ALKYLATING AGENTS

In Multiple Myeloma, On X-ray lytic lesions are seen. Bone scan is normal. Level of alkaline phosphate in the blood is normal, (despite extensive bone involvement). Generalize body pain is the commonest presentation. Hypercalcaemia, raised ESR, Anemia, are the features. Raised β2 micro globulin is a poor prognostic feature.

Alkylating DNA, causing cross-links between parallel DNA strands

Vincristine and the other vinca alkaloids bind to tubulin and impair microtubular assembly, preventing mitosis (M-phase-specific). Mechlorethamine, like cyclophosphamide (and carmustine and several others), is an alkylating agent. They are called bifunctional alkylating agents because they can covalently bind to DNA in two places (“nucleophilic attack”), thereby forming cross-links between two adjacent strands or between two bases in one strand. This ultimately disrupts DNA and RNA synthesis or may cause strand breakage. Cyclophosphamide (which can be considered the prototype of the alkylating agents) is actually a pro- drug—it requires metabolic activation in order for its effects to occur. Cyclophosphamide (and other alkylating agents) are cell cycle-nonspecific, although their efficacy is greater when cells are not in G0.Bleomycin, dactinomycin, and doxorubicin are good examples of drugs that intercalate in DNA strands. Thus, the altered DNA no longer serves as an adequately precise template for eventual synthesis of more functional DNA and RNA. They are classified as antitumor antibiotics. Etoposide and topotecan are examples of drugs that inhibit topoisomerase 11. The consequence is inhibited ability of affected cells to repair DNA strand breaks. This stops the cell cycle in G2 – The taxoid (e.g., paclitaxel) impairs mitosis, but by stabilizing assembled microtubules rather than by exerting a vinca alkaloid-like inhibition of microtubular assembly.

Alkylating agents REF: Robbin’s 7^th ed p. 322

Pro carcinogenic chemicals:

• Alkylating agents
• Aromatic amines and azo dyes
• Nitrosoamines and amides

Carmustine [Ref. Goodman Gilman 1 l^th/e p 1330]

Myelosuppression leading to neutropenia, thrombocytopenia and anemia is seen with most of the anticancer drugs.

• The characteristic feature of myclosuppression produced by carmustine is that it causes delayed myelosuppression that is prolonged too

According to Goodman Gilman

“It causes profound and delayed myelosuppression with recovery 4-6 weeks after a single dose. The myelosuppression leads to leukopenia and thrombocytopenia (may be prolonged)”

More on Carmustine:

• Carmustine belongs to nitrosoureas class of anticancer drugs
• They have an important role in the treatment of brain tumours.
• It is highly lipophilic and thus it readily crosses the blood brain barrier.

Other adverse effects of carmustine

• Delayed renal damage
• Reversible liver damage
• Leukemia
• Myocardial ischemia

Ans. is ‘a’ i.e., Alkylating agent

Ans. is ‘a’ i.e., 5 Fluorouracil

Ans. is ‘b’ i.e., Alkylatings agents

Alkylating agents may contribute to sterility by the following effects :

• Azoospermia in males
• Amenorrhea and ovarian atrophy in females

Specific toxicity of important alkylating agents.

o Cyclophosphamide          —> Cystitis, alopecia, SIADH

o Ifosfamide                     —> Cystitis, SIADH, neurotoxicity

o Cisplatin                       —>  Nephrotoxicity, peripheral neuropathy, ototoxicity, vomiting.

o Busulfan                       —> Adrenal insufficiency, hyperpigmentation,pu/monaryfibrosis.

o Procarbazine                 —> Disulfiram like reaction, secondary leukemias, CNS effects.

Ans. is ‘c’ i.e., Hypoglycemia

Toxicity of Cyclophosphamide

o Bone marrow suppression (relative platelet sparing)                          o Pulmonary toxicity               o Cardiac (at higher doses)

o Cystitis                                                                                        o Infertility                             o GI Toxicity

o Alopecia                                                                                      o Teratogenesis                      o SIADH

Ans. is ‘a’ i.e., Haemorrhagic cystitis

“Haemorrhagic cystitis can develop in patients receiving cyclophosphamide or ifbsphamide”.

Ans. is ‘b’ i.e., Cancer chemotherapy

o Mesna is used to block the cystitis caused by Cyclophosphamide and Ifophosphamide. o Note — Acetylcysteine can also be used for this purpose.

Ans. is ‘c’ i.e., Ameliorate haemorrhagic cystitis

Ans. is ‘c’ i.e., Choriocarcinoma

Ans. is ‘b’ i.e., Causes local irritation

o The drug is not a vesicant, and produces no local irritation.

o Cyclophosphomide is an alkylating agent, absorbed well orally and is used as immunossuppressant in many refractory autoimmune diseases.

Ans. is ‘b’ i.e., Lymphoid tissue

o Chlorambucil is a very slow acting alkylating agent especially active on lymphoid tissue; myeloid tissue is largely spared.

Ans. is ‘a’ i.e., Multiple myeloma

o Melphalan is an anticancer (alkylating) agent which is most effective in multiple myeloma.

Ans. is ‘b’ i.e., Toxic carditis

o Adverse effects of busulfan —> Myelosuppression, hyperuricemia, pulmonary fibrosis, sterility, impotence, amenorrhea, addison’s disease like syndrome (asthenia and hypotension).

o High dose causes veno-occlusive disease of liver, seizures, hemorrhagic cystitis, alopecia, cataract.

About option ‘a’ – In addison’s disease there is hyperpigmentation (Busulfan causes addison’s disease like syndrome).

Ans. is ‘b’ i.e., Cyclophosphamide

Drugs used for ovarian carcinoma

• First line –^p Cisplatin, Carboplatin, Paclitaxel, Cyclophosphamide, doxorubicin.
• Second line → Melphalan, chlorambucil, 5-Fu, Methotrexate, Vincristine, Topotecan.

Ans. is ‘c’ i.e., L-Asparaginase

Drug causing ^peripheral necropathy

Amiodarone                 Demeclocycline          Isoniazid

Chloramphenicol         Disopyramide             Methysergide

Chloroquine                 Ethambutol                 Metronidazole

Cisplatin                     Ethionamide               Vincristine

Clioguinol                   Glutethemide              Tricyclic antidepressant

Clofibrate                    Hydralazine                Tolbutamide

Paclitaxol                  Chlorpropamide

Mustine                     Nalidixic acid                Nitrofurantoin

Perhexiline                 Phenelzine                  Phenytoin

Streptomycin             Procarbazine               Polymyxin, colistin

Stavudine                   Didanosine               Zalcitabine

Answer is A (Treatment should be initiated as soon as diagnosis is established)

It is not essential to initiate treatment as soon as a diagnosis of CLL is established.

‘An unusual feature of CLL compared to other leukemias is that making the diagnosis is not necessarily an indication to initiate treatment’ – DeVita

Treatment need not be initiated as soon as diagnosis of CLL is established

Early stage asymptomatic disease requires no treatment. CLL may be diagnosed in an asymptomatic patient and have a prolonged course. Meta-analysis has shown no survival advantage of initiating treatment in early stage disease. Active monitoring should however be pursued and treatment initiated only if and when the patient meets established ‘criteria for treatment’.

Criteria for treatment

• Progressive marrow failure
• Massive(>10cm)/progressive lymphadenopathy
• Massive (>6cm)/progressive splenomegaly
• Progressive lymphocytosis (doubling time <6 months)
• Systemic symptoms;
• Weight loss >10%in 6 months fever>38° C for >2 weeks extreme fatigue or night sweats
• Autoimmune cytopenias (this may only require treatment of the autoimmune component not necessarily the leukaemia)

Chlorambucil and Fludarabine are the most commonly used agents.

The most common treatment for CLL are Chlorambucil or Fludarabine alone or in combination.

Chlorambucil

• Can be administered orally and has few side effects
• Less active than Fludarabine and usually unsuccessful in achieving remission
• Most common agent chosen for treatment of elderly patients requiring therapy. (Majority of elderly patients have significant comorbid conditions associated with aging and may have an indolent disease)

Fludarabine

• Administered intravenously and has significant side effects (Significant immune suppression)
• More active agent and by far the only drug associatedwith a significant incidence of complete remission
• Preferred agent for treatment of young patientsrequiring therapy Fludarabine is often used incombination with Cyclophosphamide (FC).Following theresults of LRF CC4 Trial many now consider FC to be thegold standard first Line treatment of CLL in the young

Young patients are candidates for Bone marrow transplanatation

Bendamustine is an alkylating agent structurally related to nitrogen mustards that is highly effective and is vying with fludarabine as the primary treatment of choice.

Rituximab (AntiCD20) and Alemtuzumab (anti CD52) may also be used.

`Young patients with CLL can be candidates for Allogenic bone marrow transplantation. Allogenic bone marrow transplantation can be urative but is associated with a significant treatment related mortality rate’ – Harrison

Ans. B: Pulmonary Fibrosis

Toxicity of busulphan may include:

• Interstitial pulmonary fibrosis
• Hyperpigmentation
• Seizures
• Hepatic (veno-occlusive disease)
• Wasting syndrome.

Phenytoin may be used concurrently to prevent the seizures.

Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.

Cyclophosphamide

IMPORTANT POINTS ON HEMORRHAGIC CYSTITIS:

• Drugs causing:
  • Cyclophosphamide
  • Ifosfamide
• Metabolite responsible:
  • Acrolein – In Cyclophosphamide
  • Chloracetaldehyde – In Ifosfamide
• Treatment:
• Mesna.

Ans. is ‘a’ i.e., Procarbazine

Disulfiram like reaction

• Certain drugs when taken concurrently with alcohol produce disulfiram like actions.
• That means these drugs produce similar distressing symptoms as disulfiram, when taken with alcohol → flushing, burning sensation, throbbing headache, prespiration, unesasiness, tightness in chest, vomiting, dizziness, visual disturbances, mental confusion, postural fainting and circulatory collapse.

The drugs causing Disulfiram like actions

1. Chlorpropramide            
2. Animal charcol
3. Cephalosporins (Cefoperazone, moxalactam, cefamandole) 
4. Griseofulvin
5. Metronidazole         
6. Procarbazine
7. Citrated calcium carbamide  
8. Tinidazine
9. Cynamide

Ans. is `d’ i.e., Etoposide

Ans. is ‘a’ i.e., Carmustine

Nitrosoureas

• Nitrosoureas (Lomustine and carmustine) are highly lipid soluble alkylating agents – cross blood – brain barrier → Effective in meningeal leukaemias and brain tumours.
• Nitrosoureas are highly lipid soluble and can cross blood brain barrier used in brain tumors like gliomas.
• Because they cross BBB, most common adverse effects are nausea, vomiting and other CNS effects.
• Bone marrow depression is peculiarly delayed, taking nearly 6 weeks to develop. → delayed neutropenia
• Nitrosoureas can cause visceral fibrosis and renal damage.

Ans. is ‘c’ i.e., Kidney 

• Cyclophosphomide is primarily metabolized (80%) and metabolites are excerted in urine.
• 10 to 20% is excreted unchanged in urine and 4% is excreted in bile.

Ans. is ‘c’ i.e., Kidney