VINCRISTINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C46H56N4O10
Molecular Weight	824.9576
Optical Activity	UNSPECIFIED
Defined Stereocenters	9 / 9
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC[C@]1(O)C[C@@H]2CN(C1)CCC3=C(NC4=C3C=CC=C4)[C@@](C2)(C(=O)OC)C5=C(OC)C=C6N(C=O)[C@@H]7[C@]8(CCN9CC=C[C@](CC)([C@@H]89)[C@@H](OC(C)=O)[C@]7(O)C(=O)OC)C6=C5

InChI

InChIKey=OGWKCGZFUXNPDA-CFWMRBGOSA-N

InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28)25-42)29-12-9-10-13-33(29)47-36)32-20-31-34(21-35(32)57-4)50(26-51)38-44(31)16-19-49-17-11-15-43(8-2,37(44)49)39(60-27(3)52)46(38,56)41(54)59-6/h9-13,15,20-21,26,28,37-39,47,55-56H,7-8,14,16-19,22-25H2,1-6H3/t28-,37-,38+,39+,42-,43+,44+,45-,46-/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00541
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/pro/vincristine.html

Vincristine is a vinca alkaloid antineoplastic agent used as a treatment for various cancers including breast cancer, Hodgkin's disease, Kaposi's sarcoma, and testicular cancer. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. The vinca alkaloids have become clinically useful since the discovery of their antitumour properties in 1959. Initially, extracts of the periwinkle plant (Catharanthus roseus) were investigated because of putative hypoglycemic properties, but were noted to cause marrow suppression in rats and antileukemic effects in vitro. Vincristine binds to the microtubular proteins of the mitotic spindle, leading to crystallization of the microtubule and mitotic arrest or cell death. Vincristine has some immunosuppressant effect. The vinca alkaloids are considered to be cell cycle phase-specific. The antitumor activity of Vincristine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, Vincristine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca2+-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis.Vincristine was marketed under the brand name Oncovin, but was discontinued. In 2012 the FDA approved a Liposomal formulation of Vincristine, named MARQIBO KIT.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
transformed cell apoptotic process 104 Target ID: GO:0006927 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19137911	Activator 1447
Tubulin beta chain 8 Target ID: P07437 Gene ID: 203068.0 Gene Symbol: TUBB Target Organism: Homo sapiens (Human) Sources: http://www.drugbank.ca/drugs/DB00541	Inhibitor 8504
microtubule polymerization 21 Target ID: GO:0046785 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10920282	Inhibitor 8504	1.6 µM [IC50]
CCRF-CEM 4 Target ID: CHEMBL382 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22582991	Inhibitor 8504	0.17 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202497s000lbl.pdf	Primary		Approved 8583	Marqibo Approved Use Marqibo® is indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. Launch Date 2012

C_max

Value	Dose	Co-administered	Analyte	Population
1220 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000PharmR.pdf	2.25 mg/m² steady-state, intravenous dose: 2.25 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		VINCRISTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
14566 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000PharmR.pdf	2.25 mg/m² steady-state, intravenous dose: 2.25 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		VINCRISTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
25% OTHER GOV https://www.medsafe.govt.nz/profs/Datasheet/v/Vincristinesulfatempinj.pdf			VINCRISTINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
2.25 mg/m2 1 times / week multiple, intravenous MTD Dose: 2.25 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.25 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	unhealthy, 19-62 Health Status: unhealthy Age Group: 19-62 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	Sources: https://pubmed.ncbi.nlm.nih.gov/19708032
2.4 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 2.4 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.4 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	unhealthy, 19-62 Health Status: unhealthy Age Group: 19-62 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	DLT: Motor polyneuropathy, Seizure... Dose limiting toxicities: Motor polyneuropathy (grade 3, 14.3%) Seizure (grade 4, 14.3%) Hepatotoxicity (grade 4, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19708032
2.8 mg/m2 3 times / week multiple, intravenous Highest studied dose Dose: 2.8 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.8 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	DLT: Neutropenia, Thrombocytopenia... Dose limiting toxicities: Neutropenia (grade 4, 33.3%) Thrombocytopenia (grade 4, 33.3%) Obstipation Myalgia (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
2.4 mg/m2 3 times / week multiple, intravenous MTD Dose: 2.4 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.4 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
2.25 mg/m2 1 times / week multiple, intravenous Recommended Dose: 2.25 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.25 mg/m2, 1 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf	Disc. AE: Peripheral neuropathy, Tumor lysis syndrome... AEs leading to discontinuation/dose reduction: Peripheral neuropathy (10%) Tumor lysis syndrome (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf

AEs

AE	Significance	Dose	Population
Motor polyneuropathy	grade 3, 14.3% DLT	2.4 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 2.4 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.4 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	unhealthy, 19-62 Health Status: unhealthy Age Group: 19-62 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19708032
Hepatotoxicity	grade 4, 14.3% DLT	2.4 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 2.4 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.4 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	unhealthy, 19-62 Health Status: unhealthy Age Group: 19-62 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19708032
Seizure	grade 4, 14.3% DLT	2.4 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 2.4 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.4 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19708032	unhealthy, 19-62 Health Status: unhealthy Age Group: 19-62 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/19708032
Obstipation	DLT	2.8 mg/m2 3 times / week multiple, intravenous Highest studied dose Dose: 2.8 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.8 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
Myalgia	grade 3, 33.3% DLT	2.8 mg/m2 3 times / week multiple, intravenous Highest studied dose Dose: 2.8 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.8 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
Neutropenia	grade 4, 33.3% DLT	2.8 mg/m2 3 times / week multiple, intravenous Highest studied dose Dose: 2.8 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.8 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
Thrombocytopenia	grade 4, 33.3% DLT	2.8 mg/m2 3 times / week multiple, intravenous Highest studied dose Dose: 2.8 mg/m2, 3 times / week Route: intravenous Route: multiple Dose: 2.8 mg/m2, 3 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10080616	unhealthy, 32-83 Health Status: unhealthy Age Group: 32-83 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10080616
Peripheral neuropathy	10% Disc. AE	2.25 mg/m2 1 times / week multiple, intravenous Recommended Dose: 2.25 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.25 mg/m2, 1 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf
Tumor lysis syndrome	2% Disc. AE	2.25 mg/m2 1 times / week multiple, intravenous Recommended Dose: 2.25 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2.25 mg/m2, 1 times / week Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202497s011lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946		substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C19 1119 P-gp 2052

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	likely
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000ClinPharmR.pdf#page=31 Page: 31.0	likely
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/17029589/	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000ClinPharmR.pdf#page=31; https://pubmed.ncbi.nlm.nih.gov/10613614/ Page: 31.0	yes	yes (co-administration study) Comment: the total area under the plasma concentration-time curve was 43% smaller in patients who were receiving carbamazepine or phenytoin than in the control group; the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497Orig1s000ClinPharmR.pdf#page=31; https://pubmed.ncbi.nlm.nih.gov/10613614/ Page: 31.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/15812674/ Page: 4.0

Sourcing

Vendor/Aggregator	ID	URL
AbovChem LLC	HY-N0488
AK Scientific	E375
Biopurify Phytochemicals	BP1439
Biopurify Phytochemicals	BP1440
BioSynth	Q-201925
BOC Sciences	2068-78-2
Bosche Scientific	V1207
Cayman Chemical	11764
Chem Scene	CS-1778
eMolecules	32176538
eMolecules	50241482
eMolecules	95704370
Hangzhou APIChem Technology	AC-22619
Hangzhou Yuhao Chemical Technology	RT14234
IBScreen	STOCK1N-40733
KeyOrganics	AS-12168
mcule	MCULE-1562099693
mcule	MCULE-3827132352
MedChem Express	HY-N0488
MolPort	MolPort-002-519-272
MolPort	MolPort-003-939-860
MolPort	MolPort-035-789-673
Sigma Aldrich	1714007
Sigma Aldrich	V0400000
Sigma Aldrich	V0400000\|SIAL
Sigma Aldrich	V8388\|SIAL
Sigma Aldrich	V8879\|SIGMA
ZINC	ZINC000085537024	http://zinc15.docking.org/substances/ZINC000085537024

PubMed

Title	Date	PubMed
Animal models for the comparative assessment of neurotoxicity following repeated administration of vinca alkaloids.	1979 Jan	105807
Combined intra-arterial and systemic chemotherapy for recurrent malignant brain tumors.	1992 Feb	1312230
Vincristine neurotoxicity.	1992 Mar	1319399
[Superiority of intrafascicular neurography over conventional nerve conduction studies in evaluating axonal degeneration].	1999 Apr	10363265
Altered expression of the MYCN oncogene modulates MRP gene expression and response to cytotoxic drugs in neuroblastoma cells.	1999 Apr 29	10348353
Toxic epidermal necrolysis and graft vs. host disease: a clinical spectrum but a diagnostic dilemma.	1999 Jul	10457124
[Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].	1999 May	10390891
Primary desmoplastic small cell tumor of soft tissues and bone of the hand.	1999 Nov	10555010
Vincristine treatment revealing asymptomatic hereditary motor sensory neuropathy type 1A.	1999 Nov	10519723
Low-dose vincristine-associated bilateral vocal cord paralysis.	1999 Oct	10578547
Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.	1999 Oct	10515904
Nerve growth factor prevention of aged-rat sympathetic neuron injury by cisplatin, vincristine and taxol--in vitro explant study.	1999 Oct 22	10553948
Clinical and electrophysiological studies in vincristine induced neuropathy.	1999 Sep	10499201
Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells.	1999 Sep	10454517
Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.	2000	11030069
The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance.	2000 Aug	10900222
[Syndrome of inappropriate secretion of antidiuretic hormone in a patient with myeloid antigen positive acute lymphoblastic leukemia after systemic chemotherapy including vincristine].	2000 Jan	10660739
Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.	2000 Jan	10617675
Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals.	2000 Jan 3	10685512
[Establishment of MRP-overexpression subline of bladder carcinoma and its MDR phenotype].	2000 Jul	11778547
Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy.	2000 Jun	10942065
Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia.	2000 Mar	10741703
Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy.	2000 Mar	10730638
Treatment for primary CNS lymphoma: the next step.	2000 Sep	10963643
Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat.	2000 Sep 4	10931481
Hemolytic uremic syndrome secondary to the treatment of acute lymphoblastic leukemia.	2000 Sep-Oct	11037870
[An experimental study on the blood vessel sclerosing therapeutic agents for cavernous hemangiomas].	2001 Aug	12539736
Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100.	2001 Feb 16	11178967
Treatment of classical type Kaposi's sarcoma with paclitaxel.	2001 Jan-Feb	11299806
Experience with vincristine--associated neurotoxicity.	2001 Jul	11957264
Mutation of a single conserved tryptophan in multidrug resistance protein 1 (MRP1/ABCC1) results in loss of drug resistance and selective loss of organic anion transport.	2001 May 11	11278867
Ischemic heart disease associated with vincristine and doxorubicin chemotherapy.	2001 Nov	11724093
Epidemiology of Burkitt's lymphoma in Enugu, Nigeria.	2002 Dec	12530287
Identification and characterization of the canine multidrug resistance-associated protein.	2002 Dec	12516967
Posttransplantation lymphoproliferative disorder presenting as a unilateral leg mass 10 years after kidney transplantation.	2002 Dec 15	12490805
Vincristine-induced vocal cord paralysis in an infant.	2002 Feb	11882230
Improvement of combination chemotherapy tolerance by introduction of polycistronic retroviral vector drug resistance genes MGMT and MDR1 into human umbilical cord blood CD34+ cells.	2002 Mar	11792417
Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma.	2002 Nov-Dec	12465768
Vincristine-itraconazole interaction: cause for increasing concern.	2002 Oct	12368705
Altered temporal pattern of evoked afferent activity in a rat model of vincristine-induced painful peripheral neuropathy.	2003	12710988
[Clinical analysis of 75 patients with nasopharyngeal non-Hodgkin's lymphoma].	2003 Apr	12703998
Vincristine-induced neuropathy as the initial presentation of charcot-marie-tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study.	2003 Apr	12679647
[Anaphylaxia induced by etoposide--a case report].	2003 Aug	12938279
The effects of chemotherapeutic agents on the regulation of thrombin on cell surfaces.	2003 Jan	12542493
NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21.	2003 Jan 1	12517776
Toxic neuropathy in patients with pre-existing neuropathy.	2003 Jan 28	12552058
Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells.	2003 Jul 15	12874004
Cloning and functional characterization of the multidrug resistance-associated protein (MRP1/ABCC1) from the cynomolgus monkey.	2003 Mar	12657726
The egr-1 gene is induced by DNA-damaging agents and non-genotoxic drugs in both normal and neoplastic human cells.	2003 May 16	12706485
Functional expression of the multidrug resistance protein 1 in microglia.	2003 Oct	12893836

Patents

Sample Use Guides

In Vivo Use Guide

Marqibo is liposome-encapsulated vincristine. 2.25 mg/m2 intravenously over 1 hour once every 7 days.

Route of Administration: Intravenous

In Vitro Use Guide

Treatment of macrophage monolayers for 24 h with vincristine (10(-5)-10(-7) M) inhibited the antibody dependent cellular cytotoxicity (ADCC) by PMA stimulated rat macrophages.

Name

Type

Language

TECNOCRIS

Preferred Name

English

VINCRISTINE

Official Name

English

(+)-VINCRISTINE

Common Name

English

22-OXOVINCALEUKOBLASTINE

Common Name

English

VINCALEUKOBLASTINE, 22-OXO-

Common Name

English

Vincristine [WHO-DD]

Common Name

English

ONCOTCS

Brand Name

English

VINCRISTINE [VANDF]

Common Name

English

VINCRISTINE [MI]

Common Name

English

VINCRISTINE [HSDB]

Common Name

English

VINKRISTIN

Common Name

English

VCR

Common Name

English

LEUROCRISTINE

Common Name

English

LEUCRISTINE

Common Name

English

vincristine [INN]

Common Name

English

VINCRISTIN

Common Name

English

Classification Tree Code System Code

WHO-VATC

QL01CA02