Maryam Moudi International Journal ofPreventiveMedicine, Vol 4,No 11, November, 2013 Nazre M. Vinca alkaloids.IntJPrevMed2013;4:1231-5. How tocitethisarticle: of Acceptance: Date Date ofSubmission: E‑mail: [email protected] Selangor DarulEhsan,Malaysia. 43400 UPM,Serdang, Products, Universiti PutraMalaysia, Institute ofTropicalForestryandForest Department ofBiology,FacultyScience, Dr. Rusea Go, Correspondence to: Serdang, SelangorDarulEhsan,Malaysia Forestry, Universiti PutraMalaysia,43400UPM, 2 Serdang, SelangorDarulEhsan,Malaysia, Universiti PutraMalaysia,43400UPM, 1 Serdang, SelangorDarulEhsan,Malaysia, Universiti PutraMalaysia,43400UPM, Department ofBiology,FacultyScience, Department ForestProductions,Facultyof Institute ofTropicalForestryandForestProducts,

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1 , RuseaGo MoudiM,GoR, Yien CYS,

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activity, which is of little importance comparedtotheir activity, littleimportance whichisof thesecompoundsfortheirhypoglycemic the monitoringof thisplantleadto for thefirsttime. Medicinalapplicationsof 1950’s byCanadian scientists, Robert NobleandCharles Beer G. Don bases extracted fromthepinkperiwinkle plant plant. Theyarenaturally orsemisynthetic nitrogenous occurring cancer arethevincaalkaloids. that used to treat the plant alkaloids groups of The oldest group physiological effects toothatmakethemusefulasmedicines. Many alkaloidswithhaving poisonouscharacteristicshave alkalilikesomedonotexhibitrepresents alkaline properties. derived fromplantsisnamedalkaloid.Although,thename carbon,hydrogen, nitrogen andoxygenmade upof thatisoften INTRODUCTION , , vinflunine, Keywords: out inthis regard. vinca alkaloidapplications will be carried original cancer therapies. Different researches andstudies fornew and will stay amongthe cancer drugs second‑most‑used class of being developed forother malignancies. Vinca alkaloidsare the the urothelium is second‑line transitional cell carcinoma of of , which hasbeen approved inEurope forthe treatment use inthe United States. isalsoanew synthetic vinca Vinflunine vindesine use: cancer fighters. are fourmajorvinca alkaloidsinclinical There as disinfectants. forbeing vinca alkaloidsare alsoimportant The used to treat diabetes, highbloodpressure andhave been used a hypoglycemic aswell ascytotoxic effects. have They been the pink periwinkle plant, G. Don and have arenaturally extracted from periwinkle plant. They Madagascar obtained fromthe drugs Vinca alkaloidsare asubset of ABSTRACT Vinca alkaloidsareobtainedfrom theMadagascarperiwinkle organic compounds a class of Vinca alkaloids are a material of What arevincaalkaloids? [3] (VDS). VCR, VBLandVRLhave been approved for

Madagascar periwinkle, vinblastine, Madagascar vinca alkaloids, [Figure 1 (VBL), vinorelbine , Mohd.Nazre 1]. Vinca alkaloids were found out in the [2] 3 (VRL), vincristine Catharanthus www.ijpm.in www.ijpm.ir (VCR) and

roseus 1231 [1]

Review Article Moudi, et al.: Review on vinca alkaloids

Figure 1: The flowers ofCatharanthus roseus G. Don. Catharanthus roseus (syn. Vinca rosea) an evergreen shrub, it grows to a height of 1 m with a spread of 1 m. The stem is short, erect and branching; the leaves are glossy green, oval, 5 cm long and opposite acuminate; the flowers are soft pink, tinged with red, 5 petal, open, tubular and 4 cm across, appearing in spring and autumn (three colors: pink, purple and white) (http://my.opera.com/Thachthaotim84/albums/showpic.dml) cytotoxic effects.[4] They have been used to treat see near to 16‑17 high‑affinity binding sites in diabetes, high blood pressure and the drugs have each that located at the ends of per even been used as disinfectants. Nevertheless, the microtubule. Binding of the vinca alkaloids to vinca alkaloids are so important for being cancer these sites interrupts microtubule congregation, fighters. There are four major vinca alkaloids in but one of the most important effect of low drug clinical use: Vinblastine (VBL), vinorelbine (VRL), concentrations can be decreasing the rates of both vincristine and vindesine (VDS), but only VCR, growth and shortening at the assembly end of the VBL and VRL are approved for use in the United microtubule that can cause produces a “kinetic States.[3] From 2008, there is also a new synthetic cap” and suppresses function.[10] The disturbing vinca alkaloid, vinflunine that is currently approved effects of the vinca alkaloids on microtubule in Europe for medicinal treatment.[5,6] dynamics, particularly at the ends of the mitotic spindle, which cause metaphase arrest, occur at drug concentrations below those that decrease MECHANISM OF ACTION microtubule mass.[11] The main mechanisms of vince alakaloid The vinca alkaloids and other microtubule cytotoxicity is due to their interactions with disrupting agents have power to inhibit malignant and disruption of microtubule function, angiogenesis in vitro. For example, VBL with particularly of comprising the concentrations range from 0.1 to 1.0 pmol/L mitotic spindle apparatus, directly causing blocked endothelial proliferation, chemotaxis [7] metaphase arrest. However, they can do many and spreading on fibronectin, all essential steps other biochemical activities that may or may not in angiogenesis,[12] but other normal fibroblasts be related to their effects on microtubules. Many and lymphoid tumors were unaffected at these of the effects that do not include microtubule minute concentrations. In combination with interruption happen only after treatment of antibodies against vascular endothelial growth cells with clinically irrelevant doses of the vinca factor, low doses of VBL increased antitumor alkaloids. Nevertheless, the vinca alkaloids and response considerably, even in tumors resistant other antimicrotubule agents also have an effect to direct cytotoxic effects of the drug.[13] Vinca on both non‑malignant and malignant cells in the alkaloids inhibit cell proliferation by binding to non‑mitotic , because microtubules are microtubules, which can cause a mitotic block and [3] involved in many non‑mitotic functions. apoptosis. VCR and related compounds produce The vinca alkaloids connect to binding sites destabilization of microtubules by binding to on tubulin that they are separate from those of tubulin and blocking the polymerization.[14] the , colchicine, podophyllotoxin and guanosine‑5’‑triphosphate.[8] Binding occurs rapidly and can reverse too. Existing evidence MEDICINAL USES maintains the existence of two vinca alkaloid The vinca alkaloids have been generally binding sites per mole of tubulin dimer.[9] We can included in combination regimens

1232 International Journal of Preventive Medicine, Vol 4, No 11, November, 2013 Moudi, et al.: Review on vinca alkaloids for medicinal therapies. They do not have urothelium (TCCU), is being developed for other cross‑resistance with drugs that alkylate malignancies. It has been applied for clinical deoxyribonucleic acid (DNA) and have a different development in the wide spectrum of solid tumors. mechanism of action.[3] VBL has been used as Clinically, important activity has been seen mainly an integral part of medicinal treatment regimens in the treatment of transitional cell carcinoma of for testicular carcinoma and both Hodgkin and the urothelial tract, non‑small cell lung cancer and non‑Hodgkin lymphomas.[15] It is also used in carcinoma of the breast. Vinflunine is has been breast cancer and germ cell tumors. Side‑effects also assessed in patients with TCCU and first‑line of VBL consist of toxicity to white blood cells, advanced breast cancer.[5] nausea, vomiting, constipation, dyspnea, chest or tumor pain, wheezing and fever. It is also rarely associated with antidiuretic hormone secretion.[3] TOXICITY VRL is same to VBL. It has significant antitumor Although, the vinca alkaloids are quite similar activity in patients with breast cancer and can from a structural position, their toxicologic be affected on bone tumor cells, osteosarcoma. profiles are different extensively. All vinca In addition, VRL decreases the stability of lipid alkaloids make a characteristic peripheral bilayer membranes. In the United States, VRL has neurotoxicity, but VCR has most potential in this been approved for the initial treatment of patients case. The neurotoxicity is mostly distinguished with advanced lung cancer.[16] VRL’s side‑effects by a peripheral, symmetric varied sensory‑motor are: Decreasing resistance to infection, bruising or and autonomic polyneuropathy.[7] The primary bleeding, anemia, constipation, diarrhea, nausea, pathologic effect is related to axonal degeneration numbness or tingling in the hands and feet, and decreasing of axonal transport, most fatigue (also called peripheral neuropathy) and likely caused by a drug‑induced perturbation inflammation at the injection site. Less common of microtubule function. The uptake of VCR side‑effects include hair loss and allergic reaction.[3] into the brain is low and central nervous system VCR has been approved to treat acute leukemia, effects, such as confusion, mental status changes, rhabdomyosarcoma, neuroblastoma, Wilm’s tumor, depression, hallucinations, agitation, insomnia, Hodgkin’s disease and other lymphomas. Another seizures, coma, syndrome inappropriate secretion characteristic of VCR that has been reported of antidiuretic hormone and visual disturbances is treating several non‑malignant hematologic are infrequent. Laryngeal paralysis has also been disorders such as refractory autoimmune informed. The only known effective interference thrombocytopenia, hemolytic uremic syndrome for vinca alkaloid neurotoxicity is discontinuing and thrombotic thrombocytopenia purpura. treatment or decrease of the dose or frequency VCR’s most common side‑effects are: Peripheral of drug administration. Although a number of neuropathy, suppression of bone marrow activity, antidotes, including thiamine, vitamin B12, folinic constipation, nervous system toxicity, nausea and acid, pyridoxine and neuroactive agents, have vomiting.[3,15] been applied, these treatments have not been VDS has similar effects to VBL. Antineoplastic obviously shown to be effective. The symptoms activity of VDS has been reported in acute of neurotoxicity are similar for all vinca alkaloids; lymphocytic leukemia, blast crisis of chronic severe neurotoxicity is observed less frequently myeloid leukemia, malignant melanoma, pediatric with VBL and VRL as compared with VCR. solid tumors and metastatic renal, breast, Neutropenia is the main dose‑limiting toxicity esophageal and colorectal carcinomas.[17] Recently, of VBL, VDS and VRL. Thrombocytopenia and a new synthetic vinca alkaloid, vinflunine was anemia usually have been seen less. In addition, developed through the addition of two fluor VCR is related with hematologic toxicity rarely, molecules by superacidic chemistry.[6] Vinflunine severe myelosuppression has been monitored in is the first fluorinated microtubule inhibitor that situations resulting in profoundly increased drug belongs to the vinca alkaloids. This compound exposure and hepatic deficiency.[3] has been used in Europe for the treatment of Gastrointestinal toxicities, aside from those second‑line transitional cell carcinoma of the caused by autonomic dysfunction, may be observed

International Journal of Preventive Medicine, Vol 4, No 11, November, 2013 1233 Moudi, et al.: Review on vinca alkaloids with using vinca alkaloids.[18] Gastrointestinal Overall, vinca alkaloids have the second most‑used autonomic dysfunction, as manifested by bloating, class of cancer drugs and will stay among the original constipation, ileus and abdominal pain, occur most cancer therapies. Different researches and studies for commonly with VCR or high doses of the other new vinca alkaloid applications will be carried out in vinca alkaloids. Mucositis occurs more frequently this regard. with VBL than VRL and is common with VCR. Nausea, vomiting and diarrhea may also occurred. The vinca alkaloids are effective vesicants and REFERENCES may lead to significant tissue damage too.[3] Acute 1. Sahelian R. Alkaloid substances in plants, information on cardiac ischemia, chest pains without evidence vinca, ergot and ephedra alkaloid compounds. [Cited on of ischemia, fever without an obvious source, 2011 Jul 9]. acute pulmonary effects, Raynaud phenomenon, 2. Brogan C. Alkaloids cancer treatments, 2010 Jun 7. Available from: http://www.Vinca alkaloids\Alkaloids Hand‑foot syndrome and pulmonary and hepatic Cancer Treatment Livestrong_com.mh. [Cited on toxicity have also been seen with the vinca [19] 2010 Sep 23]. alkaloids. 3. Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, These drugs should not be used by a patient Gansler TS, Holland JF, et al. Holland‑Frei cancer who is pregnant, has planning for pregnancy or medicine. 6th ed. Hamilton (ON): BC Decker Inc.; 2003. has breast‑feeding as it may cause birth defects. 4. Gidding CE, Kellie SJ, Kamps WA, de Graaf SS. Vincristine Patients should not receive any vaccinations while revisited. Crit Rev Oncol Hematol 1999;29:267‑87. taking this medication. VCR may cause weakness 5. Bennouna J, Delord JP, Campone M, Nguyen L. of immunity system and can lead to an illness.[20] Vinflunine: A new microtubule inhibitor agent. Clin Patients should notify their clinician about any Cancer Res 2008;14:1625‑32. prescription drugs taken concurrently with the 6. Schutz FA, Bellmunt J, Rosenberg JE, Choueiri TK. chemotherapy and any other medical conditions, Vinflunine: Drug safety evaluation of this novel synthetic such as, chickenpox, herpes zoster infection, gout, vinca alkaloid. Expert Opin Drug Saf 2011;10:645‑53. kidney stones, infections, liver disease, nerve or 7. Himes RH. Interactions of the catharanthus (Vinca) muscle disease.[20] Over all, drug concentration alkaloids with tubulin and microtubules. Pharmacol Ther and duration of treatment are important for 1991;51:257‑67. determining of both drug accumulation and 8. Downing KH. Structural basis for the interaction of cytotoxicity, but the importance of available tubulin with proteins and drugs that affect microtubule information show that using of drug above a critical dynamics. Annu Rev Cell Dev Biol 2000;16:89‑111. threshold concentration is the most important 9. Correia JJ, Lobert S. Physiochemical aspects of determinant.[21] tubulin‑interacting antimitotic drugs. Curr Pharm Des 2001;7:1213‑28. 10. Jordan MA, Thrower D, Wilson L. Effects of vinblastine, CONCLUSIONS podophyllotoxin and nocodazole on mitotic spindles. Vinca alkaloids have been generally included in Implications for the role of microtubule dynamics in combination chemotherapy regimens for medicinal mitosis. J Cell Sci 1992;102:401‑16. therapies. They do not have cross‑resistance with drugs 11. Toso RJ, Jordan MA, Farrell KW, Matsumoto B, Wilson L. that alkylate DNA and have a different mechanism of Kinetic stabilization of microtubule dynamic instability in vitro by vinblastine. Biochemistry 1993;32:1285‑93. action. They have been used to treat diabetes, high 12. Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, blood pressure and have been used as disinfectants and Ria R, et al. Antiangiogenesis is produced by nontoxic anti‑cancer. The vinca alkaloids have cytotoxic effects doses of vinblastine. Blood 1999;94:4143‑55. that can arrest the division of cells and causes cell death. 13. Klement G, Baruchel S, Rak J, Man S, Clark K, There are four major vinca alkaloids in clinical use: Hicklin DJ, et al. Continuous low‑dose therapy with VBL, VRL, VCR and VDS. VCR, VBL and VRL have vinblastine and VEGF receptor‑2 antibody induces been approved for use in the United States. Vinflunine sustained tumor regression without overt toxicity. J Clin is also a new synthetic vinca alkaloid, which has been Invest 2000;105:R15‑24. approved in Europe for the treatment of second‑line 14. Wang LG, Liu XM, Kreis W, Budman DR. The effect of TCCU, is being developed for other malignancies. antimicrotubule agents on signal transduction pathways

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