Abstract
Cytotoxic drugs were the first class of drugs used to effectively treat neoplasms. Nitrosourea was the first drug developed. These drugs target DNA or metabolic steps which are crucial for cell division, thus leading to apoptosis (cytotoxic). They are broadly classified as alkylating agents, antimetabolites, natural products, and miscellaneous drugs. Alkylating agents cause interstrand linking of DNA through alkylation. Platinum compounds also cause inter- and intra-strand linkage but by forming DNA adducts. Antimetabolites act by inhibiting purine, pyrimidine, or both syntheses. Natural products include microtubule-damaging drugs like vinca alkaloids and taxanes; camptothecins and epipodophyllotoxins—which act by interfering with topoisomerase function; and anti-tumour antibiotics—which cause breaks in DNA strands. Miscellaneous group includes drugs with an entirely different mechanism, for example, tretinoin (ATRA) and arsenic trioxide (ATO) induce cell differentiation. There are many newer analogues in each class of drugs. The essential pharmacokinetic parameters and important indications which help to differentiate between these analogues are presented in the chapter. Though cytotoxic chemotherapy has offered hope to patients, the use of these drugs is accompanied by a number of adverse drug reactions (ADRs) mainly due to their action on normal rapidly dividing cells of our body. Currently targeted chemotherapy has gained importance in research due to their lesser incidence of ADRs.
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1 Introduction
Cytotoxic drugs belong to the group of anticancer drugs which drive the cell into apoptosis, causing arrest in tumour progression. Hence, they target the DNA or metabolic pathways which are important for cell replication. Also, these targets should be unique in malignant cells or else it will result in toxicity due to attacks on the normal cell pathways. Nitrosourea was the first anticancer drug developed in 1898.
The U.S. army had played an important role in the development of nitrogen mustards (mechlorethamine). They derived it from the mustard gases used in the First World War. Studies of Goodman and Gilman in mouse lymphoma and clinical studies started the era of modern chemotherapy.
2 Classification and Mechanism of Action
Cytotoxic drugs can broadly be classified as below:
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Alkylating agents and platinum compounds
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Antimetabolites
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Natural products
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Miscellaneous
2.1 Alkylating Agents
The classification of alkylating agents is given in Box 63.1.
Box 63.1 Classification of Alkylating Agents
Alkylating agents | |
---|---|
Nitrogen mustards | Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine |
Ethyleneimines | Altretamine (hexamethylmelamine), thiotepa |
Alkyl sulfonates | Busulfan |
Nitrosoureas | Carmustine (BCNU), lomustine, streptozocin |
Triazenes | Dacarbazine (DTIC), temozolomide |
Methylhydrazines | Procarbazine |
Platinum compoundsa | Cisplatin, carboplatin, oxaliplatin |
Although platinum complexes are not true alkylating agents, they are discussed with this group because of the similarities in its mechanism of action and resistance with alkylating agents.
Mechanism of action of alkylating agents:
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Form reactive carbonium intermediates which covalently link to sites of high electron density (alkylation).
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Bifunctional alkylating agents mostly bind to N7 atom of guanine (key target).
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Cross-linking of two nucleic acid chain occurs (interstrand linking).
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This results in cytotoxic and mutagenic effects in the cell.
Mechanism of action of platinum compounds:
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Form covalent metal adducts with DNA rather than alkylation like with alkylating agents; results in inter- and intra-strand linking.
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Enter cell through Cu transporter CTR1 and extruded via ATB7A/B and MRP1 transporters.
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Aquation occurs in cell resulting in the development of positive charge which reacts with nucleophilic sites in DNA.
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Low chloride favours aquation in cell and urine—hence, Cl diuresis prevents nephrotoxicity.
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Cytotoxicity depends on the intact mismatch repair (MMR) system which leads to single and double strand breaks.
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Oxaliplatin however does not depend on MMR system; hence, it shows better activity in colorectal cancer. It shows less dependence on high mobility group box (HMG) proteins unlike other platinum compounds, so forms fewer DNA adducts (lesser side effects).
2.2 Antimetabolites
The classification of antimetabolites is given in Box 63.2.
Box 63.2 Classification of Antimetabolites
Antimetabolites | |
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Folic acid analogues/antagonists | Methotrexate, pemetrexed, pralatrexate, raltitrexed, lometrexol |
Pyrimidine analogues | 5-fluorouracil, capecitabine, floxuridine, trifluridine |
Cytidine analogues | Cytarabine, azacitidine, gemcitabine |
Purine analogues | 6-thiopurine analogues (6-mercaptopurine, 6-thioguanine), cladribine, pentostatin, clofarabine, nelarabine, fludarabine |
2.2.1 Mechanism of Action
2.2.1.1 Folate Analogues/Antagonists
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Drugs like methotrexate are structural analogue of folic acid and block dihydrofolate reductase (DHFR) and thus preventing the activation of folic acid.
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The active form is involved in carbon transfer reactions required for purine and pyrimidine synthesis. In the cell, methotrexate undergoes addition of polyglutamates; this form has additional inhibitory action and inhibits thymidylate synthase and other two enzymes in purine synthesis pathway (Fig. 63.1).
2.2.1.2 Pyrimidine Analogues
5-Fluorouracil (5-FU) gets converted to fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase by competing with deoxyuridine monophosphate, thus inhibiting DNA synthesis. In addition 5-FU converts to fluorouridine triphosphate (FUTP) and gets incorporated into RNA (Fig. 63.2).
2.2.1.3 Cytidine Analogues
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Cytarabine—Drug enters via ENT1 and phosphorylation phosphorylates to arabinosylcytosine triphosphate (Ara-CTP). It competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA and inhibits DNA polymerase in replication and repair.
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Azacitidine—It covalently binds to DNA methyltransferases and causes global demethylation leading to differentiation and apoptosis.
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Gemcitabine—In addition to ENT1, it uses CNT1 and a nucleobase transporter and has cytotoxic activity which is not confined to S phase.
2.2.1.4 Purine Analogues
6-Thioguanine (6TG) and 6-mercaptopurine (6MP) inhibit conversion of IMP to adenine and guanine nucleotides as well as inhibit the de novo pathway. 6-TG nucleotide gets incorporated into DNA and induces strand breaks and base mispairing (Fig. 63.3).
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Fludarabine—The active triphosphate inhibits RNA processing in addition to DNA.
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Cladribine—It produces DNA strand breaks and inhibits RNR (ribonucleotide diphosphate reductase). This drug is cytotoxic even if the cell is not in active division.
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Clofarabine is a newer congener that has better stability and uptake.
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Nelarabine—It is the only guanine nucleotide. Action is similar to other purine analogues.
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Pentostatin—It acts by inhibiting adenosine deaminase (ADA). This causes accumulation of intracellular adenosine and deoxyadenosine nucleotides which in turn block DNA synthesis.
2.3 Natural Products and Miscellaneous Drugs
The classification of natural products and miscellaneous drugs is given in Box 63.3.
Box 63.3 Classification of Natural Products and Miscellaneous Drugs
Natural products | ||
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Microtubule-damaging agents | Vinca alkaloids | Vincristine, vinblastine, vinorelbine |
Eribulin | ||
Taxanes | Paclitaxel, docetaxel | |
Estramustine | ||
Epothilones | ||
Camptothecin analogues | Topotecan, irinotecan | |
Epipodophyllotoxins | Etoposide, teniposide | |
Anticancer antibiotics | Dactinomycin, anthracyclines (doxorubicin, daunorubicin, idarubicin, mitoxantrone, epirubicin, valrubicin), mitomycin, bleomycin | |
Miscellaneous | L-asparaginase, mitotane, trabectedin, hydroxyurea, retinoids, arsenic trioxide |
2.3.1 Mechanism of Action
2.3.1.1 Microtubule-Damaging Agents
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Vinca alkaloids
Cell-cycle specific (CCS) agents similar to taxanes and epothilones block cell in mitosis. They bind specifically to β tubulin and block its polymerisation with alpha-tubulin. Thus, the mitotic spindle does not form and the cell gets arrested in metaphase. Eribulin also binds to same site and prevents microtubule assembly. Estramustine binds to beta-tubulin and prevents disassembly (Fig. 63.4).
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Taxanes bind to a different site on beta-tubulin and inhibit microtubule disassembly and hence, cell cycle is arrested in mitosis.
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Epothilones
Bind to a distinct site on beta-tubulin and cause microtubule nucleation at different sites (dysfunctional stabilisation) which causes cell cycle arrest at G2-M interface.
2.3.1.2 Camptothecin Analogues
These are S phase specific. Inhibit topoisomerase 1 and inhibit the re-ligation step, thus causing accumulation of single stranded breaks. Collision of DNA replication fork with cleaved strand leads to double strand breaks (Fig. 63.5).
2.3.1.3 Epipodophyllotoxins
These drugs make ternary complexes with topoisomerase II and DNA, hence preventing resealing of the break. S and G2 phase are the most sensitive phases (Fig. 63.5).
2.3.1.4 Anticancer Antibiotics
These are cell cycle non-specific except for bleomycin. These agents intercalate with DNA disrupting its function and also generate free radicals, which exert other cytotoxic action.
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Dactinomycin—It is one among the most potent anti-tumour agent known. It intercalates between adjacent guanine–cytosine base pairs along minor groove and blocks transcription of DNA by RNA polymerase. It also makes single strand breaks by free radical intermediate or topoisomerase II function.
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Anthracyclines—Form complex with topoisomerase II and DNA, inhibiting re-ligation leading to apoptosis. They also form free radical intermediates that oxidise DNA bases leading to apoptosis. Mitoxantrone has structural similarity and less cardiotoxic than other anthracyclines.
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Bleomycin—It is a mixture of bleomycins A2 and B2. It generates free radicals which open deoxyribose at 3′ position producing single and double stranded breaks in DNA (Fig. 63.6).
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Mitomycin—It undergoes intracellular enzymatic or spontaneous chemical alteration to bifunctional or trifunctional alkylating agents. These form cross-links between adenine (N6) and guanine (O6 and N7) leading to inhibition of DNA synthesis.
2.3.1.5 Miscellaneous
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Mitotane—Chemically similar to dichlorodiphenyltrichloroethane (DDT). Its mechanism is not well known. It causes selective destruction of adrenocortical cells.
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Trabectedin—It acts as alkylating agent and forms DNA adducts. This is recognised by the NER complex and leads to double strand break in the attempt to repair it.
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L-Asparaginase—Leukemic lymphocytes lack enough asparaginase synthase for L asparagine. Hence, it obtains the amino acids from plasma. L-asparaginase catalyses the hydrolysis of amino acids in the plasma, thus leading to cell death.
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Hydroxyurea (HU)—It inhibits the enzyme ribonucleotide reductase (RNR) which catalyses the conversion of ribonucleotides to deoxyribonucleotides. The drug is specific for S phase of cell cycle.
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Tretinoin (ATRA) and arsenic trioxide (ATO)—Induce differentiation of cells. ATO is also cytotoxic by increasing the concentration of ROS in leukemic cells.
3 Indications and Pharmacokinetics
Table 63.1 summarises the important indications and pharmacokinetics of cytotoxic drugs used in cancer treatment.
4 Adverse Drug Reactions (ADRs)
Common ADRs to cytotoxic drugs—nausea, vomiting, alopecia, mucositis, stomatitis, and myelosuppression.
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Methotrexate (high dose or chronic therapy) given with folinic acid reduces risk of myelosuppression, mucositis, and alopecia.
Figure 63.7 gives the risk of myelosuppression associated with various drugs
A few examples of adverse reactions characteristic of each drug are given in Table 63.2.
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Benjamin, B. (2021). Cytotoxic Drugs. In: Paul, A., Anandabaskar, N., Mathaiyan, J., Raj, G.M. (eds) Introduction to Basics of Pharmacology and Toxicology. Springer, Singapore. https://doi.org/10.1007/978-981-33-6009-9_63
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