1.8 Principles of Veterinary Anti-Cancer Drugs

Question 1

Chemotherapy refers to the treatment of cancer with drugs. Most are cytotoxic and interfere with cell growth and division - their action is not specific to cancer cells, but is often most effective in cancer cells.

Question 2

What are the terms for chemotherapy indications?

Answer 2

• induction chemotherapy: induce remission
• consolidation chemotherapy: sustain remission - short-term additional treatment to increase success
• maintenance chemotherapy: continuous, low-grade treatment to maintain remission (controversial)
• adjuvant: additional - typically in addition to surgery
• neo-adjuvant: pre-surgical, to shrink the size

other: re-induction, and rescue chemotherapy

Question 3

What is true about conventional chemotherapy?

Answer 3

• cytotoxic: interfere with cell growth or division
• some act at specific stages of the cell cycle, some do not
• most are more effective in hightly dividing cells (high mitotic index)
• cells in G0 (resting between divisions) are less likely to be sensitive to treatment

this discrepancy is the basis of conventional chemotherapy

Question 4

How is conventional chemotherapy often administered (timing, dose, effectiveness, etc)?

Answer 4

(1) timing: as soon as possible

• cancer cells tend to grow rapidly and then plateau; the fast growth phase is the best time to treat, as the mitotic index is at its greatest

(2) dose:

• cell kill hypothesis: at a given dose of chemotherapy agent, a given percentage of tumor cells will be killed
• cannot kill the tumor in one dose, instead aim for the greated fractional kill with the least amount of normal tissue injured

(3) pulse dosing:

• give medication multiple times at intervals, with rest in between
• allow normal tissue to recover, but not long enough for tumor to regrow

(4) surface area vs body weight:

• toxicity relates more to surface area, therefore drugs often dosed in mg/m^2
• BUT small animals often get overdosed on this basis, so if under 10kg may dose via mg/kg

Question 5

How can glucocorticoids affect chemotherapy?

Answer 5

chronic iatrogenic glucocorticoid therapy can cause MDR1 upregulation, leading to chemotherapy resistance to doxorubicin and vinca alkaloids

Question 6

What are the 6 main chemotherapy groups?

and their MoAs

Answer 6

(1) alkylating agents

• alkylate DNA: DNA cannot undergo transcription or replication
• not cell-cycle specific

(2) vinca alkaloids(AKA mitotic spinde inhibitors)

• M phase (and G2)
• bind to tubulin and interfere with the mitotic spindle: metaphase arrest

(3) antimetabolites

• S phase
• non-functional or inhibitory enzymes that mimic normal substrates in DNA/RNA synthesis

(4) platinum agents

• cross link DNA strands
• not cell-cycle specific

(5) anti-tumor antibodies

• multiple actions: break and cross-link DNA, inhibit topoisomerase II, form free radicals, etc.
• not cell-cycle specific

(6) L-asparaginase (enzyme)

• breaks down L-asparagine which neoplastic lymphoid cells depend on
• inhibits protein synthesis

Question 7

How can NSAIDs and Prednisolone be used in cancer therapy?

Answer 7

Prednisolone:

• causes apoptosis of lymphoid and mast cells

NSAIDs:

• COX-2 inhibition = anti-angiogenic, promotes apoptosis, anti-inflammatiory, and analgesic
• effects on stromal cells

Question 8

List some chemotherapy adverse effects

Answer 8

• myelosuppression
• GI: V+/D+/anorexia
• hair loss/ whisker loss
• drug extravasion

Question 9

What factors effect the success of chemotherapy?

Answer 9

• tumor cell type: intrinsic resistances (e.g., many carcinomas, melanomas)
• drug distribution: blood supply to tumor (e.g., BBB, angiogenesis, etc)
• development of resistance: tumors are unstable; drig exposure can lead to the selection of resistance cell lines