Nam Deuk Kim, Ph.D.

Purine Antimetabolites

Contents Guanine analogs

6-Mercaptopurine (6-MP), 6-Thioguanine (6-TG),

Azathioprine

Adenosine analogs

Fludarabine, Pentostatin, Cladribine

Allopurinol

The amount of chemotherapeutic agent used

(항암제 분류)

2

Guanine analogs

3

1. Guanine analogs

6-MP

Extensive hepatic, cellular metabolism after dosing

1) Activated intracellularly by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form 6-thioinosine monophosphate (TIMP ; inhibit purine synthesis) sequential metabolism to thioguanine monophosphate(TGMP), 6-TGTP incorporated into DNA, RNA trigger programmed cell death by mismatch repair pathway

2) methylation ; antiproliferative property through inhibition of purine synthesis by methylmercaptopurine nucleotides

6-TG

Converted to 6-thioguanylic acid (TGMP) by HGPRT incorporated into DNA, RNA

6-TG into thioguanine nucleotide ; fewer metabolic steps & higher cellular conc. than 6-MP

4

1) Guanine analogs : Mechanism of action (MOA)

5

Azathioprine

Cleaved by nonenzymatic mechanisms to 6-MP &

imidazole derivatives

1) incorporation of false nucleotides into DNA, inhibition of purine

synthesis

2) Modify immune response

Inhibit T-lymphocyte activity than B-lymphocytes

6-TGTP ; bind & inhibit Rac1 (small GTP-binding protein, major

role in T cell development, differentiation, proliferation)

mitogen-activated kinase (MEK), NF-κB I, bcl-XL suppression

apoptosis

1) Guanine analogs : Mechanism of action

1) Guanine analogs : Mechanism of action

6

7

6-MP (1)

Formulation ; 50 mg tab (Purinethol Ⓡ 삼일제약)

Use ; ALL (little role in solid tumor, myeloid leukemia), inflammatory bowel disease

Dosage ; 75 mg/m2 or Acute lymphoid leukemia (FDA labeled indication), as induction and maintenance therapy: induction, 2.5 mg/kg/day (100-200 mg) ORALLY ; if no clinical improvement after 4 weeks, may increase dose to 5 mg/kg daily

Absorption ; bioavailability (BA) 5-37%

Metabolism ; liver 1) Oxidized to 6-thiouric acid (inactive) by xanthine oxidase (high in

intestinal mucosa, liver large 1st pass effect, low BA)

2) S-methylation to 6-methyl mercaptopurine by thiopurine methyl transferase (TPMT)

2) Guanine analogs : Clinical pharmacology

8

6-MP(2)

Drug interaction

Allopurinol ; xanthine oxidase inhibitor, increase 6-MP BA by 500%

MTX ; weak inhibitor of xanthine oxidase , small increase of BA

Precaution ; Inherited deficiency of TPMT

Marked myelosuppression with low activity

Frequency ; one in 200-300 subjects has absent activity, 10% intermediate , the

rest have high activity

Race ; blacks, less activity than whites

Eight TPMT polymorphism associated with reduced activity ; TPMT3 , the

most common mutation genotype, more than 80% of heterozygotes

Dosage adjustments in hepatic, renal function impairment

2) Guanine analogs : Clinical pharmacology

9

6-TG

40 mg tab (Lanvis Ⓡ 삼일제약) / BA 14-46%

Median half life ; 90 min

Metabolism ; different from 6-MP Converted to 6-thioinosine (inactive) by guanase

※ not a substrate for xanthine oxidase

Methylation by TPMT ; less active 2-amino-6-metylthiopurine than 6-TG, more extensive than 6-MP

Azathioprine

Prodrug, metabolized to 6-MP by oxidation or methylation in the liver and erythrocytes

Use ; immunosupressant in the renal transplant rejection, adjunct, autoimmune disease (rheumatoid arthritis, lupus, ulcerative colitis)

50 mg tab (Imuran Ⓡ, Azafrin Ⓡ), IV (Imuran Ⓡ 100mg/20ml/vial)

2) Guanine analogs : Clinical pharmacology

10

6-MP

Myelosuppression Dose-limiting, 1-4 weeks following the onset of therapy, reversible.

Platelet, granulocyte, erythrocyte

Weekly monitoring of blood counts during the 1st 2 months

Related to TPMT phenotype ; excessive toxicity with TPMT deficiency or heterozygosity (65%)

Gastrointestinal mucositis, stomatitis ; adults > children

Nausea, vomiting, anorexia ; 25% / Pancreatitis

Hepatotoxicity ; mild, reversible. Not associated TPMT polymorphism, correlated with dose and methylated metabolite

6-TG

Primary ; Myelosuppression

GI toxicity ; less frequently than 6-MP

Jaundice, hepatic veno-occlusive disease

3) Guanine analogs : Toxicity

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Azathioprine

similar to 6-MP

Hypersensitivity ; fever, chills, severe nausea, diarrhea,

hypertension, hepatic dysfunction

Chronic immunosuppressive therapy ; 2ndary infection, malignant

tumor risk

3) Guanine analogs : Toxicity

A. 6-Mercaptopurine

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B. 6-Thioguanine

13

C. Azathioprine

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2. Adenosine analogs

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16

Monophosphate analog of adenosine arabinoside ; F-ara-AMP

MOA

After IV, rapidly, completely dephosphorylated in plasma (5’ nucleotidase

in erythrocyte, endothelial cell) to F-ara-A enters cells via carrier-

mediated transport, phosphorylated to active form, F-ara-ATP

(fludarabine triphosphate) ; inhibit DNA replication by inhibiting

DNA plymerase, ribonucleotide reductase, DNA primase, DNA ligase Ι

F-ara-AMP ; incorporation into DNA as a false nucleotide DNA

chain terminator apoptosis

“S- phase agent” but, also active in non-dividing cells

Inhibit RNA polymerase by incorporation into RNA

Depletion of nicotinamide adenine dinucleotide (NAD) cellular energy store ↓

Interferance with normal DNA repair processes

1) Fludarabine : 9-Arabinofuranosyl-2-fluoroadenosine monophosphate

1) Fludarabine

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Dosage form ; Fludara Ⓡ 10 mg tab, 50 mg vial (바이엘, 희귀약품)

Use ; CLL 25-30 mg/m2 IV (40 mg/m2 orally ) days 1-5 q4 weeks &

hairy cell leukemia, non-Hodgkin’s lymphoma

Absorption ; BA 70%(not affected by meal), Tmax 1.5 hrs orally

Elimination ; terminal half life 7-33 hr

F-ara-A is excreted primarily in the urine (50-60%) ; in renal impairment, dose

reduction needed

F-ara-ATP

major intracellular metabolite, the only metabolite with known

cytotoxicity, Tpk 4hr

Long intracelluar half life ; 15 hr

Drug interaction ; synergistic with cytosine arabinoside (increase

intracellular accumulation of ara-C)

1) Fludarabine : clinical pharmacology

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Myelosuppression

Dose-limiting, reversible leukopenia, thrombocytopenia, lymphopenia

Immunosuppression ; inhibition of signal transduction of lymphocyte

activation

Infection ; Dose-limiting, opportunistic infection ( CD4, CD8 T-

lymphocyte↓)

Fever of unknown origin(2/3), autoimmune hemolytic anemia, acute

tumor lysis

Neurotoxicity ; 16%

Irreversible ; optic neuritis, encephalopathy, general seizure, coma

Reversible ; lower doses, increased frequency

Pulmonary ; fever, cough, hypoxia, diffuse interstitial pneumonitis

(corticosteroid therapy)

1) Fludarabine : Toxicity

20

MOA

Potent adenosine deaminase (ADA) inhibitor ; tight ADA binding,

Accumulation of deoxyadenosine, dATP negative feedback on ribonucleotide reductase imbalance in deoxynucleotide pools slows DNA synthesis, alter DNA replication, repair

S-adenosylhomocysteine hydrolase inhibition ; block normal cellular methylation reactions

Pharmacology

Not orally bioavailable, stable at neutral pH (unstable at pH ≤5)

Large Vd with little protein binding, cross BBB

Terminal elimination T1/2 6 hr

Metabolism ; only a small amount

Excreted in urine unchanged

Dose reduction for patients with renal impairment

2) Pentostatin : 2’-deoxycoformycin (dCF)

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Toxicity

Neutropenia, increase risk of opportunistic infections

Nausea & vomiting(12-72 hr after adm.), mild to moderate lethargy,

rash, reactivation of herpes zoster

Immunosuppression, conjunctivitis, hepatic enzyme elevation, renal

impairment, CNS disturbances with higher doses

Renal toxicity(10 to 20 days after), cardiac complications in older

patients

Use ; no apparent advantage over standard therapy except hairy-

cell leukemia (responses in over 90% of patients)

2) Pentostatin

2) Pentostatin

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23

MOA

Resistant to ADA

Prodrug ; intracellular phosphorylation for activation ; cladribine 5’-

triphosphate (2CdATP) accumulates in cells rich in deoxycytidine

kinase

Incorporated into DNA, DNA strand breaks, DNA synthesis inhibition

Inhibition of DNA polymerase, ribonucleotide reductase →DNA synthesis & repair impairment

Apoptosis triggering in non-dividing cells ; interact with cytochrome C and

protease activating factor-1(PAF-1) to initiate caspase cascade leading to DNA

degradation

Cladribine resistance ; by deficiency in deoxycytidine kinase, p53

mutation, multidrug resistance protein 4

3) Cladribine : 2-chlorodeoxyadenosine (2-CdA)

3) Cladribine

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25

Dosage form ; Leustatin Ⓡ 10mg/10ml /vial 바이엘, 희귀의약품

Use ; similar to fludarabine

Hairy cell leukemia, CLL, low grade NHL, AML

Higher(several hundred fold) intracellular conc. than plasma conc.

long intracellular T1/2(9-30hr) ; intermittent administration

Protein binding 20%

BA ; 100% with sc. 40-50% with oral adm.

Renal clearance 50% (20-30% unchanged drug)

Drug interaction

with cytarabine – increase intracellular accumulation of ara-CTP (active

metabolite of cytarabine) by 40%

increased frequency of drug rash with allopurinol

3) Cladribine : clinical pharmacology

26

Myelosuppression ; dose-limiting

Immunosuppression and opportunistic infection

Fever ; 2/3 of patients , mostly during neutropenia

Autoimmune hemolytic anemia, eosinophilia, nausea, fatigue

3) Cladribine : toxicity

3) Cladribine

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No antineoplastic activity, but frequently used in pts with leukemia,

lymphoma to prevent hyperuricemia, uric acid nephropathy

Available in 100 mg tab

MOA (Mechanism of action)

Allopurinol (hypoxantine analog) & oxipurinol (major metabolic

product of allopurinol, xanthine analog) ; inhibit xanthine oxidase,

block conversion to uric acid decrease total purine (xanthine,

hypoxanthine, uric acid) excretion by 30-40%

Allopurinol ; decreasing the rate of purine synthesis

3. Allopurinol

3. Allopurinol

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Fig. 9.7 Feedback inhibition of de novo purine biosynthesis.

3. Allopurinol

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* 5’phosphoribosyl-1-pyrophosphate (PRPP) aminotransferase ; critical

enzyme involved in purine synthesis

3. Allopurinol

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Toxicity

Skin rash ; 2%

Life-threatening hypersensitivity syndrome

fever, eosinophilia, skin rash including toxic epidermal neurolysis (TEN), renal

dysfunction, hepatic failure

2-4 weeks after initiation

Underlying renal failure when therapy in started dose adjustment

Clinical use

Gout

Prevent marked increases in UA excretion after chemotherapy ;

hydration & allopurinol before chemotherapy recommended

Renal failure due to precipitation of urate crystals from sudden rise in UA after

chemotherapy

Interaction ; azathioprine, 6-MP to 6-thiouric acid(inactive) by

xanthine oxidase dose reduction

3. Allopurinol

4. 항암화학요법제 분류_심사평가원

33

2군 항암제는 보건복지가족부장관이 정하여 고시하는 항암화학요법제(분류번호 245, 247, 249, 313, 339, 392, 399, 421, 429, 617,

639)중 각 약제의 개발시기ㆍ재심사대상ㆍ희귀의약품 등을

기준으로 암질환심의위원회에서 2군으로 분류한 약제임

위 분류에 해당하지 아니하는 경우는 1군으로 분류됨.

항암화학요법의 투여대상, 투여단계, 투여요법은 1군 항암제의 경우에는 진료의사의 의학적 판단에 따라 사용하며, 2군 항암제의 경우에는 각 암종별 “항암화학요법”에 명시된 투여대상, 투여단계, 투여요법을 적용함

주요항암제 심평원 EDI 청구현황 (메디팜스투데이)

34

2010.9.16 *단위; 백만원

2010.2.22

*EDI, Electronic Data Interchange (전자문서교환)

35

product Generic Class (use) product generic Class (use)

1 글리벡 Imatinib Protein tyrosine kinase

inhibitor(CML) 13 페마라정 Letrozole Aromatase

inhibitor

2 탁소텔 Docetaxel Anti-microtubule 14 벨케이드주 Bortezomib Proteosome

inhibitor

3 엘록사틴 Oxliplatin Platinum – alkylating

agent 15 아리미덱스 Anastrozole Aromatase

inhibitor

4 알림타주 Pemetrexed Antifolate (NSCLC) 16 수텐캡슐 Sunitinib Tyrosine kinase

inhibitor

5 캠푸토주 Irinotecan Topoisomerase inhibitor 17 티에스원

캡슐 Tegafur,gemeracil,

Oteracil

Pyrimidine analog

6 젬자주 Gemcitabine antimetabolite

(deoxycytidine analog) 18 아그릴린

캡슐 Anagrelide Platelet reduction

7 허셉틴주 Trastuzumab Monoclonal antibody 19 다코젠주 Decitabine Pyrimidine analog

(골수이형성)

8 타쎄바정 Erlotinib Tyrosine kinase inhibitor

(NSCLC) 20 테모달캡슐 Temozolomide Alkylating agent

(astrocytoma)

9 맙테라주 Rituximab Monoclonal antibody 21 하이캄틴주 Topotecan Topoisomerse1

inhibitor

10 젤로다정 Capecitabine Antimetabolite ; breast,

colorectal Ca 22 캄토벨주 Belotecan Other (SCLC)

11 이레사정 Gefitinib Tyrosine kinase inhibitor

(NSCLC) 23 넥사바정 Sorafenib Raf kinase

inhibitor

12 탁솔주 Paclitaxel Anti-microtubule

1군 항암제

2군 항암제

36

product generic Class (use) product generic Class (use)

1 토뮤덱스 Raltitrexed Antimetabolite(folat

e analog) (colorectal

Ca)

12 선플라주 Heptaplatin Platinum analog

2 부설펙스주 Busulfan Alkylating agent 13 맵캠파스주 alemtuzumab Monoclonal

antibody (CLL)

3 탈리도마이드

thalidomide immunosuppressant 14 스프라이셀정 Dasatinib Tyrosine kinase

inhibitor

4 비다자주 Azacitidine Pyrimidine analog

(골수이형성) 15 케릭스주 Loposomal

doxorubicin

anthracycline

5 류스타틴주 Cladribine Purine analog 16 자베도스캡슐 Idarubicin anthracycline

6 부몬주 Tenipocid podophyllotoxin

17 제바린키트 (ibritumomab

tiuxetan

Other (NHL)

7 선라빈주 Enocitabine Pyrimidine analog 18 아바스틴주 bevacizumab Monoclonal

antibody

8 프로류킨주 Aldesleukin-2 T-cell growth factor 19 얼비툭스주 cetuximab Monoclonal

antibody

9 플루다라 Fludarabine Purine analog 20 나벨빈캡슐 Vinorelbine Vinca alkaloid

10 베스타틴

슐

Ubenimex other 21 마일로타그주 gemtuzumab

ozogamicin

Monoclonal

antibody(AML)

11 아로마신정 Exemestane Aromatase inhibitor 22 아브락산주 albumin-bound

paclitaxel 전이성 유방암

2군 항암제

37

Product class product class product class

Ifosfamide

(Holoxan)

Alkylating

agent

carboplatin Platinum –

alkylating agent

dacarbazine Alkylating agent

Melphalan

(Alkeran)

Alkylating

agent

cisplatin Platinum –

alkylating agent

Actinomycin D Antitumor

antibiotic

6-MP

(Purinethol)

Purine

analog

6-TG

(Lanvis)

Purine analog

Daunorubicin Antitumor

antibiotic

Methotrexat

e (MTX)

antifolate Cyclo

phosphamide

Alkylating agent Doxorubicin

(Adriamycin)

Antitumor

antibiotic

Mitomycin Antitumor

antibiotic

cytarabine DNA polymerase

inhibitor

Epirubicin(Pha

rmorubicin)

Antitumor

antibiotic

Chlorambuc

il(Leukeran)

Alkylating

agent

Etoposide

(Lastet)

Epipodophyllo

toxin

Fluorouracil

(5-FU)

Pyrimidine

analog

Thiotepa Alkylating

(Bladder)

Hydroxyurea

(Hydrea)

Pyrimidine

antagonist

idarubicin Antitumor

antibiotic

vincristine Vinca

alkaloid

flutamide antiandrogen Goserelin GnRH analog

tamoxifen SERM Toremifen

(Fareston)

SERM azathioprine Purine analog

Chemotherapy regimen (example)

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Metastatic colorectal cancer

FOLFOX 3

Oxaliplatin 85 mg/m2 IV day 1

Folinic acid 200 mg/m2 IV day 1

5-FU 400 mg/m2 then 600 mg/m2 IV days 1-2 q2 weeks

Breast cancer

CAF

Cyclophophamide 500 mg/m2 IV day 1

Doxorubicin 50 mg/m2 IV day 1

Fluorouracil 500 mg/m2 IV day 1, 8 q3 weeks

CMF

Cyclophophamide 100 mg/m2 PO day 1-14

Methotrexate 40 mg/m2 IV day 1, 8

Fluorouracil 600 mg/m2 IV day 1, 8 q4 weeks