Purine & Pyrimidine Analogs

Since rapidly multiplying cancer cells are dependent upon the synthesis of deoxythymidilate (dTMP) from

deoxyuridylate (dUMP), a prime target in cancer therapy has been inhibition of dTMP synthesis. The anticancer drug fluorouracil is converted in vivo to fluorodeoxyuridylate (FdUMP), which is an analogue of dUMP. FdUMP irreversibly forms a covalent complex with the enzyme thymidylate synthase and its substrate N5,N10-methylene- tetrahydrofolate. This is a case of suicide inhibition, where an enzyme actually participates in the change of a substrate into a covalently linked

inhibitor that irreversibly inhibits its catalytic activity.

Valacyclovir REF: Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007), http://en.wikipedia.org/ wiki/Prodrug

A prodrug is a pharmacological substance (drug) administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation

Cytarabine [Ref Katzung 10⁶/e p. 890]

Cerebellar neurotoxicity with cytarabine

• Acute cerebellar neurotoxicity with ataxia and dvsarthria is a well known complication of high dose crturabine therapy.
• Cytarabine is used in high doses to treat refractory leukemia.
• The neurotoxicity seen with cytarabine is dose related and is seen in 60% of patients receiving high dose cytarabine.
• It is aggravated by renal failure.
• Cytarahine (Ara-C) is the most important antimetabolite used in the therapy of acute myelogenous leukemia. It is the single most effective agent for induction of remission in this disease.
• Cytarabine is an antimetabolite thus it inhibits the S phase of the cell cycle.
• Cytarabine or (AraC) must first be converted to its active metabolite Ara-CMP. The active Ara-CMP inhibits DIVA synthesis by inhibiting the DNA polymerase.

Adverse effect:-

• Cytarabine is a potent myelosuppressive agent and may produce acute severe leucopenia, thrombocytopenia and anemia with striking megaloblastic changes.
• High doses of cytarabine produces cerebellar neurotoxicity i.e. cerebellar ataxia and neuropathy. Cerebellar toxicity manifests as ataxia and slurred speech.
• Intrathecal injections may lead to cerebral toxicity which causes seizures, dementia and coma.
• Other toxic manifestations may include:?

– Gastrointestinal disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevation, noncardiogenic pubnonar^y edema and dermatitis.

Cladirabine [Ref: Nelson 18thle p. 2161
Management of langherhan’s cell histiocytosis

1) Single system disease

• The clinical course of single system disease is usually benign with a high chance of spontaneous remission. Therefore t/t should be minimal and is directed at arresting the progression of a bone lesion that could result in permanent damage before it resolves spontaneously.

– This can be achieved by low dose local radiotherapy or curettage.

2) Multisystem disease

• It should be treated with systemic multiagent chemotherapy
• The drugs employed are

i)   Etoposide

ii)  Vinbiastin

For unresponsive disease, following drugs are available

i)   Cyclosporine / antithymocyte globulin

ii)  Imatinib

iii) 2-chlorodeoxyadenosine (cladirabine)

iv) Stem cell transplantation

• The most common treatments for patients with typical B cell CLL/small lymphocytic lymphoma have been chlorambucil or fludarabine. 
• Chlorambucil can be administered orally while fludarabine is administered IV
• Fludarabine is the more active agent and is the only drug associated with a significant incidence of complete remission. 
• For young patients regimens containing fludarabine are the treatment of choice. 
• Bendamustine also used as the primary agent in treatment.

Genetic variation in drug metabolism pathway dihydropyrimidine dehydrogenase results in severe toxicity of capecitabine, fluorouracil.

A i.e. Cytarabine

Ans. is ‘a’ i.e., GI toxicity

o The earliest untoward symptoms during a course of 5-FU are anorexia and nausea; these are followed by stomatitis and diarrhea.

Ans. is ‘b’ i.e., Pancreatic cancer

o Gemcitabine is the DOC for pancreatic carcinoma.

Ans. is ‘c’ i.e., Adenosine deaminase enzyme

o Pentostatin inhibit adenosine deaminase (ADA)

Ans. is ‘b’ i.e., Capecitabine

Hand foot syndrome

o Hand foot syndrome is a form erythromyelalgia manifested as tingling, numbness, pain, erythma, swelling and increased pigmentation of hands and feet.

o Two most common drugs causing ‘Hand foot’ syndrome are:

i)        Capecitabine (most common)

ii)      5-FU (2nd most common)

Drugs causing ‘Hand foot’ syndrome

Commonly associated drugs

o Capecitabine      o Surafenib                                  o Cytarabin

o 5-FU                 o Doxorubicin (liposomol)

Rarely associated drugs

o Cisplatin                         o Etoposide                  o 6-MP

o Cyclophosphamide          o Hydroxyurea              o Suramin

o Docetaxel                      o Methotrexate             o Paclitaxel

o Daunorubicin                 o Mitotane

Ans. is ‘a’ i.e., 5 Fluorouracil

o 5 Fluorouracil is rapidly absorbed from the blood into the tissue in which it accumulates quickly in high concentration and is excreted quickly from the body.

o Its V/2 is 15 minutes. It is excreted mainly by extrarenal routes.

o The metabolism of 5-Fluorouracil occurs mainly in the liver and results in degradation products (e.g. CO₂, Urea, fluorobalanine) which are inactive.

o Only 15% of the dose is excreted in urine rest of it is excreted as respiratory CO₂ in 8-12 hours.

Ans. is ‘c’ i.e., Cladaribine

Treatment of LCH

1. Single system disease

o The clinical course of single system disease is usually benign with a high chance of spontaneous remission.

o Therefore, treatment should be minimal and should be directed at arresting the progression of a bone lesion that could result in permanent damage before it resolve spontaneously.

• Curettage or less often low dose local radiotherapy may accomplish this.

2. Multisystem disease

o It should be treated with systemic multiagent chemotherapy.

o Any one, of following two should be included in regimen —> i) Etoposide             ii) Vinblastin o For unresponsive disease following therapies are available :

i) Cyclosporine/antithymocyte globulin                       ii) Imatinib

iii) 2-chlorodeoxyadenosine (Cladribine)   iv) Stem cell transplantation.

A. i.e. Cladarabine

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. is ‘c’ i.e., Pancreatic

Ans. is ‘c’ i.e., 6-mercaptopurine 

Azathioprine

• It is an analogue of mercaptopurine.
• It selectively affects T cells → cellular immunity is predominantly affected.
• It selectively affects defferentiation and formation of T cells.
• Azathioprine is converted to active metabolite 6-mercaptopurine.
• It can inhibit the synthesis of both DNA & RNA.
• Azathioprine and 6-MP are metabolize by xanthine oxidase →dose should be reduced if allopurinol (a xanthine oxidase inhibitor) is used concurrently.
• The most important action of azathioprine is prevention of renal and other graft rejection.