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.

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).