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300 Anticancer Drugs Luellmann, Color Atlas of Pharmacology © 2005 Thieme All Rights Reserved. Usage Subject to Terms and Condi Luellmann, Color Atlas of Pharmacology © 2005 Thieme 300 Anticancer Drugs Inhibition of DNA and RNA synthesis (A). Inhibition of nucleobase synthesis (2). Tet- Mitosis is preceded by replication of chro- rahydrofolic acid (THF) is required for the mosomes (DNA synthesis) and increased synthesis of both purine bases and thymi- protein synthesis (RNA synthesis). Existing dine. Formation of THF from folic acid in- DNA(gray)servesasatemplateforthesyn- volves dihydrofolate reductase (p. 274). The thesis of new (blue) DNA or RNA. De-novo folate analogues aminopterin and methotrex- synthesis may be inhibited by the following ate (amethopterin) inhibit enzyme activity. mechanisms. Cellular stores of THF are depleted. The effect of these antimetabolites can be reversed by Damagetothetemplate(1).Alkylating cy- administration of folinic acid (5-formyl-THF, tostatics arereactivecompoundsthattrans- leucovorin, citrovorum factor). Hydroxyurea fer alkyl residues into a covalent bond with (hydroxycarbamide) inhibits ribonucleotide DNA. For instance, mechlorethamine (nitro- reductase that normally converts ribonu- gen mustard) is able to cross-link double- cleotides into deoxyribonucleotides subse- stranded DNA on giving off its chlorine quently used as DNA building blocks. atoms. Correct reading of genetic informa- tion is thereby rendered impossible. Other Incorporation of false building blocks (3). alkylating agents are chlorambucil, mel- Unnatural nucleobases (6-mercaptopurine; phalan, thio-TEPA, cyclophosphamide, ifos- 5-fluorouracil) or nucleosides with incorrect famide, lomustine,andbusulfan. Specific sugars (cytarabine) act as antimetabolites. adverse reactions include irreversible pul- They inhibit DNA/RNA synthesis or lead to monary fibrosis due to busulfan and hemor- synthesis of missense nucleic acids. rhagic cystitis caused by the cyclophospha- 6-Mercaptopurine results from biotrans- mide metabolite acrolein (preventable by formation of the inactive precursor azathio- the uro-protectant mesna = sodium 2-mer- prine (p. 37). The uricostatic allopurinol captoethanesulfonate). The platinum-con- (p. 327) inhibits the degradation of 6-mer- taining compounds cisplatin and carbopla- captopurine such that coadministration of tin release platinum, which binds to DNA. thetwodrugsrequiresdosereductionof Cystostatic antibiotics insert themselves the latter. into the DNA double strand; this may lead to strand breakage (e. g., with bleomycin). The Combination therapy. Cytostatics are fre- anthracycline antibiotics daunorubicin and quently administered in complex therapeu- adriamycin (doxorubicin) may induce cardio- tic regimens designed to improve ef cacy myopathy. Bleomycin can also cause pul- and tolerability of treatment. monary fibrosis. Induction of strand breakage may result Supportive therapy. Cancer chemotherapy from inhibition of topoisomerase. The epi- can be supported by adjunctive medications. podophyllotoxins etoposide and tenoposide Thus, 5-HT3 serotonin receptor antagonists interact with topoisomerase II, which func- (e. g., ondansetron, p. 342) afford effective tions to split, transpose, and reseal DNA protection against vomiting induced by strands (p. 276); these agents cause strand highly emetogenic drugs such as cisplatin. breakage by inhibiting resealing. The “te- Bone marrow depression can be counter- cans” topotecan and irinotecan are deriva- acted by granulocyte and granulocyte/mac- tivesofcamptothecinfromthefruitsofa rophage colony-stimulating factors (filgras- Chinesetree(Camptotheca acuminata). They tim and lenograstim and molgramostim, re- inhibit topoisomerase I, which induces spectively). breaks in single-strand DNA. Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. Luellmann, Color Atlas of Pharmacology © 2005 Thieme Chemotherapy of Malignant Tumors 301 A. Cytostatics: alkylating agents and cytostatic antibiotics (1), inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3) DNA Damage Cl CH CH to template 2 2 NCH3 Alkylation, e.g., by Cl CH2 C 2 H2N mechlorethamine MechlorethamineH NH Pt Binding N O of platinum NN+ Insertion CH2 CH2 CH3 into DNA, e.g., N doxorubicin H2C Induction of H2C + NN strand breaks Topoisomerase inhibitors: O N epipodophyllo- HN toxins, tecans 1 NH2 Inhibition of nucleotide synthesis Building blocks Purines Tetrahydro- Dihydrofolate folate reductase Thymine nucleotide Folic acid H2N NN RNA N Inhibition by N CH2 N OH H Methotrexate NH2 CH3 2 DNA DNA Insertion of incorrect building blocks Purine antimetabolite SH NH2 H 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 Arabinose instead of Desoxyribose 3 Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. 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