Antimetabolite抗代謝物

定義

模擬生物體內代謝路徑中的某一種代謝物以擾亂代謝的物質，化學療法中常見的藥物作用原理

分類

依機轉分類

• polymerase inhibitor (須先被轉成三磷酸鹽)
• elongation inhibitor (須先被轉成三磷酸鹽)
• other enzyme inhibitors
• polymerase inhibitor 常常也是 elongation inhibitor

依治療學分類可以分成

• 抗菌抗代謝物
• 抗癌抗代謝物:DNA polymerase inhibitor and elongation inhibitor and other enzyme inhibitors
• 抗病毒抗代謝物
• 核苷反轉錄酶抑制劑:retrotranscriptase(RNA-dependent DNA polymerase) inhibitor and elongation inhibitor
  • 核苷反轉錄酶抑制劑:也是抑制反轉錄酶，但是非核苷反轉錄酶抑制劑因為不是核苷的類似物所以更無毒性
• polymerase inhibitor 未必是 elongation inhibitor，像是抗病毒藥中，pencyclovir比acyclovir多出一個OH所以他只能polymerase inhibitor 而不能當 elongation inhibitor
• elongation inhibitor的致癌性比其他種類的antimetabolite大Foye2007-1179

依作用對象可以分成

• indirect inhibitor of thymidylate synthase (Folic acid antagonists)(Antifolate drug)
• 核苷酸抗代謝物
• direct inhibitor of thymidylate synthase : Pyrimidine analogue
• Purine antagonists : amidophosphoribosyl transferase inhibitors
• DNA polymerase/DNA chain elongation inhibitor
  • Pyrimidine analogue
  • Purine analogue : adenosine analogue
• Others

重點整理

*folates and one-carbon source:

metabolite	和何enzyme有關?
Dihydrofolate(DHF)	Dihydrofolate reductase(DHFR):受folate antagonist inhibit
dUMP→dTMP	E: thymidine synthase coE: N5, N10-methylenetetrahydrofolate
Glycine amide rebonucleotide(GAR)	E: formyltransferase(= GAR transformylase) 受MTX and pemetrexed to inhibit coE: 10-formylTHF(= , -methyl-H4-folate)
thiopurin	E: thiopurine methyl transferase(TPMT) coE: S-adenosylmethionine

*4大 antimetabolite cancer drugs的M和其他M:

M.	☆
M1. indirect inhibitor of thymidylate synthase (Folic acid antagonists)(Antifolate drug)(hard drug)	-(-)→ATCG
M2. direct inhibitor of thymidylate synthase : Pyrimidine analogue: 5-fluoro-dUMP(5-FdUMP) prodrugs(Kcat inhibitor)	-(-)→TC
M3. Thiopurins(Purine antagonists) (prodrug): amidophosphoribosyl transferase inhibitors-(HGPRT)→2M 有cross-resistance	-(-)→AG
M4. DNA polymerase/DNA chain elongation inhibitors(IV)(prodrug)-(M)→triphosphate→apoptosis→引起突變     Pyrimidine analogue nucleoside     Purine analogue : adenosine analogue(2-halogenated purine)(又inhibit adenosine deaminase)
M5. Other antimetabolite

DHFR

GAR transformylase(formyltransferase)

Thymidine synthase(dUMP→dTMP)

Amido phosphoribosyl transferase inhibitors(PRPP→)(PRPP glutamyl amidotransferase)

Xanthine oxidase

DNA polymerase

Adenosine deaminase, cytidine deaminase

Ribonucleotide reductase(NDP→dNDP)

*記活化的E, 抑制的E, and 代謝的E

name		structure	活化的酶	Name(活化態)	M作用對象和結果	代謝	resistance
M1. aminopterin		Folate analogue	no	no	*二氫葉酸還原酶DHFR(dihydrofolate reductase)→不能生成THF→thymineless death *Pemetrexed有3M. -(-)→ DHFR Thymidylate synthase GAR transformylase		*Lack of transporter intaking methotrexate *enhanced efflux from the tumor cell polygkutamation rate↓
Piritrexin
trimetrexate			→PCP
Raltitrexed
Pemetrexed		pyrrolopyrimidine
M2. Fluorouracil (5FU)(prodrug)		uracil	a.先形成核苷再deoxy uridine kinase b. phosphoribosyl transferase a.	FdUMP (active)	*Thymidylate synthase →no dTMP →thimineless death (irreversible) *加上leucovorin會增加毒性(和methotrexate相反)	Dihydropyrimidine deHase, 可併服inhibitor of dihydropyrimidine deHase: 5-ethynluracil	*代謝↓ uridine kinase↓
Tegafur(prodrug of 5FU)
Floxuridine(FUDR)(prodrug of 5FU, Sy↑)		deoxyribonucleotide	2’-deoxyuridine kinase	FdUMP (active)	同5FU
Doxifluridine?
Capecitabine(prodrug)		Carbamylated cytosine analogue	Thymidine phosphorylase	FdUMP (active)			*D-Dinteraction: **inhibit CYP2C9 **pt.-binding **D-D interaction with warfarin and phenytoin
Trifluridine( triflurothymidine)		thymidine	Thymidine kinase	Trifluorothymidylic acid difluoromethylene	Thymidylate synthase →no dTMP →thimineless death (irreversible) Noncompetitive動力學	Glycine conjugation( phase II)	若as antivirus則因為太毒所以當作局部用的後線藥物
M3. Mercaptopurine (prodrug)(inactive)		inosine	Hypoxanthine guanine phosphoribosyl transferase (HGPRT) ↓ Thiopurine methyl transferase (TPMT) ☆Glutathione conjugation取代活化	Thiopurine ribonucleotide(active) (非deoxyribonucleotide) 6-thioinosinic acid 6-thioguanylic acid | (TPMT, SAM) ↓ S-methylthiopurine ribonucleotide	1.Rate-limiting enzyme of purine nucleotide synthesis- amidophosphoribosyl transferase( =phosphoribosyl pyrophosphate amido transferase)( =PRPPglutamyl amido transferase)(mercaptopurine的主效果) 2.incorporation of di- and triphosphate deoxy and ribonucleotides into tumor DNA or RNA and lead to termination of elongation (main M. of thioguanine) P.S. mercaptopurine有4M.(見 白RxCRxlogy)	1. E: thiopurine methyl transferase(TPMT) coE: S-adenosylmethionine BRxC f4232 2.xanthine oxidase( mercaptopurine), 所以併服allopurinol	*活化代謝↓ HPRT↓ *代謝↑ TPMT太多 Mercaptopurine效果↑ Thioguanine效果↓
Thioguanine (prodrug)(inactive)		guanine
Thionosine?
Azathiopurin 為prodrug(mercaptopurine)							用在移植已被mycophenolate mofetil取代了
M4. S1. Cytarabine(Ara-C) 血癌 ↓ Ancitabine 抵抗去胺 TI比Ara-C高 Gemcitabine(健擇)		Cytidine	| (deoxycytidine kinase) ↓monophosphate | (pyrimidine monophosphate and diphosphate kinase) ↓ Diphosphate, triphosphate	triphosphate	DNA polymerase inhibition and termination (reversible competitive)	Cytidine and deoxycytidylate( deoxycytidine monophosphate) deaminase (Ancitabine and Gemcitabine triphosphate inhibit 此E, 所以longer t1/2) Ara-C -(E)→arabinofuranosyluracil(inactive) Gemcitabine -(E)→dFdU(inactive)	*吸收↓ 缺乏selective nucleoside transportor pt.(此transportor pt.的對象為nucleoside) *代謝deoxycytidine kinase ↓ Deoxycytidine deaminase↑
M4. S2. Fludarabine monophosphate( increase water Sy for IV)		2-halogenated adenosine analogue (所以more resistant to adenosine deaminase degradation)	Deoxycytidine kinase	triphosphate	*inhibition of DNA polymerase and chain termination *fludarabine亦inhibit ribonucleotide reductase *clofarabine亦inhibit DNA修復時的enzyme, ribonucleotide reductase, and facilitate the release of proapototic pt. from mitochondria.	Adenosine deaminase( 2-halogenated purine亦iinhibit it的功能)
Cladribine
Clofarabine
M5. DON		似glutamine			干擾purine的3 and 9
Azaserine
Azaribine (2’, 3’, 5’- triacetate-6-azauridine)		6-azauridine					Parent drug抗癌ester抗牛皮癬
5-Azacitidine		Cytidine	Phosphorylation ↓Deamination(成5-azauridine)		Misreading and inhibit Orotidylate decarboxylase而防止pyrimidine nucleotide的形成		Phosphorylation↓, 併入核酸↓, RNA and DNA polymerase activity↑
Pentostatin(2'-deoxycoformycin)(DCF)		Purine nucleotide analogue	X	X	Inhibit adenosine deaminase( irreversible)而造成接下來的 inhibition of ribonucleotide reductase
Hydroxyurea		Urea	X	X	Inhibit ribonucleotide reductase		Increase the effectiveness of radiation therapy by stalling the cell cycle in the G1 stage
☆EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine)		Adenine	?	?	inhibit adenosine deaminase
Vidarabine(Ara-A) Adenosine kinase活化		Adenine	Adenosine kinase		M4. m1.inhibit early steps of ribonucleotide reductase and DNA polymerase	Adenosine deaminase去活化(可投予其inhibitor to potentiate it(ENHA))成arabinosyl hypoxanthine	HSV-1, HSV-2 encephalitis(持續點滴)
M.	cytidine deaminase inhibitor
	Ancitabine
	Gemcitabine(Gemzar健擇)
M.	adenosine deaminase inhibitor
	Fludarabine		2-halogenated adenosine
	Cladribine
	Clofarabine
	Pentostatin(2'-deoxycoformycin)(DCF)				先抑制adenosine deaminase
	EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine)				當antivirus-Ara-A輔助用藥
M.	Ribonucleotide reductase inhibitor
	Ara-A-(-)→ Ribonucleotide (diphosphate) reductase (NDP→dNDP) DNA polymerase Ara-C 沒
	Fludarabine(似Vidarabine) -(-)→ DNA polymerase and chain elongation Ribonucleotide reductase Clofarabine DNA polymerase and chain elongation Ribonucleotide (diphosphate) reductase
	Pentostatin(2'-deoxycoformycin)(DCF) 先inhibit adenosine deaminase 再Ribonucleotide reductase Hydroxyurea-(-)→ Ribonucleotide reductase

ADR

• 早期的抗代謝物由於選擇性不佳常常也作用於宿主而造成毒性：諸如血液毒性(骨髓抑制、貧血......)
  • trifluridine:因為太毒所以局部用
  • idoxuridine:因為太毒所以局部用
  • ribavirin:貧血
• 致畸胎
  • ribavirin:貧血
• purine analogue會引起痛風