15. Principles of Anti-cancer Therapy

Principles of Cancer Chemotherapy

Cancer chemotherapy → lethal cytotoxic event/_________ in the cancer cells → ______ a tumor’s progression. Ideally, these anti-cancer drugs should interfere only with _________ __________ that are unique to __________ cells. Most currently available drugs do not specifically recognize _________ cells but, rather, affect all kinds of _____________ cells (normal and abnormal). Therefore, almost all anti-tumor agents have a _____ dose-response curve for both therapeutic and toxic effects.

• apoptosis

• arrest

• cellular processes

• malignant

• neoplastic

• proliferating

• steep

List the clinical settings for chemotherapy.

1. Primary induction treatment

2. Neo-adjuvant treatment

3. Adjuvant treatment

4. Combined modality approach

Clinical Settings for Chemotherapy

What is primary induction treatment used for?

Advanced cancers with no other effective treatment

Clinical Settings for Chemotherapy

What is the goal of neo-adjuvant therapy?

To reduce size of primary tumor for easy surgical resection

Clinical Settings for Chemotherapy

What is adjuvant therapy and what is its goal?

• Chemotherapy is administered after surgery/radiotherapy has been performed

• Goal is to reduce incidence of both local and systemic recurrence

Clinical Settings for Chemotherapy

Describe combined modality approach.

Anticancer drugs are used in conjunction with surgery, radiotherapy, and immunotherapy for many solid tumors, especially metastatic

List the goals of cancer chemotherapy.

1. To cure cancer

2. Prolong remission (i.e. disease-free period)

3. Palliation: shrinkage of tumor, alleviation of symptoms, prolongation of life-span

4. As adjuvant therapy following surgery or radiotherapy

List the options for cancer treatment.

1. Surgery

2. Radiation therapy

3. Chemotherapy

4. Biologic therapy (immunotherapy, antibodies, targeted therapies)

What are the 2 categories of chemotherapeutic agents?

1. Cell cycle specific drugs (act on specific phase of dividing cells)

2. Cell cycle non-specific drugs (act in all phases)

Many of the effective anti-cancer drugs exert their action on cells __________ the cell cycle and are called cell cycle-specific (CCS) drugs. A second group of agents called cell cycle non-specific (CCNS) drugs can _________ tumor cells, whether they are _______ or _______ in the G₀ compartment. They can kill both G₀ and cycling cells, but _______ cells are more ________.

• traversing

• sterilize

• cycling

• resting

• cycling

• sensitive

What are cell cycle specific drugs effective for?

High-growth fraction malignancies, such as hematological cancers

What are cell cycle non-specific drugs effective for?

Both low-growth (solid tumors) and high-growth fraction malignances

List cell cycle specific drugs.

1. Antimetabolites

2. Bleomycin

3. Vinca alkaloids

List cell cycle non-specific drugs.

1. Alkylating agents

2. Antibiotics (Dactinomycin)

3. Cisplatin

Resistance

Some neoplastic cells are __________ resistant to most anticancer drugs. Other tumor types may _______ resistance. How do they do this?

• inherently

• acquire

1. Mutating

2. Reduced cellular drug uptake

3. Use of alternative metabolic pathways

4. Increased activation of drug compound within the cancer cell

5. Reduced activation of prodrugs

How is development of drug resistance minimized?

• Minimized by short-term intensive, intermittent therapy with combinations of drugs

• Drug combinations are effective against a broader range of resistant cells in the tumor population

What other forms of drug resistance can occur in cancer?

• Multidrug resistance

• Cross-resistance - following use of structurally unrelated agents

List the toxic effects of anticancer drugs.

1. Bone marrow depression

2. Lymphocytopenia: decreased immunity, repeated infections

3. GIT: stomatitis (inflammation of mouth and lips), diarrhoea, nausea, vomiting

4. Alopecia (hair loss)

5. Hyperuricemia

6. Generalized edema due to corticosteroids

List the advantages/indications for combination chemotherapy.

1. May be curative for small tumors

2. Adjuvant therapy after radiotherapy or surgery

3. Drug resistance avoided

4. Less individual drug toxicity

5. May be administered in pulses (3 monthly); CCS drugs administered in short courses (pulses) of treatment; 2-5 drugs administered in intermittent pulses to achieve total tumor cell kill; allows bone marrow to recover

List and describe how anticancer drug toxicity is managed.

1. Combination therapy: cytotoxic agents w/qualitatively different toxicities, and w/different molecular sites and mechanisms of action, are usually combined at full doses; results in higher response rates, due to additive and/or potentiated cytotoxic effects and non-overlapping host toxicities

2. Pulse therapy rather than continuous therapy: decreases exposure to drugs

3. Recruitment therapy: increases cellular immunity

4. Rescue therapy: replenishing deficiencies due to therapy, to avoid adverse effects of cytotoxic drugs

List the drugs used for rescue therapy/correcting adverse effects.

1. Folinic acid

2. Acetylcysteine

3. Ondansetron

4. Allopurinol

5. Bisphosphonates

Rescue Therapy

Describe folinic acid.

• Methotrexate (Mtx) exerts major toxicity on bone marrow

• Low doses of Mtx given repeatedly can cause megaloblastic anemia

• Folinic acid rapidly reverses the effects

Rescue Therapy

Describe acetylcysteine.

Expectorant to expel dead cells from respiratory tract

Rescue Therapy

Describe ondansetron.

Anti-emetic agent (5-HT3 receptor antagonist) to combat vomiting

Rescue Therapy

Describe allopurinol.

Anti-gout drug; to excrete uric acid generated by cell lysis

Rescue Therapy

Describe bisphosphonates.

For osteoporosis by corticosteroids