Cancer Chemotherapy Flashcards

1
Q

Differentiate between primary and acquired resistance. List examples within each category:

A

Primary: absence of response at first exposure to chemotherapy

  • tumor cell heterogeneity
  • insensitive (ie not in a sensitive part of the cell cycle)
  • protected (ie P-glycoproteins - MDR- ABCB1 - note, use of Verapamil (inhibits L-type calcium channels was used to also block P-gp, but with serious cardiac side effects)

Acquired: may be due to increased expression of specific genes

  • alterations in drug transport or uptake into cells
  • decreased metabolic capacity to inactivate drugs
  • increased capacity to inactivate drugs (ie induction of enzymes or elevated sulfhydryl scavengers- glutathione)
  • Enhanced DNA repair (ie changes in topoisomerase I/II)
  • gene amplification
  • increased anti-apoptosis proteins (ie Bcl-2)
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2
Q

List the pros to combination chemotherapy

A

A. Additive or synergistic cytotoxicity
B. Targets multiple biochemical pathways
C. Subclones are resistant to only one agent
D. Alternate myelosuppressive agents with non-suppressive drugs during recovery periods
E. Avoids too much damage to one organ; avoids overlapping toxicity’s, optimize dosing schedule for recovery

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3
Q

Account for cytotoxic chemotherapy drugs and their toxicity to specific organs: cardiac, pulmonary, nervous system, renal, liver, local and carcinogenic

A

Cardiotoxicity- doxorubicin > daunorubicin, cyclophosphamide
Pulmonary fibrosis- bleomycin, busulfan
Nervous system- vincristine, cisplatin, hexamethylamine, paclitaxel, cytarabine
Renal- cisplatin, streptozocin, methotrexate
Liver- methotrexate, L-asparaginase, mercaptopurine, azathioprine
Local- anthracyclines, vinca alkaloids, mechlorethamine, nitrosureas, mitomycin C
Carcinogenic- alkylation agents, anthracyclines, procarbazine

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4
Q

Differentiate the major chemotherapeutic drug classes based on whether they are cell cycle specific (CSS) or cell cycle non-specific (CCNS):

A

CCS- proliferative cells; antimetabolites, alkaloids, topoisomerase inhibitors, bleomycins

CCNS: alkylating drugs, nitrosoureas, anti tumor antibiotics, procarbazine, cisplatin, dacarbazine

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5
Q

Carmustine, lomustine, streptozocin and temozolomide are all examples of nitrosoureas chemotherapeutic drugs. What characteristic do these drugs posses, allowing them to treat brain tumors?

A

Nitrosoureas drugs are lipid soluble and can cross the BBB.

However, note that carmustine can cause acute and chronic pulmonary injury.

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6
Q

How can glutathione, cysteine and glutathione S-transferase be used by cancer cells to acquire resistance to chemotherapeutic treatments?

A

These compounds can act as nucleophiles and compete with DNA for alkylating drugs. Thus, more DNA is not alkylated and there is less DNA damage = cancer cell survival

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7
Q

Alkylating agents are CCNS chemotherapeutic drugs that act to inhibit cell cycle progression mainly at the late G1-S phase of the cell cycle. Explain the characteristics of these agents, giving examples of important drugs within the alkylating agents:

A

Alkylating agents include:

  1. Nitrogen mustards (ie cyclophosphamide, mechlorethamine)
  2. Nitrosoureas (ie carmustine)
  3. Combination drugs (ie cisplatin, carboplatin, oxaliplatin)

Critical differences within stability, requirements for metabolic activation, and lipophilicity

Although these are CCNS, cytotoxicity is expressed as cells enter S phase and progression is blocked at the G2 (pre-mitosis) phase. Cells are more sensitive in late G1 or S where the DNA is more likely to be unpaired and more sensitive to alkylation.

Nitrogen mustards and nitrosoureas must be metabolically activated for use as strong electrophoresis, attacking neutrophilic DNA at: Guanine nitrogen 7, adenine N1 and N3, cytosine N3, guanine O6.

Binding at these locations will result in:

  • G-T mispairing, opening of the imidazole ring
  • DNA cross linking which prevents strand separation
  • mutagenesis or cytotoxicity
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8
Q

Cisplatin, carboplatin and oxaliplatin are great chemotherapeutic agents for combination therapy. Explain their mechanisms of action as well as potential contraindications:

A

MOA: electrophoresis react with DNA nucleophiles, forming cross-linkage.
Toxicity: nausea, vomiting can be dose-limiting
- Cisplatin: nephrotoxicity
- Carboplatin: myelosuppression
- Oxaliplatin: neurotoxicity

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9
Q

Describe the mechanism of action of methotrexate. How is this useful as a chemotherapeutic agent. Also, are their any contraindications for using methotrexate. List possible indications for the use of this drug. Note toxicity as well. Also, what drug can be useful in reversing the effects of methotrexate?

A

METHOTREXATE is a anti metabolite drug and a folic acid antagonist responsible for inhibiting dihydrofolate reductase (DHFR), which reduces dihydrofolate into tetrahydrofolate. Thus, dihydrofolate accumulates, further inhibiting folate dependent enzymes. Tetrahydrofolate is responsible for providing one carbon (methyl group) which the enzyme thymidylate synthase uses to convert dUMP to dTMP. The de novo synthesis of purines is prevented. Lack of DNA bases may lead to apoptosis and cell death.

Toxicity/contraindications:
Methotrexate may cause renal damage at high concentrations and liver damage. The drug Leucovorin may be used to reverse the effects of MTX by supplying reduced folate that the thymidylate synthase can use to produce dTMP.

Indications:

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10
Q

Describe the characteristics of anti metabolite drugs.

A
  • Usually kill in the S-phase and are CCS (cell cycle specific)
  • major target is incorporation into nuclei acids and inhibition of cell replication
  • examples of chemotherapeutic agents that act as antimetabolites include: Methotrexate, Purine analogs (mercaptopurine, thioguanine, cladribine) and pyramiding analogs (flourouracil, floxuridine, cytarabine, and gemcitabine)
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11
Q

Purine analogs, such as 5-flourouracil (FU), floxuridine, and capecitabine act as antimetabolites, which works to inhibit cell replication by blocking critical enzymes in cell proliferation pathways. Explain the mechanism of action of FU.

A

FU is a modified uracil, containing a stronger C-F bond compared to a normal C-H bond in uracil. In the target cell, FU will undergo transformation into 5-FUTP and 5-FdUMP via phosphorylation, ribosylation and reduction. 5-FUTP will incorporate into RNA (via pyramidine monophosphate kinase) and exerts its effects by interfering with RNA processing and mRNA translation. 5-FdUMP, will become a substrate for thymidylate synthase. However, due to the strength of the C-F bond, C5 methylation of normal dUMP to dTMP does not occur and DNA synthesis is inhibited.

Note that cytarabine and gemcitabine are deoxycytidine and difluorodeoxycytidine analogs. Recall that cytarabine can cause cerebral damage.

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12
Q

Explain how potential synergism can exist between the two drugs 5-flourouracil and methotrexate.

A

MTX is responsible for preventing the production of tetrahydrofolate, used by thymidylate synthase to dorm dTMP, a nuclei acid building block critical in the de novo purine synthesis pathway. 5-flourouracil is responsible for blocking thymidylate synthase, producing a 5-FdUMP instead of the normal dUMP substrate required by the enzyme. Thus, both drugs work to inhibit or limit the activity of thymidylate synthase and therefore impair DNA synthesis.

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13
Q

Purine analogs are important antimetabolite chemotherapeutic agents. Explain the mechanisms of action of two purine analogs, 6-mercaptopurine- hypoxanthine analog, and thioguanine- guanine analog. Include in explanation enzyme that is inhibited by these analogs.

A

6-mercaptopurine and thioguanine are analogs of hypoxanthine and guanine, respectively, and have a -SH group instead of the normal -OH group on C6. When these drugs are metabolized by the enzyme HGPRT, they become thioinosinate (T-IMP) and thioguanylate (T-GMP), respectively. These metabolites will either inhibit enzymes involved in purine synthesis or insert into DNA. Both mechanisms act to decrease purine biosynthesis in the salvage pathway.

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14
Q

Explain how pyrimidine analogs and purine analogs can both be useful as antimetabolites. Explain the enzymes inhibited and the pathways affected by this inhibition.

A

Pyrimidine analogs, such as 5-flourouracil inhibits de novo synthesis of purines by inhibiting thymidylate synthase. Purine analogs, such as 6-mercaptopurine and thioguanine inhibits the salvage pathway of purine synthesis by inhibiting HGPRT.

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15
Q

What drug can be given with chemotherapy to prevent hyperuricemia after tumor cell lysis?

A

Allopurinol, an xanthine oxidase inhibitor, can be given with chemotherapy to prevent hyperuricemia. Xanthine oxidase metabolizes 6-MP; 6-TG however is not oxidized by XO because it is deaminated.

However, note that when Allopurinol and 6-MP are given together, mercaptopurine toxicity may result. Therefore, allopurinol can be given with 6-TG.

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16
Q

Vinca alkaloids operate as CCS inhibitors by blocking the polymerization of microtubules. This causing cell-cycle arrest in metaphase. What major toxicities are associated with vineblastin, vincristine, and vinorelbine?

A

Vineblastin- myelosuppressive
Vincristin- neuromuscular toxicity
Vinorelbine- less neurotoxicity; neutropenia is dose-limiting

17
Q

Paclitaxel and docetaxel

A

Taxanes. Binds to tubular diners and microtubulin filaments, promotes filament assembly, prevents depolymerization which disrupts mitosis.

Major toxicity is myelosuppression that greatly affects neutrophils.

18
Q

Topoisomerase I and II inhibitors

A

Topo I: irinotecan, topotecan

Topo II: etoposide, teniposide

19
Q

Tamoxifen, raloxifene, and toremifene are examples of selective estrogen receptor modulators. What are the mechanism of action of these drugs as well as important toxicities of each?

A

Tamoxifen: partial agonist inhibitor of estradiol binding to estrogen receptor. Importantly, it is a chemopreventative agent for prophylactic treatment of women at high risk for breast cancer.

Raloxifene: treatment and prevention of osteoporosis and prophylactic treatment of post menopausal women at high risk of invasive breast cancer.

Toremifene: inhibitor of estradiol binding to the estrogen receptor

20
Q

What drug can be used for tamoxifen-resistant breast cancer?

A

Fulvestrant, a selective estrogen receptor down-regulator. This drug binds to the estrogen receptor with high affinity.

21
Q

List four aromatase inhibitors

A

Aminoglutethimide, anastrozole, letrozole, and exemestane