MECHLORETHAMINE (NITROGEN MUSTARD, MUSTINE)
Mechlorethamine is administered intravenously, and has a half-life of approximately 3 minutes due to rapid hydroly-sation. It has extremely vesicant properties, and can also cause severe phlebitis and sclerosis of the vein used. The major use is in the treatment of Hodgkin’s disease, as part of the combination MOPP (nitrogen mustard, vincristine, procarbazine and prednisolone). It is also occasionally administered by direct intra-cavity infusion for the treatment of malignant effusions.
MELPHALAN
Melphalan is another bifunctional alkylating agent, and is a phenylalanine derivative of mechlorethamine. It is active against a broad cross-section of tumours (lymphomas, breast and ovarian cancers, multiple myeloma) and can be administered orally, intravenously or intraperitoneally. Although the oral bioavailability is variable, with 20-50 per cent being excreted in the stool, the ease of oral administration makes this the most common route employed. It routinely causes myelosuppression, with nadir counts occurring at 4-5 weeks following a short, 7-day, oral course. Doses require to be adjusted according to the level of myelosuppression. It is also used in high-dose chemotherapy regimens for haematological malignancies and multiple myeloma, due to exponential cell killing demonstrated in cell culture. Occasionally, it is used intraperitoneally for relapsed ovarian cancer, although efficacy data are not well established.
CHLORAMBUCIL
This bifunctional alkylating agent is a benzene butanoic derivative of mechlorethamine, and is also a close structural congener of melphalan. It is almost completely absorbed when given by the oral route, and is used either continuously or intermittently for long periods in low-grade lymphoma, chronic lymphocytic leukaemia and multiple myeloma. It can also be given to elderly patients with ovarian cancer who are unable to tolerate more aggressive chemotherapy. The toxicity is predictable myelosuppression, which makes dose adjustments fairly straightforward. However, stem-cell damage is cumulative and irreversible, leading to problems of severe myelosuppression with subsequent cytotoxic drug use. Longer-term use (e.g. 1 year) has been associated with pulmonary toxicity and the development of second malignancies.
OXAZAPHOSPHORINES (CYCLOPHOSPHAMIDE AND IFOSFAMIDE)
Cyclophosphamide differs from the previously described alkylating agents in that it is a pro-drug, requiring activation to develop cytotoxicity. It undergoes a complex multi-step activation process, initially being metabolized by the cytochrome P450 system in the liver and eventually converted to a variety of active metabolites, of which phospho-ramide mustard is thought to be the major cytotoxk derivative. One of the main metabolites, acrolein, is excreted in the urine and can cause a chemical (haemorrhagic) cystitis in up to 10 per cent of patients. Adequate hydration and the concurrent administration of sodium-2-mercaptoethane (MESNA), which inactivates acrolein in the urine, can prevent this toxicity. Cyclophosphamide has good oral bioavailability of around 90 per cent and therefore is often utilized by this route. The main toxicity is myelosuppres-sion, with the nadir occurring 10-21 days after intravenous administration. Doses of 750 mg/m2 are common in regimens such as intravenous CMF (cyclophosphamide, methotrexate and 5-FU), whereas higher doses may be given as part of high-dose stem-cell transplantation. Such high doses can lead to problems such as hyponatraemia, haemorrhagic carditis, cardiomyopathy and pulmonary fibrosis. Like all alkylating agents, there is a risk of developing second malignancies. The major use of cyclophosphamide is as a component of combination regimens for cancers of the breast, small-cell lung and haematological malignancies. The CMF regimen is still one of the mainstays of chemotherapy for breast cancer, with variations existing that deliver different dose intensity and toxicity. It has recently fallen out of favour in ovarian cancer treatment, with the introduction of newer, more active combinations.
Ifosfamide is a structural analogue of cyclophosphamide, which exhibits a similar spectrum of activity but different pharmacological properties and toxicity profile. It is generally administered as prolonged infusions, with concurrent MESNA and hydration, due to a higher incidence of urothelial toxicity. In addition, ifosfamide can cause a severe but reversible neurological syndrome, characterized by altered mental state, cerebellar dysfunction, cranial neuropathies and epileptiform seizures. Risk factors for the development of neurotoxicity are impaired renal or hepatic function. Both ifosfamide and cyclophosphamide can cause impairment of gonadal function. The usefulness of ifosfamide is evidenced by its incorporation into chemotherapy regimens that have been shown to be curative in germ-cell malignancies. It is also used in the treatment of sarcomas and lymphomas and has demonstrated activity in ovarian cancer. As part of the ICE regimen (ifosfamide, carboplatin and etoposide) or combined with vin-cristine, VICE, it has been used in the treatment of small-cell lung cancer.
NITROSOUREAS (BU, CU)
BU (1,3-bis-(2-chloroethyl)-l-nitrosourea,carmustine) and CU (1-(2-chlorothyl)-3-cyclohexyl-l-nitrosourea, lomus-tine) are important agents in that they exhibit only partial cross-resistance with the other alkylating agents. They are highly lipid soluble and easily cross the blood-brain barrier. Clinical activity has been observed in lymphoma, melanoma, myeloma and malignant glioma. Major toxici-ties are emesis and delayed myelosuppression, which can be severe. BU is given intravenously, whereas CU can be administered orally.
ALKYLAKLANE SULPHONATES (BUSULFAN, TREOSULFAN)
Busulfan is an orally available bifunctional alkylating agent which, when hydrolysed, binds extensively to nucleophilic sites on DNA to form crosslinks. It is used mainly in haematological malignancies, and is an integral component of many high-dose chemotherapy regimens preceding stem-cell transplantation. Myelosuppression can be severe and long lasting after excessive dosing. Other notable tox-icities include ‘busulfan lung’, a form of interstitial pulmonary fibrosis, and increased pigmentation in an Addisonian distribution. Treosulfan was synthesized in 1961 as dihydroxybusulphan and is a bifunctional alkyla-tor, structurally related to busulfan. It is a pro-drug, activated to the reactive epoxide in a non-enzymatic, first-order, pH-dependent process. It has demonstrated specific activity in ovarian cancer and is available in intravenous and oral form. The predominant toxicity is mild-to-moderate myelosuppression.
AZIRIDINYL DRUGS (THIOTEPA, MITOMYCIN C)
Thiotepa (N,N,N-triethylenethiophosphoramide) is a complex drug that acts as a monofunctional DNA-alkylating agent. It is thought to act as a pro-drug, being metabolized to highly reactive aziridine moieties via hydrolysis, following diffusion into the cell. It is delivered by the intravenous or intra-cavity route and readily crosses the blood-brain barrier. It has a role in the palliation of refractory ovarian cancer as an intraperitoneal agent, and recently there has been a resurgence of interest in its use as part of high-dose chemotherapy due to its relative lack of non-myelogenous toxicity.
Mitomycin C is related to the anthracycline anti-tumour antibiotics, being derived from Streptomyces species, but differs substantially in that it is the prototype bioreductive agent, undergoing preferential activation in the hypoxic environment found in solid cancers. Once activated, mitomycin C performs bifunctional alkylation, crosslinking DNA with the adduct in the minor groove and causing strand breaks. The utility of mitomycin C is limited by delayed myelosup-pression, similar to that of the nitrosureas. Other notable tox-icities include renal failure and cardiomyopathy, both related to the total cumulative dose of mitomycin C administered. The elucidation of the mechanism of action of mitomycin C has evoked great interest due to the potential of tumour selectivity through preferential reductive activation in hypoxic solid tumour masses. A range of aziridinyl agents, including E09, has been developed and is undergoing clinical evaluation.
N-METHYLTRIAZINES AND MELAMINES
Dacarbazine (DTIC) was initially thought to function as an anti-metabolite, given that its genesis was as an analogue of 5-amino-imidazole-4-carboxamide, a purine precursor. However, it is now thought to be hepatically activated to function as an alkylating agent. It is decomposed by exposure to light and is administered by intravenous infusion. It is active against a broad spectrum of tumours, but the main clinical utility is in the treatment of malignant melanoma, lymphoma and sarcomas.
Hexamethylmelamine has an uncertain mechanism of action, but is likely to act as a DNA-methylating agent, with crosslink formation. However, it is incompletely cross-resistant with classical alkylating agents such as cyclophosphamide. It is administered by the oral route, but bioavailability is erratic due to variable first-pass metabolism. It is used in the treatment of ovarian cancer, but eme-sis can be problematic. In addition, it can produce neurological toxicity in some patients.
Procarbazine is metabolically activated in the liver microsomes into a DNA-methylating species. It is generally administered orally in the treatment of Hodgkin’s disease and is also useful in the treatment of brain tumours due to its ability to penetrate well into the cerebrospinal fluid. Side effects are usually not severe, but care should be taken with co-administration of other drugs, due to the inhibitory effect of procarbazine on monoamine oxidase.
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