Chemotherapeutic Drugs

Chapter 29 Chemotherapeutic Drugs

I. General Considerations

• Cancer is a disease in which the cellular control mechanisms that govern proliferation and differentiation are changed.

A. Pathology of cancers (See Rapid Review Pathology)

B. Drugs used in cancer chemotherapy

1. Target important biosynthetic processes in proliferating cells (Fig. 29-1)

29-1 Sites of action of chemotherapeutic drugs.

Know the molecular targets of antineoplastic drugs.

2. Affect different stages of the cell cycle (Fig. 29-2)

a. Cell cycle-specific (CCS) drugs

(1) Antimetabolites

(3) Podophyllotoxins

(5) Vinca alkaloids

b. Cell cycle-nonspecific (CCNS) drugs

(1) Alkylating agents

(2) Anthracyclines

(3) Dactinomycin

(5) Platinum analogues

29-2 Cell cycle activity of anticancer drugs. Progress through the cycle is promoted by proteins called cyclins (A, B, D, E),which are controlled by the cyclin-dependent kinases.

(From Brenner G and Stevens C: Pharmacology, 3rd ed. Philadelphia, Saunders, 2010, Figure 45-1.)

Know CCS and CCNS antineoplastic agents.

C. Goals of cancer chemotherapy

1. Selectively destroy cancer cells

2. Minimize toxicity to normal cells

D. Adverse effects of chemotherapeutic drugs (Table 29-1)

1. Individual drugs have “signature” adverse effects

2. Common shared adverse effects

TABLE 29-1 Therapeutic Uses and Adverse Effects of Selected Drugs Used in Cancer Chemotherapy

Drug	Use: Type(s) of Cancer*	Important Adverse Effect(s)
Aminoglutethimide	Breast, prostate	Adrenal suppression, dizziness, rash
Anastrozole	Breast	Hot flashes
Bleomycin	Testicular, ovarian, cervical, thyroid	Pulmonary fibrosis; very little bone marrow toxicity
Busulfan	CML, polycythemia vera	Interstitial pulmonary fibrosis
Carmustine/lomustine	Brain	Leukopenia, thrombocytopenia, hepatotoxicity
Cisplatin	Head and neck, lung, testicular, cervical, thyroid, ovarian	Ototoxicity, severe nephrotoxicity, mild bone marrow suppression
Cyclophosphamide	Leukemias/lymphomas	Hemorrhagic cystitis, alopecia
Cytarabine	Leukemias	Bone marrow suppression, CNS toxicity, immunosuppression
Dactinomycin	Wilms’ tumor	Hepatotoxicity
Daunorubicin/doxorubicin	Acute leukemia, Hodgkin’s disease, breast and lung	Cardiomyopathy (daunorubicin)
Etoposide	Lung, testicular	Bone marrow suppression
5-Fluorouracil	Colon, stomach, prostate, breast	Bone marrow suppression, GI toxicity
Imatinib	CML, gastrointestinal stromal tumors	Fluid retention
Irinotecan	Colon	Bone marrow suppression
Leuprolide	Prostate, breast	Hot flashes
Melphalan	Multiple myeloma	Bone marrow suppression
6-Mercaptopurine	Leukemias	Bone marrow suppression
Methotrexate	Wilms’ tumor, choriocarcinoma, leukemias	Bone marrow suppression, oral and GI tract ulceration, diarrhea, hepatotoxicity^†
Paclitaxel	Breast, ovarian	Bone marrow suppression
Procarbazine	Hodgkin’s disease	Secondary malignancies, teratogenic
Tamoxifen	Breast	Hot flashes
Trastuzumab	Breast	Fever and chills
Vinblastine	Lymphomas	Bone marrow suppression
Vincristine	Acute lymphocytic leukemia	Neurotoxicity/peripheral neuropathy, low bone marrow suppression

CML, chronic myelogenous leukemia; CNS, central nervous system; GI, gastrointestinal.

* Not a complete list; for most cancers, drug combinations are used.

† Adverse effects, especially toxicity, may be reversed with folic acid (“leucovorin rescue”).

Learn the “shared” and “signature” adverse effects of antineoplastic agents.

a. Bone marrow suppression

b. Toxicity to mucosal cells of the gastrointestinal tract

(1) Nausea and vomiting

c. Toxicity to skin

d. Toxicity to hair follicles (hair loss)

e. Teratogenic effects

g. Immunosuppression (opportunistic infections)

Antineoplastic drugs are toxic to rapidly proliferating cells: bone marrow, GI, skin, hair follicles, reproductive organs.

3. Acute effects

a. Nausea and vomiting

(1) Most prominent acute effect

(2) Can cause dehydration, malnutrition, metabolic disorders

(3) Treat with antiemetics

(a) 5-HT₃ antagonists (ondansetron)

Ondansetron and other -setron drugs are used to treat the nausea and vomiting associated with anticancer drugs.

(b) Phenothiazines (prochlorperazine)

4. Delayed effects

a. Myelosuppression

(1) Usually leukopenia (neutropenia) and thrombocytopenia

(2) Risk of infection, bleeding

(3) Treat with:

(a) Granulocytic/monocytic colony stimulating factor (GM-CSF)

(b) Granulocytic colony stimulating factor (G-CSF)

(c) Oprelvekin (IL-11)

• Supports megakaryocytopoiesis

(d) Platelet transfusions

(e) Erythropoietin

• Supports erythropoiesis

Give growth factors to facilitate recovery of hematopoietic cells after dosing with antineoplastic drugs: Erythropoietin, GM-CSF, G-CSF, Oprelvekin.

(4) Gastrointestinal effects

(5) Alopecia (e.g., cyclophosphamide)

(6) Neuropathies (e.g., vicristine)

(7) Hand and foot syndrome (ex. fluorouracil)

Fluorouracil noted for causing hand-and foot syndrome.

(8) Know “signature” adverse effects of individual agents

E. Drug Resistant Mechanisms

1. Therapy selects for resistance

a. Can’t achieve total kill

b. Combination chemotherapy is the rule, not the exception

2. Primary resistance

a. Tumor cells initially not sensitive to a given drug

b. Test by in vitro sensitivity

3. Secondary resistance

a. Tumor cells develop resistance during therapy.

(1) Changes in drug permeability

(2) Amplification/alteration of targets

(3) Enhanced repair

(4) P-glycoprotein (Pgp, mdr1) can export multiple classes of anti-cancer drugs (multidrug resistance)

Extrusion of drugs from cancer cells by P-glycoprotein is one mechanism of multidrug resistance.

(a) Antimetabolites

(b) Antibiotics

(c) Plant alkaloids

b. Multi-drug resistance can be blocked by inhibition of transporters (ex. verapamil)

II. Drugs That Alter DNA ( Box 29-1)

A. Alkylating drugs

1. Cyclophosphamide

a. Mechanism of action

(1) Prodrug that requires activation by the cytochrome P-450 system (Fig. 29-3)

(a) Phosphoramide mustard (active)

(b) Acrolein (bladder cystitis)

(2) Cross-links DNA strands

29-3 Bioactivation of cyclophosphamide.

(From Wecker L, et al.: Brody’s Human Pharmacology, 5th ed. Philadelphia, Mosby, 2010, Figure 54-6.)

Bifunctional alkylating agents cross-link DNA strands.

(3) Stops DNA processing

(4) Cell cycle nonspecific (CCNS)

(1) Chronic lymphocytic leukemia (CLL)

(2) Acute lymphocytic leukemia (ALL)

(3) Non-Hodgkin’s lymphoma

(4) Multiple myeloma

(5) Breast cancer

(6) Ovarian cancer

(7) Lung cancer

Cyclophosphamide widely used as an anticancer and immunosuppressive drug.

(8) Immunologic disorders such as

(a) Lupus nephritis

(b) Nephrotic syndrome

(c) Wegener’s granulomatosis

(d) Rheumatoid arthritis

(e) Graft-versus-host disease or graft rejection

“Signature” adverse effect of cyclophosphamide: hemorrhagic cystitis treated with mesna

a. Mechanism of action

(1) Cross-links strands of DNA

(2) Inhibits protein and DNA synthesis

(1) Testicular cancer

(2) Used off label for several other cancers

a. Mechanism of action

(1) Cell cycle nonspecific (CCNS)

(2) Bifunctional alkylating agent

(1) Chronic granulocytic leukemia (drug of choice)

(2) Conditioning regimens for bone marrow transplantation

“Signature” adverse effect of busulfan: pulmonary fibrosis

4. Mechlorethamine

a. Mechanism of action

(1) Nitrogen mustard alkylating agent

(2) Cell cycle nonspecific (CCNS)

(1) Hodgkin’s disease

(2) Non-Hodgkin’s lymphoma (NHL)

(3) Mycosis fungoides

Mechlorethamine first used as a “War Gas” in World War I; very toxic to lungs

5. Chlorambucil

a. Mechanism of action

(1) Cross-links strands of DNA

(2) Interferes with DNA replication and RNA transcription

(1) Chronic lymphocytic leukemia (CLL)

(2) Hodgkin’s lymphoma

(3) Non-Hodgkin’s lymphoma (NHL)

a. Mechanism of action

(1) Cross-links strands of DNA

(2) Acts on both resting and rapidly dividing tumor cells

(1) Palliative treatment of multiple myeloma

Melphalan plus prednisone for multiple myeloma

(2) Nonresectable epithelial ovarian carcinoma

7. Nitrosoureas

a. Mechanism of action

(1) Cross blood-brain barrier (BBB)

The nitrosoureas are unique anticancer agents because they cross the blood-brain barrier.

(2) Cell cycle nonspecific (CCNS)

(3) Cross-links strands of DNA and RNA

(a) Primary and metastatic brain tumors

(b) Multiple myeloma

(c) Hodgkin’s disease (relapsed or refractory)

(d) Non-Hodgkin’s lymphomas (relapsed or refractory)

(e) Melanoma (off-label)

(a) Brain tumors

Carmustine and lomustine for brain tumors

(b) Hodgkin’s disease

(3) Streptozocin

(a) Metastatic islet cell carcinoma of the pancreas

Streptozocin used experimentally to create animal models of diabetes mellitus

(b) Carcinoid tumor and syndrome

(c) Hodgkin’s disease

(d) Palliative treatment of colorectal cancer

8. Platinum compounds

a. Mechanism of action

(1) Cross-links DNA stands or protein structures

(2) Inhibits DNA replication

(3) Inhibits RNA transcription

(4) Inhibits protein synthesis

(5) Cell cycle nonspecific (CCNS)

(a) Testicular cancer (in combination with vinblastine and bleomycin)

(b) Ovarian cancer

(c) Urinary bladder cancer

(d) Non-small cell lung cancer

(2) Carboplatin

(a) Ovarian cancer

(b) Several other cancers (off-label)

(3) Oxaliplatin

(a) Stage III colon cancer and advanced colorectal cancer

(b) Several other cancers (off-label)

c. Dose-limiting toxicities

(1) Cisplatin: Nephrotoxicity, ototoxicity

“Signature” adverse effects of cisplatin: nephrotoxicity (treated with amifostine), ototoxicity

(2) Carboplatin produces severe bone marrow suppression

“Signature” adverse effect of carboplatin is bone marrow toxicity.

(3) Oxaliplatin produces neurotoxicity

“Signature” adverse effect of oxaliplatin is neurotoxicity.

9. Bendamustine

a. Mechanism of action

(1) Alkylating structure (nitrogen mustard) linked to a purine structure

Bendamustine is a nitrogen mustard alkylating structure linked to a purine structure.

(2) Causes cell death via single and double strand DNA cross-linking

(3) Active against quiescent and dividing cells

(2) Progressed indolent B-cell NHL

10. Estramustine

a. Mechanism of action

(1) Nitrogen mustard linked to estradiol

Estramustine is a nitrogen mustard alkylating structure linked to estradiol.

(2) Antitumor effect due to an estrogenic effect

(3) Causes a marked decrease in plasma testosterone and increase in estrogen levels

• Palliative treatment of progressive or metastatic prostate cancer

a. Mechanism of action

(1) Alkylating agent that reacts with DNA phosphate groups

(2) Cross-links DNA strands

(3) Causes inhibition of DNA, RNA, and protein synthesis

(1) Superficial tumors of the bladder

(2) Palliative treatment of adenocarcinoma of breast or ovary

(3) Lymphomas and sarcomas

(4) Central nervous system (CNS) leukemia/lymphoma; CNS metastases (intrathecal)

12. Drugs related to alkylating agents

a. Procarbazine

(1) Used in the treatment of Hodgkin’s disease

MOPP (Mechlorethamine, vincristine [Oncovin], Procarbazine, and Prednisone) is used less today for Hodgkin’s disease because both procarbazine and mechlorethamine are amongst the most carcinogenic antineoplastic agents.

(2) Highly teratogenic

(3) Causes secondary malignancy

Procarbazine is highly carcinogenic.

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Tags: Rapid Review Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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