Table 48.9: Summary

Table 48.9: Summary of the clinical pharmacology of the vinca alkaloids DNA TOPOISOMERASE II INHIBITORS A component of the cytotoxic action of anthracyclines (e.g. doxorubicin, see above) is due to inhibition of DNA topoisomerase II. Etoposide and teniposide, synthetic derivatives of podophyllotoxin (which is extracted from the American mandrake or May apple, and is topically effective against warts), are also reversible inhibitors of topoisomerase II. ETOPOSIDE Uses Etoposide is one of the most active drugs against small-cell lung cancer and is used in combination therapy. It is also used to treat lymphomas, testicular and trophoblastic tumours. Mechanism of action DNA topoisomerase II is a nuclear enzyme that binds to and cleaves both strands of DNA. It is necessary for DNA replication and RNA transcription. Etoposide stabilizes the topoisomerase II–DNA complex, leading to apoptosis, as for camptothecins. Adverse effects These include the following: • nausea and vomiting; • alopecia; • bone marrow suppression (dose-dependent and reversible). Pharmacokinetics Etoposide is given by intravenous injection or orally (50% bioavailability). It undergoes hepatic metabolism (CYP3A) to inactive metabolites and a small amount is eliminated in the urine. MICROTUBULAR INHIBITORS (VINCA ALKALOIDS AND TAXANES) VINCA ALKALOIDS The Madagascar periwinkle plant was the source of vincristine and vinblastine, the first agents in this class. Newer synthetic DRUGS USED IN CANCER CHEMOTHERAPY 379 Drug Route Side effects Pharmacokinetics Additional comments Vincristine i.v. Vesicant if extravasated, Hepatic metabolism (CYP3A4). reversible peripheral neuropathy, alopecia, SIADH t1/2 � 85 h, non-linear kinetics Vinblastine i.v. Less neurotoxic, but more Hepatic metabolism (CYP3A4) – active myelo-suppressive than vincristine, SIADH metabolite, t1/2 � 24 h Vinorelbine i.v. injection Bone marrow suppression, Hepatic metabolism (CYP3A4), Refractory breast and or infusion, weekly SIADH t1/2 � 30–40 h advanced lung cancer SIADH, syndrome of inappropriate antidiuretic hormone. analogues include vinorelbine. Despite their close structural relationship, these drugs differ in their clinical spectrum of activity and toxicity. Vincristine is used in breast cancer, lymphomas and the initial treatment of acute lymphoblastic leukaemia. Vinblastine is a component of the cytotoxic combinations used to treat testicular cancer and Hodgkin’s disease. Vinorelbine has activity against advanced breast cancer and non-small-cell lung cancer, where it is often combined with platinum compounds. Mechanism of action Vinca alkaloids bind to β-tubulin, a protein that forms the microtubules which are essential for the formation of the mitotic spindle. They prevent β-tubulin polymerizing with α-tubulin and thus inhibit mitosis. Blockade of microtubular function involved in neuronal growth and axonal transport probably accounts for their neurotoxicity. Further important clinical pharmacology of vinca alkaloids is summarized in Table 48.9. Key points Practical ‘do’s and don’ts’ of cytotoxic therapy • Patients should have recovered fully from the toxic effects of the previous cycles of cytotoxic therapy before starting the next treatment cycle. • Ensure that the dose and schedule of certain drugs is adjusted for concurrent renal and hepatic impairment. • Avoid the concomitant use of platelet-inhibiting drugs. • Haematopoietic growth factors (for myelosuppression) reduce the duration of the nadir neutropenia, but should not be prescribed routinely. TAXANES PACLITAXEL AND DOCETAXEL Uses Paclitaxel (Figure 48.7) was derived from the bark of the Pacific yew tree and is used as single agent or in combination therapy for the treatment of a broad range of solid tumours, including carcinoma of the lung, breast, ovary and cervix and head and neck tumours, and for lymphomas. Paclitaxel is given intravenously.

380 CANCER CHEMOTHERAPY (a) (b) (c) Mechanism of action Paclitaxel binds to the β-subunit of tubulin and antagonizes the depolymerization of microtubules, halting mitosis. Cells are blocked in the G 2/M phase of the cell cycle and undergo apoptosis. Adverse effects These include the following: • hypersensitivity reactions; • bone marrow suppression (dose-dependent and reversible); • myalgias and arthralgias; • sensory peripheral neuropathy; • cardiac dysrhythmias; • nausea and vomiting; • alopecia. Pharmacokinetics Paclitaxel is poorly absorbed orally and requires intravenous administration. It is inactivated by hepatic CYP450 and �5% of the parent drug is excreted in the urine. The dose should be reduced in hepatic dysfunction. Docetaxel is a semi-synthetic taxane derivative with a similar anti-tumour spectrum as paclitaxel. It causes myelosuppression and peripheral fluid retention, but less cardio- and neurotoxicity than paclitaxel. MOLECULARLY TARGETED AGENTS This recently developed family of compounds is grouped together because they were developed to target specific molecules or cellular processes on or within the malignant cell. It is likely this heterogeneous group of compounds will O O�C 2‘CHOH HC N H grow considerably, as much research is being undertaken in tumour biology and defining targets. The agents discussed here include tyrosine kinase inhibitors (TKIs) (e.g. imatinib, gefitinib and erlotinib), multi-targeted TKIs (sorafenib, sunitinib), proteasome inhibitors (bortezomib) and histone deacetylase inhibitors (vorinostat). Several of these drugs have yet to be licensed in the UK or Europe, but it is important to be aware of them as they are important advances in what had, until recently, been a rather static area of therapeutics. TYROSINE KINASE INHIBITORS (TKIS) Tyrosine kinases are critical components of many signal transduction pathways. They signal from the cell membrane or cytoplasm to the nucleus-modulating DNA synthesis and gene transcription. There are approximately 500 protein tyrosine kinases coded in the human genome. They are classified into tyrosine kinases, serine-threonine kinases and tyrosineserine-threonine kinases. The tyrosine kinases are further subdivided into non-receptor tyrosine kinases and receptor tyrosine kinases. Abnormal activity of tyrosine kinases was found in many cancers and this has proven a useful drug target (Figure 48.8). NON-RECEPTOR TYROSINE KINASE INHIBITORS (CYTOPLASMIC TKIS) IMATINIB Uses Imatinib mesylate is primarily used to treat Philadelphiapositive chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumours (GIST). It is administered orally on a daily basis. Initial response rates are high, but after 12 months of therapy about 90% of CML patients develop drug-resistant clones. 13 12 HO 5‘C�O OCOCH 3 10 9 11 OC O O 8 OH 7 O H OCOCH 3 Figure 48.7: Taxus brevifolia (a, b), the source of paclitaxel. The chemical structure is shown in panel (c). ((a) Source: Pacific Yew (Taxus brevifolia) O’Daniel Tigner, Canadian Forest Tree Essences, provided courtesy of Tree Canada Foundation. (b) © Natural History Museum, London. Reproduced with permission.)