Alkylating Agents

ALKYLATING AGENTS

These compounds produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. The position 7 of guanine residues in DNA is especially susceptible, but other molecular sites are also involved. Alkylation results in cross linking/abnormal base pairing/ scission of DNA strand. Cross linking of nucleic acids with proteins can also take place.

Alkylating agents have cytotoxic and radiomimetic (like ionizing radiation) actions. Many are cell cycle nonspecific, i.e. act on dividing as well as resting cells. Some have CNS stimulant and cholinergic properties.

Mechlorethamine (Mustine HCl)

It is the first nitrogen mustard; highly reactive and local vesicant—can be given only by i.v. route. It produces many acute effects like nausea, vomiting and haemodynamic changes. Extravasation during i.v. injection may cause sloughing.

Dose: 0.1 mg/kg i.v. daily x 4 days; courses may be repeated at suitable intervals.

MUSTINE 10 mg dry powder in vial.

Cyclophosphamide

It is inactive as such: produces few acute effects and is not locally damaging. Transformation into active metabolites (aldophosphamide, phosphoramide mustard) occurs in the liver, and a wide range of antitumour actions is exerted. It has prominent immunosuppressant property. Thus, it is one of the most popular anticancer drugs. It is less damaging to platelets, but alopecia and cystitis (due to another metabolite acrolein) are prominent. Chloramphenicol retards the metabolism of cyclophosphamide.

Dose: 2–3 mg/kg/day oral; 10–15 mg/kg i.v. every 7–10 days, i.m. use also possible.

ENDOXAN, CYCLOXAN 50 mg tab; 200, 500, 1000 mg inj.

Ifosfamide

This congener of cyclophosphamide has a longer and dose-dependent t½. It has found utility in bronchogenic, breast, testicular, bladder, head and neck carcinomas, osteogenic sarcoma and some lymphomas. The dose limiting toxicity of ifosphamide is haemorrhagic cystitis. To prevent the same mesna is routinely given with it. Mesna is a –SH compound that is excreted in urine—binds and inactivates the vasicotoxic metabolites of ifosfamide and cyclophosphamide. Ifosfamide causes less alopecia and is less emetogenic than cyclophosphamide.

HOLOXANUROMITEXAN 1 g vial + 3 amps of mesna 200 mg inj.; HOLOXAN, IPAMIDE 1 g inj.

Chlorambucil

It is a very slow acting alkylating agent, especially active on lymphoid tissue: Myeloid tissue is largely spared. It is the drug of choice for long-term maintenance therapy for chronic lymphatic leukaemia; Hodgkin’s disease and some solid tumours also resolve. It has some immunosuppressant property.

Dose: 4–10 mg (0.1–0.2 mg/kg) daily for 3–6 weeks, then 2 mg daily for maintenance; LEUKERAN 2, 5 mg tab.

Melphalan

It is very effective in multiple myeloma and has been used in advanced ovarian cancer. Bone marrow depression is the most important toxicity. Infections, diarrhoea and pancreatitis are the complications.

Dose: 10 mg daily for 7 days or 6 mg/day for 2–3 weeks— 4 weeks gap—2 to 4 mg daily for maintenance orally. Also used for regional perfusion in malignant melanoma. ALKERAN 2, 5 mg tab, 50 mg per vial for inj.

Thio-TEPA

It is an ethylenimine: does not require to form an active intermediate. It has high toxicity: seldom used now.

Dose: 0.3–0.4 mg/kg i.v. at 1–4 week intervals.

THIOTEPA 15 mg per vial inj.

Busulfan

It is highly specific for myeloid elements; granulocyte precursors being the most sensitive, followed by those of platelets and RBC. It produces little effect on lymphoid tissue and g.i.t. Hyperuricaemia is common and pulmonary fibrosis is a specific adverse effect. Sterility also occurs. It is the drug of choice for chronic myeloid leukaemia.

Dose: 2–6 mg/day (0.06 mg/kg/day) orally.

MYLERAN, BUSUPHAN 2 mg tab.

Nitrosoureas

These are highly lipid soluble alkylating agents with a wide range of antitumour activity. They cross bloodbrain barrier—are effective in meningeal leukaemias and brain tumours. Nausea, vomiting are common and CNS effects also occur. Bone marrow depression is peculiarly delayed, taking nearly 6 weeks to develop. Visceral fibrosis and renal damage can occur:

Lomustine (CCNU): 100–130 mg/m2 BSA single oral dose every 6 weeks; LOMUSTINE 40, 100 mg cap.

Dacarbazine (DTIC)

It is different from other alkylating agents in having primary inhibitory action on RNA and protein synthesis (others mainly affect DNA). It is activated in the liver. The most important indication is malignant melanoma; also used in Hodgkin’s disease. Nausea and vomiting are prominent side effects.

Dose: 3.5 mg/kg/day i.v. for 10 days, repeat after 4 weeks. DACARIN 100, 200, 500 mg inj; DACARZINE 200 mg/ vial inj.