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298 Anticancer Drugs

Chemotherapy of Malignant Tumors

A tumor (neoplasm) consists of cells that proliferate independently of the body’s inherent “building plan.” A malignant tumor (cancer) is present when the tumor tissue destructively invades healthy surrounding tissue or when dislodged tumor cells form secondary tumors (metastases) in other organs. A cure requires the elimination of all malignant cells (curative therapy). When this is not possible, attempts can be made to slow tumor growth and thereby prolong the patient’s life or improve quality of life (palliative therapy). Chemotherapy is faced with the problem that the malignant cells are endogenous and almost lacking in specific metabolic properties.

Cytostatics (A) are cytotoxic substances that particularly affect proliferating or dividing (mitotic) cells. Rapidly dividing malignant cells are preferentially injured. Damage to mitotic processes not only retards tumor growth but also may initiate apoptosis (programmed cell death). Tissues with a low mitosis rate are largely unaffected; likewise, most healthy tissues. This, however, also applies to malignant tumors consisting of slowly dividing differentiated cells.

Tissues that have a physiologically high mitosis rate are bound to be affected by cytostatic therapy. Thus, typical adverse effects occur. Loss of hair results from injury to hair follicles; gastrointestinal disturbances, such as diarrhea, from inadequate replacement of enterocytes whose lifespan is limited to a few days; nausea and vomiting from stimulation of area postrema chemoreceptors (p.342); and lowered resistance to infection from weakening of the immune system (p.304). In addition, cytostatics cause bone marrow depression. Resupply of blood cells depends on the mitotic activity of bone marrow stem and daughter cells. When myeloid proliferation is arrested, the short-lived granulocytes are the first to be affected (neu-

tropenia), then blood platelets (thrombopenia) and, finally, the more long-lived erythrocytes (anemia). Infertility is caused by suppression of spermatogenesis or follicle maturation. Most cytostatics disrupt DNA metabolism. This entails the risk of a potential genomic alteration in healthy cells (mutagenic effect). Conceivably, the latter accounts for the occurrence of leukemias several years after cytostatic therapy (carcinogenic effect). Furthermore, congenital malformations are to be expected when cytostatics must be used during pregnancy (teratogenic effect).

Cytostatics possess different mechanisms of action.

Damage to the mitotic spindle (B). The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p.326) that arrest mitosis at metaphase by disrupting the assembly into spindle threads of microtubuli. These consist of the proteins α-and β-tubulin. Surplus tubuli are broken down, enabling the tubulin subunits to be recycled.

The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant, Vinca rosea), inhibit the polymerization of tubulin subunits into microtubuli. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms.

Paclitaxel, from the bark of the pacific yew (Taxus brevifolia), inhibits disassembly of microtubules and induces formation of atypical ones, and thus impedes the reassemblage of tubulins into properly functioning microtubules. Docetaxel is a semisynthetic derivative.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Chemotherapy of Malignant Tumors

299

A. Chemotherapy of tumors: principal and adverse effects

 

Malignant tissue

Cytostatics inhibit

Healthy tissue

with numerous mitoses

with few mitoses

cell division

 

 

Wanted effect:

 

Little effect

inhibition of

 

 

tumor growth

 

 

 

Healthy tissue with

Lymph node

 

numerous mitoses

 

 

 

Inhibition of

 

 

lymphocyte

Damage to hair follicle

 

multiplication:

 

immune

Hair loss

 

weakness

 

 

Lowered resistance

 

 

to infection

 

Unwanted effects

Bone marrow

 

 

 

 

Inhibition of

 

 

granulo-,

 

 

thrombocyto-,

Inhibition of

 

and erythropoiesis

ephithelial renewal

 

 

Diarrhea

Germinal cell damage

 

B. Cytostatics: inhibition of mitosis

 

 

Inhibition of

Microtubules

Inhibition of

of mitotic spindle

formation

 

degradation

Vinca alkaloids,

 

Taxoids,

e.g., vinblastine

 

e.g., paclitaxel

Vinca rosea

 

Western yew tree

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

300 Anticancer Drugs

Inhibition of DNA and RNA synthesis (A).

Mitosis is preceded by replication of chromosomes (DNA synthesis) and increased protein synthesis (RNA synthesis). Existing DNA (gray) serves as a template for the synthesis of new (blue) DNA or RNA. De-novo synthesis may be inhibited by the following mechanisms.

Damage to the template (1). Alkylating cytostatics are reactive compounds that transfer alkyl residues into a covalent bond with DNA. For instance, mechlorethamine (nitrogen mustard) is able to cross-link doublestranded DNA on giving off its chlorine atoms. Correct reading of genetic information is thereby rendered impossible. Other alkylating agents are chlorambucil, melphalan, thio-TEPA, cyclophosphamide, ifosfamide, lomustine, and busulfan. Specific adverse reactions include irreversible pulmonary fibrosis due to busulfan and hemorrhagic cystitis caused by the cyclophosphamide metabolite acrolein (preventable by the uro-protectant mesna = sodium 2-mer- captoethanesulfonate). The platinum-con- taining compounds cisplatin and carboplatin release platinum, which binds to DNA.

Cystostatic antibiotics insert themselves into the DNA double strand; this may lead to strand breakage (e.g., with bleomycin). The anthracycline antibiotics daunorubicin and adriamycin (doxorubicin) may induce cardiomyopathy. Bleomycin can also cause pulmonary fibrosis.

Induction of strand breakage may result from inhibition of topoisomerase. The epipodophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276); these agents cause strand breakage by inhibiting resealing. The “tecans” topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA.

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 274). The folate analogues aminopterin and methotrexate (amethopterin) inhibit enzyme activity. Cellular stores of THFare depleted. The effect of these antimetabolites can be reversed by administration of folinic acid (5-formyl-THF, leucovorin, citrovorum factor). Hydroxyurea (hydroxycarbamide) inhibits ribonucleotide reductase that normally converts ribonucleotides into deoxyribonucleotides subsequently used as DNA building blocks.

Incorporation of false building blocks (3).

Unnatural nucleobases (6-mercaptopurine; 5-fluorouracil) or nucleosides with incorrect sugars (cytarabine) act as antimetabolites. They inhibit DNA/RNA synthesis or lead to synthesis of missense nucleic acids.

6-Mercaptopurine results from biotransformation of the inactive precursor azathioprine (p.37). The uricostatic allopurinol (p.327) inhibits the degradation of 6-mer- captopurine such that coadministration of the two drugs requires dose reduction of the latter.

Combination therapy. Cytostatics are frequently administered in complex therapeutic regimens designed to improve ef cacy and tolerability of treatment.

Supportive therapy. Cancer chemotherapy can be supported by adjunctive medications. Thus, 5-HT3 serotonin receptor antagonists (e.g., ondansetron, p.342) afford effective protection against vomiting induced by highly emetogenic drugs such as cisplatin. Bone marrow depression can be counteracted by granulocyte and granulocyte/macrophage colony-stimulating factors (filgrastim and lenograstim and molgramostim, respectively).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Chemotherapy of Malignant Tumors

301

A.Cytostatics: alkylating agents and cytostatic antibiotics (1), inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3)

DNA

Damage

 

 

 

Cl

CH2

CH2

 

 

to template

 

 

 

 

 

 

 

 

 

 

 

 

 

Alkylation,

 

 

 

 

 

N

CH3

 

 

 

 

Cl

CH2

C

 

 

 

 

e.g., by

H2N

 

2

 

 

 

mechlorethamine

 

 

 

H

 

 

 

 

 

NH

Mechlorethamine

 

 

 

 

 

 

 

 

 

 

 

Pt

Binding

N

 

O

 

 

 

 

 

 

of platinum

 

 

 

 

 

 

 

 

 

Insertion

N

N+

CH2

CH2

 

CH3

 

 

 

 

 

N

 

 

 

into DNA, e.g.,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

doxorubicin

 

 

 

H2C

 

 

 

 

 

 

 

 

 

 

 

 

Induction of

 

 

 

H2C

+

N

 

 

strand breaks

 

 

 

 

 

N

 

 

Topoisomerase

 

 

 

 

O

 

N

 

 

inhibitors:

 

 

 

 

HN

 

 

epipodophyllo-

 

 

 

 

 

 

 

1

toxins, tecans

 

 

 

 

 

 

NH2

 

 

 

 

 

 

 

 

 

 

 

Inhibition of nucleotide synthesis

 

 

Building blocks

 

 

 

 

 

 

Purines

 

Tetrahydro-

Dihydrofolate

 

 

 

 

 

 

 

 

 

 

Thymine

 

folate

reductase

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

nucleotide

 

 

 

 

Folic acid

 

 

 

 

H2N

N

N

 

 

RNA

 

Inhibition by

 

N

N

 

 

 

 

 

CH2

N

 

 

 

 

 

 

 

 

 

OH

 

 

H

 

 

 

 

 

 

 

 

 

 

Methotrexate

 

NH2

 

CH3

 

2

 

 

 

 

 

 

 

DNA

DNA

 

Insertion of incorrect building blocks

 

Purine antimetabolite

 

 

 

 

 

 

SH

H

 

 

 

NH2

 

 

 

 

 

 

 

H

 

 

N

N

 

 

N

N

 

 

 

 

 

 

 

 

N

N

 

 

 

N

N

 

 

6-Mercaptopurine

instead of

Adenine

 

 

from azathioprine

 

 

 

 

 

 

Pyrimidine antimetabolite

 

 

 

 

 

 

5-Fluorouracil

instead of

Uracil

 

 

Cytarabine

Cytosine

 

 

Cytosine

 

 

3

 

Arabinose

instead of

Desoxyribose

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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