

Answer 23

Antibodies are large, they are not absorbed well.

They also cannot penetrate cancer cell walls. Which is why you don’t have mAb conjugated drugs inhibiting receptors intracellularly (like small molecule TK inhibitors)

Question 24

List the drugs that target cellular survival proteins.

Answer 24

Imatinib: Small molecular TK inhibitor that inhibits the intracellular TK receptor, BCR-ABL (BCR-ABL upregulates Bcl-2)

Question 25

What is the most common reason for drug resistance in cancer therapy?

Primary resistance?
Acquired resistance?

Answer 25

Primary resistance: Impaired responses to cell death signals in tumor cells.

Acquired resistance: Adaptation and mutation of tumor cells

Question 26

List three adaptations which could render cancer cells drug resistant.

Answer 26

DNA repair mechanisms upregulated: Eg. protects against alkylating agents and radiation

Alteration in drug targets: Eg. upregulation of enzyme targeted by drug, such dihydrofolate reductase, resistance against methotrexate

Removal of drug from target cells: Eg. through upregulation of p-glycoprotein pumps.

Question 27

Which drugs are particular sensitive to the upregulatio nof p-glycoprotein pumps?

Answer 27

• Antibiotics
• Vinca alkaloids
• Taxanes
• Small molecule inhibitors (eg. the -nib agents)

Question 28

Describe hormone sensitive cancers.

Answer 28

Tumor cells grow and proliferate in response to hormone receptor activation.

Eg. ovarian, breast and prostate cancers (though not all of these are hormone sensitive)

Question 29

List drugs against estrogen positive cancer. (3)

Answer 29

Leuprolide: Analogue of GnRH (gonadotropin releasing hormone), inhibits anterior pituitary release of FSH and LH, inhibiting gonadal release of estrogen and testosterone.

Letrozole: Inhibits the aromatase enzyme necessary for the conversion of estrogen from progesterone

Tamoxifen: Estrogen antagonist, competes for estrogen receptor binding in tumor cells.