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 col-chicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vin-blastine (from the periwinkle plant, Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to micro tubule-operated axonal transport mechanisms.

Paclitaxel, from the bark of the pacific yew (Taxus brevifolia), inhibits disassembly of microtubules and induces atypical ones. Docetaxel is a semisyn-thetic derivative.

Effect Cytarabine Mitosis
A. Chemotherapy of tumors: principal and adverse effects
Etopos Los Mitosis
B. Cytostatics: inhibition of mitosis

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:

Damage to the template (1). Alky-lating cytostatics are reactive compounds that transfer alkyl residues into a covalent bond with DNA. For instance, mechlorethamine (nitrogen mustard) is able to cross-link double-stranded DNA on giving off its chlorine atoms. Correct reading of genetic information is thereby rendered impossible. Other alkylat-ing agents are chlorambucil, melphalan, thio-TEPA, cyclophosphamide (p. 300, 320), ifosfamide, lomustine, and busul-fan. Specific adverse reactions include irreversible pulmonary fibrosis due to busulfan and hemorrhagic cystitis caused by the cyclophosphamide metabolite acrolein (preventable by the uroprotectant mesna). Cisplatin binds to (but does not alkylate) DNA strands. 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 (doxorubi-cin) may induce cardiomyopathy. Ble-omycin can also cause pulmonary fibro-sis.

The epipodophyllotoxins, etopo-side and teniposide, interact with topo-isomerase II, which functions to split, transpose, and reseal DNA strands (p. 274); these agents cause strand breakage by inhibiting resealing.

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. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed by administration of folinic acid (5-for-myl-THF, leucovorin, citrovorum factor).

Incorporation of false building blocks (3). Unnatural nucleobases (6-mercaptopurine; 5-fluorouracil) or nucleosides with incorrect sugars (cytara-bine) 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 allo-purinol inhibits the degradation of 6-mercaptopurine such that co-administration of the two drugs permits dose reduction of the latter.

Frequently, the combination of cy-tostatics permits an improved therapeutic effect with fewer adverse reactions. Initial success can be followed by loss of effect because of the emergence of resistant tumor cells. Mechanisms of resistance are multifactorial:

Diminished cellular uptake may result from reduced synthesis of a transport protein that may be needed for membrane penetration (e.g., metho-trexate).

Augmented drug extrusion: increased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipo-dophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance (mdr-1 gene amplification).

Diminished bioactivation of a pro-drug, e.g., cytarabine, which requires intracellular phosphorylation to become cytotoxic.

Change in site of action: e.g., increased synthesis of dihydrofolate re-ductase may occur as a compensatory response to methotrexate.

Damage repair: DNA repair enzymes may become more efficient in repairing defects caused by cisplatin.

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