Vincristine sulfate Property

Melting point:

300 °C

Boiling point:

273-281 °C

alpha 

D26 +8.5° (c = 0.8)

storage temp. 

Sealed in dry,Store in freezer, under -20°C

solubility 

methanol: soluble20mg/mL

form 

lyophilized powder

color 

white to off-white

Water Solubility 

>=1 g/100 mL at 24 ºC

BRN 

3924631

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in distilled water may be stored at -20° for up to 3 months.

InChI

InChI=1/C46H56N4O10.H2O4S/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;1-5(2,3)4/h9-13,15,20-21,26,28,37-39,47,55-56H,7-8,14,16-19,22-25H2,1-6H3;(H2,1,2,3,4)/t28-,37-,38+,39+,42-,43+,44+,45-,46-;/s3

InChIKey

AQTQHPDCURKLKT-HSMPTBRCNA-N

SMILES

[C@]123CCN4CC=C[C@@](CC)([C@@H](OC(=O)C)[C@](O)(C(=O)OC)[C@@]1(N(C1C=C(OC)C([C@@]5(C(=O)OC)C[C@]6([H])C[C@@](CC)(CN(CCC7C8=C(C=CC=C8)NC5=7)C6)O)=CC2=1)C=O)[H])[C@@]34[H].S(=O)(=O)(O)O |&1:0,7,10,15,21,29,35,38,61,r|

IARC

3 (Vol. 26, Sup 7) 1987

EPA Substance Registry System

Vincristine sulfate (2068-78-2)

Safety

Hazard Codes 

T

Risk Statements 

61-36/37/38-63-23/24/25-68-62-25

Safety Statements 

22-24/25-53-45-37/39-26-36/37/39-36/37

RIDADR 

UN 2811 6.1/PG 2

WGK Germany 

3

RTECS 

OH6340000

F 

8-10

HazardClass 

6.1(a)

PackingGroup 

II

HS Code 

29399990

Toxicity

LD50 intraperitoneal in mouse: 3mg/kg

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H300Fatal if swallowed

H341Suspected of causing genetic defects

Precautionary statements

P202Do not handle until all safety precautions have been read and understood.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P301+P310IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.

P405Store locked up.

Vincristine sulfate Chemical Properties,Usage,Production

Description

Vincristine sulfate (2068-78-2) arrests cell cycle at G2/M by interfering with mitotic spindle formation. Depolymerizes microtubules and blocks binding of tubulin to microtubule proteins.1,2?Induces apoptosis.3?Vincristine sulfate is a clinically useful cancer chemotherapeutic agent.

Chemical Properties

Crystalline Solid

Originator

Oncovin,Lilly ,US ,1963

Uses

Vincristin sulfate USP (Oncovin) is used to treat acute leukemia in children; lymphocytic leukemia; Hodgkin’s disease; non-Hodgkin’s lymphomas; Wilm’s tumor; neuroblastoma; rhabdomyosarcoma.

Uses

Vincristine sulfate, is used as an anticancer agent, microtubule disrupter, Induces apoptosis in human lymphoma cells. Other applications include as a cell cycle arresting, apoptotic inducing alkaloid.

Uses

An antitumor alkaloid isolated from Vinca rosea Linn. An antineoplastic.

Uses

H1-antihistamine

Manufacturing Process

The alkaloid mixture from the extraction of Vinca rosea plants (as in vinblastine extraction) was chromatographed to give vincristine which was then converted to the sulfate, according to US Patent 3,205,220.
Vincristine may also be prepared in a semisynthetic process starting from vinblastine. Vinblastine or a salt thereof, preferably the sulfate, is oxidized with chromic acid or with one of its salts at a low temperature, the reaction mixture is neutralized or rendered alkaline and the product is separated therefrom by extraction, the extract is evaporated to dryness, the dry residue is optionally formylated, vincristine, and optionally N-demethylvinblastine also, are isolated from the product, and the product(s) are optionally converted into their salts; preferably into the sulfates, according to US Patent 3,899,493.

brand name

Oncovin (Lilly); Vincasar (Sicor).

Therapeutic Function

Cancer chemotherapy

General Description

Vincristine sulfate appears as an anticancer drug. White to slightly yellow, amorphous or crystalline powder. Sensitive to light. Odorless. pH (0.1% solution) 3.5 - 4.5. (NTP, 1992)

Air & Water Reactions

Very hygroscopic. Water soluble.

Reactivity Profile

Sensitive to hydrolysis, oxidation and heat. Incompatible with strong oxidizing agents. .

Fire Hazard

Flash point data for Vincristine sulfate are not available; however, Vincristine sulfate is probably combustible.

Biological Activity

Anticancer agent; microtubule disrupter. Induces apoptosis in human lymphoma cells.

Clinical Use

Vincristine sulfate is available as a 1-mg/mL solution in 1-,2-, and 5-mL vials for IV administration in acute leukemiaand as part of a multidrug regime for Hodgkin’s and neuroblastoma, Ewing sarcoma, Wilms tumor, soft tissuesarcoma, testicular cancer, liver cancer, and head and neckcancers. It has also been utilized in treating pediatric cancer.

Veterinary Drugs and Treatments

Vincristine is used as an antineoplastic primarily in combination drug protocols in dogs and cats in the treatment of lymphoid and hematopoietic neoplasms. In dogs, it may be used alone in the therapy of transmissible venereal neoplasms.
Because vincristine can induce thrombocytosis (at low doses) and has some immunosuppressant activity, it may also be employed in the treatment of immune-mediated thrombocytopenia.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: possible increased risk of ventricular arrhythmias with delamanid.
Antiepileptics: phenytoin levels may be reduced.
Antifungals: metabolism possibly inhibited by itraconazole and posaconazole (increased risk of neurotoxicity).
Antimalarials: avoid with piperaquine with artenimol.
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).
Cytotoxics: toxicity possibly increased by asparaginase, crisantaspase and pegasparagase - give at least 3-24 hours before asparaginase, crisantaspase and pegasparagase; increased risk of hepatotoxicity with dactinomycin.

Metabolism

Vincristine is metabolised in the liver by the cytochrome P450 isoenzymes CYP3A4 and CYP3A5 and excreted mainly in the bile; about 70-80 % of a dose is found in faeces, as unchanged drug and metabolites (40-50 %), while 10-20 % appears in the urine.
Vincristine is highly protein bound (75%) and may also bindto platelets that contain large amounts of tubulin. Numerousmetabolites have been detected and several have been identified,one of which is the 4-O-desacetyl derivative. The metabolismthat does occur is believed to largely be mediatedby CYP3A. Elimination occurs primarily in the bile with aterminal elimination half-life of 23 to 85 hours.

storage

Store at -20°C

Purification Methods

The salt is recrystallised from MeOH. It has UV max at 220, 255 and 296nm (log  4.65, 4.21 and 4.18). It is a monoamine oxidase inhibitor and is used in cancer research [Son et al. J Med Chem 33 1845 1990, Horio et al. Proc Natl Acad Sci USA 85 3580 1988].

Mode of action

Vincristine Sulfate is the sulfate salt of a natural alkaloid isolated from the plant Catharanthus roseus (Vinca rosea L.) with antimitotic and antineoplastic activities. Vincristine binds irreversibly to microtubules and spindle proteins in S phase of the cell cycle and interferes with the formation of the mitotic spindle, thereby arresting tumor cells in metaphase. This agent also depolymerizes microtubules and may also interfere with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent Ca(2+)-activated ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis.

Toxicity evaluation

The mostcommonly seen toxicity for vincristine is a dose-limitingneurotoxicity caused by effects on axonal microtubules.Symptoms are variable and include peripheral neuropathy,ataxia, seizure, bone pain, and coma. Constipation is also acommonly seen toxicity, and laxatives may be used prophylactically.Other toxicities include alopecia, skin rash, mildmyelosuppression, secretion of antidiuretic hormone,azospermia, and amenorrhea.

References

1) Jordan et al. (1998), Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle; Med. Res. Rev., 18 259 2) Lobert et al. (1996), Interaction of vinca alkaloids with tubulin: a comparison of vinblastine, vincristine, and vinorelbine; Biochemistry, 35 6806 3) Wang et al. (1999), The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review: Cancer Chemother. Pharmacol., 44 355