Cancer Chemotherapy

Dr. Jane Maddox

Objectives

Understand the general adverse effects of cancer

chemotherapeutic agents.

Know the mechanisms of action, specific adverse

effects and mechanisms of resistance for
representative drugs from each class of
chemotherapeutic agents.

Introduction

Cancer is the number one natural

cause of death in geriatric cats and
dogs, and it accounts for nearly 50
percent of deaths each year.

CSU CVM&BS Animal

Cancer Center

Inflammatory Mammary
Cancer Survival
.

(Median Survival = 57 days

(Median Survival = 35 days)

Chemotherapy:
- mitoxantrone
- vincristine
- cyclophosphamide

Palliative treatment:
- amox/clav
and
- glucocorticoid or NSAID

Clemente M et al. The Veterinary Record 2009;165:78-81

2009 by BMJ Publishing Group Limited

Canine Lymphoma Survival Comparison

Median Survival Time (weeks)

100
90
80
70
60
50
40
30
20
10
0

no treatment

CHOP

CHOP+mitoxantrone

General indications and uses

of chemotherapy

Largely limited to small animals

Principle mode of treatment for systemic

cancers such as hematologic malignancies
and metastatic carcinomas or sarcomas

Adjuvant chemotherapy after local treatment

with surgery or radiation

Use of single agents or combinations of

agents

Cell cycle kinetics

G1

Synthesis of RNA and protein

G0
M

Mitosis

Cell cycle

DNA synthesis

G2
Synthesis of cellular
constituents for
mitosis

Growth fraction loosely

is the fraction of cells
traversing the cell cycle.

Cell cycle, contd.

Antineoplastic drugs are:

1)

cycle nonspecific (e.g., alkylating agents)

2)

cell cycle-specific (e.g., doxorubicin)

3)

cell cycle-phase-specific (e.g.,

methotrexate, vincristine)

Drug dosage and timing of

chemotherapy

Try to achieve maximal tumor cell killing with

minimal death of normal cells
Intervals are chosen to allow normal cells to
recover without allowing tumor cells to
replicate; or may use lower dose, more
compressed metronomic therapy
Dosage calculations for most cancer
chemotherapeutic drugs are based on animal
body surface area:

Body surface area in m2 = Km x (body weight in

kg)2/3 x 10-2
K = 10.1 for dogs; K = 10.4 for cats

Resistance to
chemotherapeutic agents
1)

Pharmacokinetic resistance: drug delivery

to tumor is impaired
- e.g., decreased vascularization

2)

Kinetic resistance: smaller fraction of cells

in susceptible state
- larger tumors generally have a smaller growth
fraction

3)

Genetic resistance: development of

biochemical resistance in previously
susceptible cells
- e.g., multidrug resistance transporter, defective
drug activation, etc.

General adverse effects

1)

Bone marrow toxicity: This is the major

dose-limiting toxicity in veterinary cancer
chemotherapy.
Myelosuppression results in:

leukopenia (neutropenia)

thrombocytopenia

anemia

Can be treated with recombinant granulocytecolony stimulating factor (G-CSF)

General adverse effects

2)

Gastrointestinal toxicity: Many

antineoplastic drugs produce vomiting,
diarrhea, anorexia and mucosal damage.

3)

Vomiting may be treated with metoclopramide or

ondansetron

Alopecia: Dogs can lose hair secondary to

chemotherapy (breed-dependent); cats may
lose whiskers.

Cancer Chemotherapy
CANCER THERAPY DRUG CLASSES
1)

Alkylating agents

2)

Antimetabolites

3)

Mitotic inhibitors

4)

Platinum drugs

5)

Antitumor antibiotics

6)

Molecular targeted therapy

7)

Miscellaneous agents

1) Alkylating agents
Mechanism of action: Covalent
alkylation and cross-linking of DNA
Generally

cycle-nonspecific
Replicating cells are most susceptible

Example: Cyclophosphamide, a
nitrogen mustard

1) Alkylating agents, contd.

Pharmacokinetics:

Cyclophosphamide requires
bioactivation in liver

Acrolein is a toxic metabolite (bladder)

Excreted by the kidneys

1) Alkylating agents, contd.

Specific adverse effects: Long-term
treatment in dogs can result in a sterile
hemorrhagic cystitis (via acrolein
metabolite)
Treat with hydration, diuretics, and/or sodium 2mercaptoethane sulfonate (mesna)

Clinical indications: In combination therapy

for canine and feline lymphoma

2) Antimetabolites
These resemble normal cellular
constituents
compete in enzyme reactions (to slow
processes)
OR
replace endogenous substrates (to
generate inactive products)

2) Antimetabolites, contd.
Example: Methotrexate
Mechanism of action: Folic acid analog
- Competitive inhibition of dihydrofolate
reductase
- Leads to decreased synthesis of purine
and pyrimidine bases
- most effective in S-phase

Folate Function
Folic acid
Dihydrofolate
Dihydrofolate reductase
(DHFR)

Tetrahydrofolate
Methotrexate
Purines

Thymidine

2) Antimetabolites, contd.
Resistance: develops due to decreased
uptake of the drug
- Methotrexate must be actively transported
into cells by a carrier-mediated process

Clinical indications: Generally limited to

lymphoma

2) Antimetabolites, contd.
Adverse effects: GI toxicity is most

common, also myelosuppression

Leucovorin: a folic acid derivative that acts

as an antidote to adverse effects of

methotrexate

3) Mitotic inhibitors
Mechanism of action: Bind to tubulin
- Inhibit mitosis in M phase
- Cell cycle phase-specific

Examples: Vinca alkaloids - Vincristine;

Taxanes - Paclitaxol

3) Mitotic inhibitors, contd.

Clinical indications: Lymphoma and
leukemia
Vincristine

is the drug of choice for

transmissible venereal tumors in the dog

Vincristine

is well-tolerated by cats

3) Mitotic inhibitors, contd.

Specific adverse effects:
Vincristine

can cause peripheral neuropathy

with long-term use

Irritating

if extravasated

3) Mitotic inhibitors, contd.

Paclitaxel: a taxane
Binds

to tubulin and stabilizes

microtubules, preventing normal cell
division

Traditional

adverse side effects included

serious hypersensitivity due to carrier, but
a water-soluble form now available
(Paccal Vet) that eliminates the problem.

Good for mast cell tumors

3) Mitotic inhibitors, contd.

Paclitaxel
Main mechanisms of resistance
- increased efflux, Multi-Drug
Resistance (MDR) phenotype
- altered interaction with microtubules

4) Platinum drugs
Examples: Cisplatin
Cisplatin

was developed at
Serendipitous discovery

Barnett Rosenberg

4) Platinum drugs, contd.

Mechanism of action: Heavy metal
compounds that crosslink DNA
- Inhibit DNA, RNA, and protein
synthesis
- Cycle nonspecific
Examples: Cisplatin and Carboplatin

4) Platinum drugs, contd.

Specific adverse effects:
Cisplatin is contraindicated in cats due to
risk of fatal pulmonary edema.
Carboplatin can be given safely in cats
Cisplatin is a powerful emetic
Nephrotoxicity with cisplatin, but not
carboplatin, is a major concern
Do not use cisplatin with needles/IV sets
with aluminum parts

4) Platinum drugs, contd.

Resistance: multiple mechanisms:
- Increased expression of DNA damage/repair
proteins
- Decreased uptake or increased efflux of the
drug
- Increased inactivation of drug
- Increase in antiapoptotic proteins

5) Antitumor antibiotics
Example: Doxorubicin
Mechanism(s) of action:
- intercalates in DNA
- inhibits topoisomerase II activity
- generates free radicals
- impairs DNA, RNA and protein synthesis
- cell cycle-specific

5) Antitumor antibiotics, contd.

Resistance: develops through MDR
(MultiDrug Resistance) proteins
Clinical indications: Lymphoma, leukemias
and a variety of carcinomas and sarcomas

5) Antitumor antibiotics, contd.

Specific adverse effects

Cardiotoxicity in the dog

- Free radicals damage myocardium
- Dexrazoxane has been used to lessen
cardiac effects (iron chelator: dramatic in
free radical formation)

Massive local tissue damage:

- if extravasation occurs

6) Molecular targeted therapy

Tyrosine Kinase Inhibitors
Toceranib

(Palladia)

and

Masitinib

(Kinavet)

inhibit

TK activity associated with kit,

platelet-derived growth factor receptor, and
(Vascular Endothelial GFR toceranib only)

Direct
GI

antitumor and antiangiogenic effects

toxicity is main adverse effect

specifically

veterinary drugs for dogs

6) Molecular targeted therapy

Targeted immunotherapy
Melanoma vaccine, DNA
Vaccine

(ONCEPT)

contains human DNA sequence for

tyrosinase, found only in melanocytes
Human tyrosinase seen as foreign by dog,
antibodies produced against it
Leads to destruction of cells containing
tyrosinase (i.e., cancerous melanocytes)

7) Miscellaneous agents
Corticosteroids: Prednisone and
Dexamethasone:
pain

relief and reduction of edema

direct

lymphocytotoxic effects in
lymphomas and lymphoid leukemias

bind

to steroid receptors, altering

transcription of specific genes
- such as those important in cellular growth and
proliferation

7) Misc. Agents: Steroids,

contd.
Side effects: muscle atrophy,
polydipsia and polyuria
Resistance: develops due to
receptors or inhibition of gene expression
changes

7) Miscellaneous agents cont.

L-Asparaginase
Some

tumor cells are incapable of

synthesizing asparagine and are
dependent on extracellular sources

L-asparaginase

hydrolyzes asparagine,
decreasing availability of this amino acid to
cells

Lymphoma,

lymphoid leukemias

Study guide suggestion

Drug name

Mechanism(s) of
action

Mechanism(s) of
resistance

Adverse
effects/toxicity