Anticancer agents against malaria: time to revisit?

Anticancer agents against malaria: time to revisit?

Alexis Nzila1,2, John Okombo1, Ruy Perez Becker3, Roma Chilengi1,2, Trudie Lang1,2, andTim Niehues3Alexis Nzila: [email protected] Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Programme,PO Box 230, 80108, Kilifi, Kenya2University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK3Helios Klinikum Krefeld Academic Hospital, Lutherplatz 40, 47805 Krefeld, Germany

AbstractThe emergence of artemisinin resistance could adversely impact the current strategy for malariatreatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarialsis to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate areactive against malaria. However, they are commonly perceived to be toxic and thus not suitable formalaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just amatter of dose or ‘only dose makes the poison’, as coined in Paracelsus’ law. Thus, the opportunityexists to discover new antimalarials using the anticancer pharmacopoeia.

The need for new antimalarial drugsThe malaria parasite, the cause of one of the most significant infectious diseases, ischaracterised by an intrinsic ability to select for resistance against drugs. To slow down thepace of resistance selection, it has been recommended that antimalarials be used incombinations of at least two drugs with different modes of action, and the currentrecommendation is to use artemesinin-based combinations [1]. However, recent reportsindicate that resistance to artemesinin is emerging in Southeast Asia, and there are concernsthat the therapeutic life span of artemisinin combinations might be compromised [2]. Thechoices for combination therapy could be reduced and, as a result, drug resistance would remaina limitation to sustaining effective malaria treatment.

One approach for discovering new antimalarials is to re-use drugs developed for the treatmentof other diseases. The literature is replete with examples of new uses for old drugs. For example,among the few drugs that are available in the treatment of malaria, quinine is used to treatmuscle cramps [3], and chloroquine (CQ) (preferably hydroxyl-chloroquine) is used for themanagement of rheumatoid arthritis and systemic lupus erythematosus [4]. Artemisinin isbeing investigated for the treatment of schistosomiasis and cancer [5,6]. However, thus far,there is no drug that has been re-used for acute malarial treatment, in spite of the richness ofthe human pharmacopoeia. Only drugs, such as the antibiotic doxycycline, azithromycin anderythromycin, have been used, or are currently being investigated, for prophylaxis againstmalaria [7,8]. Dapsone, a drug used to treat leprosy and dermatitis herpetiformis [9], wascombined with chlorproguanil (Lapdap®) [10]; however, this combination has been phasedout because of dapsone toxicity.

Antimalarial potential of methotrexate and trimetrexate, in vitroThere is evidence that anticancer compounds methotrexate (MTX) and trimetrexate (TMX)are active against both pyrimethamine (PM)-sensitive and PM-resistant laboratory strains and

Sponsored document fromTrends in Parasitology

Published as: Trends Parasitol. 2010 March ; 26(3-3): 125–129.

Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

https://www.researchgate.net/publication/50592323_Malaria_prevention_in_travellers?el=1_x_8&enrichId=rgreq-b4349ecb82222d17499e2de96c15ed3b-XXX&enrichSource=Y292ZXJQYWdlOzQwODk0NDcwO0FTOjk4NTQwMjYwOTU0MTIyQDE0MDA1MDUyMzc3MTk=

field isolates of Plasmodium falciparum, including those carrying the Ileu164-Leu dhfr codon(dihydrofolate reductase, DHFR), with IC50 < 85 nM (inhibitor concentration that kills 50%of parasitaemia) [11], and IC90/99 values for these folate antagonist agents fall between 150and 350 nM; thus, if such a concentration can be achieved in vivo with an acceptable toxicityprofile, these compounds could potentially be used as antimalarials. However, anticanceragents in general, and MTX in particular, are perceived to be toxic and therefore not suitablefor malaria treatment. Yet the literature is replete with examples of new uses of anticanceragents in the treatment of non-neoplastic diseases (Table 1).

Anticancer toxicity and Paracelsus’ lawThe inhibition of pathways or enzymes in tumour cells also affects normal human cells. Someanticancer agents are directed against cancer-specific targets [e.g. Imatinib mesylate(Gleevec™) targets cancer-specific tyrosine kinases] and thus can be used at doses with arelatively better toxicity profile than most drugs [12]. However, most anticancer agents areused at doses that also lead to the inhibition of growth of normal cells, in addition to blockingtumourous cells. Most specifically affected are cells that multiply actively, such as bonemarrow cells, e.g. leukocytes, cells of the gastrointestinal mucosa and hair follicle cells,explaining why bone marrow suppression, mucositis and alopecia (hair loss) are among themost common side effects of anticancer compounds. However, according to Paracelsus’ law,for any drug (including anticancers), there is always a dose range at which a drug is safe.

Paracelsus’ law states ‘Sola dosis facit venenum (only dose makes the poison)’, meaning thatall substances are poisons and there are none which are not. The right dose differentiates apoison from a remedy; this principle is also known as the ‘dose–response effect’ [13,14] (Figure1). Thus, a molecule becomes a drug if the dose required to treat a complication ispharmacologically active with minimal toxicity.

The example of CQ is noteworthy. CQ is used at 10 mg kg–1 as a starting dose on days 1 and2, and at 5 mg kg–1 on day 3 [15]. At this dose regimen, CQ has an acceptable safety profile.However, a dose of 20 mg kg–1 is considered toxic [15], and fatal cases have been reportedfrom doses as low as 30 mg kg–1, only three times higher than the therapeutic dose [16,17].This indicates that a slight dose increase shifts the effect of CQ from the second range(acceptable safety profile with a pharmacological effect) to the third range (life-threateningtoxicity) (Figure 1). Thus, CQ has a very low safety margin, and yet it has been used widely(at the correct dose) and is considered to be one of the safest antimalarial agents available.

Different uses of MTX in humansMTX is another interesting example. MTX is used at high dose, up to 5000–12,000 mg persquare meter (m2) per week (130–300 mg kg–1) for several weeks for the treatment of cancer,and this dose can yield serum concentrations of >1000 μM, i.e. within the range ofconcentrations that is associated with MTX life-threatening toxicity [18]. By contrast, a 1000-fold lower dose of MTX (LD–MTX) [0.1–0.4 mg kg–1 (7.5–30 mg per adult)] is used onceweekly in the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis in children(including infants <1 year old) and psoriasis [19,20].

The most common side effect of LD–MTX is mucositis (oral ulcers) and gastrointestinal (GI)tract disturbances, particularly nausea. Commonly, these adverse effects are observed afterseveral weeks and somewhat higher doses of MTX (more than 15 mg in adults) [19]. Indeed,in the treatment of adult RA, MTX starts at a dose of 7.5 mg once weekly. After a few weeks,this dose is increased by 2.5 mg per week (the timing of the increase could vary, depending onhow the patient is responding to the treatment), to reach a final dose of 25–35 mg per week.The toxicity of MTX is observed when it is used at doses >7.5 mg per week and several weeks

Nzila et al. Page 2


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

after the first drug administration. The toxicity of MTX is a result of inhibition of the DHFRenzyme in normal cells. To prevent toxicity, a folate derivative is administered several hoursafter the dose of MTX. The addition of folate derivatives increases either dihydrofolate ortetrahydrofolate (DHFR substrate and product, respectively). In either case, the action of MTXagainst DHFR will be minimal because of the high folate content, leading to normal synthesisof pyrimidine and the restoration of cell growth. In juvenile arthritis, MTX is used at a higherdose, and there is still debate over the benefit of the addition of a folate derivative becausemucositis and GI tract disturbances are rare: this drug is better tolerated by children than byadults [19], probably as a result of high cell multiplication processes in children. Overall, it isclear that the toxicity of LD–MTX result from chronic use of doses >7.5 mg per week, as hasbeen clearly demonstrated with the use of MTX in the treatment of multiple sclerosis [21].

MTX is also being evaluated in the treatment of various disease conditions includinginflammatory bowel disease [22], urticaria [23], ankylosing spondylitis [24], idiopathichypertrophic cranial pachymeningitis [25], chronic cholestatic disorder [26], Wegener'sgranulomatosis [27], primary biliary cirrhosis [28], systemic lupus erythematosus [29] andinflammatory eye disease [30], haemophagocytic lymphohistiocytosis (HLH), a disease thataffects younger children, including infants (<12 months of age) [31].

Worldwide, it is estimated that 0.5–1 million adults and 50,000–100,000 children receive LD–MTX weekly for the treatment of RA and juvenile idiopathic arthritis, respectively. The drugis now being used in the African population, and its safety profile is similar to that reported inthe Western world [32].

Proof of concept of MTX as an antimalarial in humansThe antimalarial potential of MTX has been established for almost 40 years. Two relativelysmall clinical trials, involving seven patients, have demonstrated that doses as low as 2.5 mgper day for 3–5 days were effectively treating malaria infection in humans (Plasmodiumfalciparum and/or Plasmodium vivax) [33,34]. However, MTX has not come into widespreaduse because of concerns over toxicity [35,36]. At the time of the clinical trials (in the 1970 s),no information was available on the safety of LD–MTX. Indeed, LD–MTX started to be usedfor the treatment of arthritis from the 1980 s; before then, MTX was used only at high doses,associated with toxicity in cancer treatment. We now have 30 years experience on the safetyof LD–MTX in adults and in children, and thus this drug could now be re-evaluated as apotential antimalarial. Unlike its use in immune diseases, MTX would not be used on a chronicbasis against malaria; it would be used for 3–5 days only and thus the risk of toxicity wouldbe even lower.

The in vivo efficacy of LD–MTX is also supported by pharmacokinetics. Indeed, a daily doseof 5 mg in adults (0.035–0.1 mg kg–1) could yield serum MTX concentrations between 250and 500 nM [37,38], concentrations which exceed the IC90/99 concentrations required to killthe parasite in vitro [11]. Taken together, the information warrants further investigation of thisdrug as an antimalarial.

Potential of trimetrexate (TMX) as an antimalarialTMX is used primarily for the treatment of solid tumours [39]. Evidence is also available thatTMX has good activity against P. falciparum, and the addition of the folate derivative 5-methyltetrahydrofolate (5-Me-THF) does not reduce TMX activity [40]. Thus, this form of folatecould be used as an adjuvant, in combination with TMX, to increase its safety margin. 5-Me-THF would protect the host against drug toxicity and it would not negate the antimalarialactivity of TMX. The same rationale has been used in the combination TMX + folinic acid(FNA) for the treatment of Pneumocystis jiroveci infection (an opportunistic infection

Nzila et al. Page 3


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

commonly found in association with HIV infection). TMX is active against P. jiroveci and thismicroorganism does not salvage folate derivatives because of lack of folate receptors andtransporters; thus, the addition of folate derivatives does not negate TMX activity. As a result,the combination of TMX + FNA is as active as TMX alone [41]. In cancer, a TMX dose of100 mg per day is used for several weeks and this is associated with toxicity. In P. jiroveciinfection, the same dose is used (100 mg per day for 28 days) but the addition of 200 mg ofFNA completely reverses the toxicity of the drug, making the combination TMX + FNA welltolerated. As a result, TMX has become useful against P. jiroveci infection [42].

For the treatment of malaria, a much lower dose of TMX would be required. Indeed, 100 mgof TMX yields plasma concentrations of ∼5000 nM [43] and this is ∼100 times higher thanthe IC50 value (i.e. <50 nM) of TMX against P. falciparum. Thus, it is reasonable to proposethat doses <10–20 mg of TMX would be effective to treat malaria. Such a low dose could besafe and the addition of 5-CH3-THF could even improve the therapeutic index of the drug.Although the potential exists for TMX to become an antimalarial, more work is needed toestablish whether this concept could be translated in vivo.

Other anticancer drugs in the treatment of malaria and other non-neoplasticdiseases

We have also shown that the folate antagonist pemetrexate is active against P. falciparum invitro, with activity in the nanomolar range (IC50 <50 nM) (A. Nzila et al. unpublished). Becausethe anticancers MTX, aminopterin and pemetrexate, all inhibitors of DHFR enzymes, are activeagainst P. falciparum, other anticancer inhibitors of DHFR, such as edatrexate, pralatrexate,and piritrexim might also be active against P. falciparum. Several other anticancer agents havealso been shown to have activity against P. falciparum malaria. For example, the inhibitors ofthe microtubulin assembly tubulozole, vinblastine, docetaxel, paclitaxel and dolastatin [44–48], the DNA crosslinking agent cisplatin [49] and the proteasome inhibitor Bortezomib [50]are effective antimalarials in vitro. If these drugs were active in vivo at low and tolerable doses,they could potentially become antimalarials. This is all the more possible in view of the factthat many anticancer drugs have already been used in the treatment of non-neoplastic diseasesat low dose (Table 1).

Concluding remarksThe burgeoning problem of antimalarial resistance highlights the need to have a strong pipelineof new drugs to treat malaria. Development of new drugs takes time and is associated withsignificant costs, explaining (at least partly) the paucity of available antimalarials, particularlyas this is not a profitable market and thus there is little incentive for the pharmaceutical industryto develop new treatments. The re-use of existing drugs is an attractive strategy to discovernew antimalarials as the development costs would be lower and the time to licensure shorter.Moreover, in the case of anticancer agents, the in-human toxicity profile would have alreadybeen well documented at much higher doses than could ever be achieved for any other productprimarily developed for malaria. Many antineoplastic drugs, including MTX, were shown tobe effective against the malaria parasite almost 40 years ago; however, their perceived toxicityhas prevented their development as antimalarials. It is now known, and as stated by Paracelsus(more than 400 years ago), that it is ‘the dose that makes a drug’; this principle has beenexploited in the use of such drugs at lower doses in several non-neoplastic diseases. It issurprising that the antimalarial potential of MTX has not been fully investigated. Exploitationof the available pharmacopoeia could be a cost-effective and efficient channel to develop muchneeded alternative treatments for challenging diseases such as malaria.

Nzila et al. Page 4


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

References1. NostenF.WhiteN.J.Artemisinin-based combination treatment of falciparum malariaAm. J. Trop. Med.

Hyg.772007181192181654912. DondorpA.M.Artemisinin resistance in Plasmodium falciparum malariaN. Engl. J. Med.

3612009455467196412023. MillerT.M.LayzerR.B.Muscle crampsMuscle Nerve322005431442159026914. SibiliaJ.PasqualiJ.L.Systemic lupus erythematosus: news and therapeutic perspectivesPresse Med.

372008444459182420455. EfferthT.Willmar Schwabe Award 2006: Antiplasmodial and antitumor activity of artemisinin – from

bench to bedsidePlanta Med.732007299309173541636. UtzingerJ.Artemisinins for schistosomiasis and beyondCurr. Opin. Investig. Drugs820071051167. ChicoR.M.Azithromycin-chloroquine and the intermittent preventive treatment of malaria in

pregnancyMalar. J.72008255190872678. Croft, A.M. (2005) Malaria: prevention in travellers. Clin. Evid. 954–9729. WolfR.DapsoneDermatol. Online J8200221216521210. NzilaA.The past, present and future of antifolates in the treatment of Plasmodium falciparum

infectionJ. Antimicrob. Chemother.572006104310541661706611. KiaraS.M.In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium

falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-LeumutationAntimicrob. Agents Chemother.5320093793379819528269

12. PytelD.Tyrosine kinase blockers: new hope for successful cancer therapyAnticancer Agents Med.Chem.92009667619149483

13. LangmanL.J.KapurB.M.Toxicology: then and nowClin. Biochem.3920064985101673025414. RozmanK.K.DoullJ.Paracelsus, Haber and ArndtToxicology16020011911961124613915. TaylorW.R.WhiteN.J.Antimalarial drug toxicity: a reviewDrug Safety27200425611472008516. CannH.M.VerhulstH.L.Fatal acute chloroquine poisoning in

childrenPediatrics271961951021369044517. RiouB.Treatment of severe chloroquine poisoningN. Engl. J. Med.318198816333637918. ChabnerB.A.Antineoplastic agentsBruntonL.The Pharmacological Basis of Therapeutics9th

edn2006McGraw–Hill1315146519. NiehuesT.LankischP.Recommendations for the use of methotrexate in juvenile idiopathic

arthritisPaediatr. Drugs820063473561715464220. SwierkotJ.SzechinskiJ.Methotrexate in rheumatoid arthritisPharmacol. Rep.

5820064734921696379321. GrayO.M.A systematic review of oral methotrexate for multiple sclerosisMultiple

Sclerosis1220065075101690076622. DomenechE.Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practiceJ.

Clin. Gastroenterol.4220083953991827789923. Montero MoraP.Autoimmune urticaria. Treatment with methotrexateRev. Alerg. Mex.

5120041671721579440524. ChenJ.Is methotrexate effective for the treatment of ankylosing spondylitis?Nat. Clin.

Practice3200749049125. BosmanT.Idiopathic hypertrophic cranial pachymeningitis treated by oral methotrexate: a case report

and review of literatureRheumatol. Int.2820087137181809497126. NovakK.SwainM.G.Role of methotrexate in the treatment of chronic cholestatic disordersClin. Liver

Dis.1220088196viii1824249827. SpecksU.Methotrexate for Wegener's granulomatosis: what is the evidence?Arthritis Rheum.

522005223722421605254028. GongY.GluudC.Methotrexate for primary biliary cirrhosisCochrane Database Syst. Rev.

2005CD0043851603492929. WongJ.M.EsdaileJ.M.Methotrexate in systemic lupus erythematosusLupus14200510110515751813

Nzila et al. Page 5


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

https://www.researchgate.net/publication/50592323_Malaria_prevention_in_travellers?el=1_x_8&enrichId=rgreq-b4349ecb82222d17499e2de96c15ed3b-XXX&enrichSource=Y292ZXJQYWdlOzQwODk0NDcwO0FTOjk4NTQwMjYwOTU0MTIyQDE0MDA1MDUyMzc3MTk=

30. StawellR.Methotrexate in inflammatory eye diseaseOcul. Immunol. Inflamm.11200379821453302631. HenterJ.I.HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic

lymphohistiocytosisPediatr. Blood Cancer4820071241311693736032. TahiriL.Therapeutic maintenance level of methotrexate in rheumatoid

arthritisSante1620061671721728439233. SheehyT.W.DempseyH.Methotrexate therapy for Plasmodium vivax malariaJ. Am. Med. Assoc.

214197010911434. WildbolzA.Methotrexate in the therapy of malariaTher. Umsch.301973218222456962935. FeroneR.Methotrexate therapy for P. vivax malariaJ. Am. Med. Assoc.215197111736. LaingA.B.Methotrexate in malariaTrans. R. Soc. Trop. Med. Hyg.661972518519504638937. ChladekJ.Low-dose methotrexate pharmacokinetics and pharmacodynamics in the therapy of severe

psoriasisBasic Clin. Pharmacol. Toxicol.9620052472481573322438. ChladekJ.Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of

psoriasisBr. J. Clin. Pharmacol.5420021471561220763439. HallerD.G.Trimetrexate: experience with solid tumorsSemin. Oncol.241997S18-71-S18-7640. NduatiE.Effect of folate derivatives on the activity of antifolate drugs used against malaria and

cancerParasitol. Res.1022008122712341825977641. WalzerP.D.Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of

Pneumocystis carinii pneumoniaAntimicrob. Agents Chemother.36199219351942141688442. FultonB.Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and

therapeutic potential in the treatment of Pneumocystis cariniipneumoniaDrugs4919955635767789290

43. MarshallJ.L.DeLapR.J.Clinical pharmacokinetics and pharmacology of trimetrexateClin.Pharmacokinet.2619941902008194282

44. FennellB.J.Effects of the antimitotic natural product dolastatin 10, and related peptides, on the humanmalarial parasite Plasmodium falciparumJ. Antimicrob. Chemother.51200383384112654761

45. KokaS.Influence of paclitaxel on parasitemia and survival of Plasmodium berghei infected miceCellPhysiol. Biochem.23200919119819255513

46. SchrevelJ.Interactions between docetaxel (Taxotere) and Plasmodium falciparum-infectederythrocytesProc. Natl. Acad. Sci. U.S.A.911994847284767915841

47. SinouV.In vitro and in vivo inhibition of erythrocytic development of malarial parasites bydocetaxelAntimicrob. Agents Chemother.4019963583618834880

48. UsangaE.A.Mitotic inhibitors arrest the growth of Plasmodium falciparumFEBS Lett.209198623273542560

49. NairL.BhasinV.K.Cure with cisplatin (II) or murine malaria infection and in vitro inhibition of achloroquine-resistant Plasmodium falciparum isolateJpn. J. Med. Sci. Biol.4719942412527739147

50. KreidenweissA.Comprehensive study of proteasome inhibitors against Plasmodium falciparumlaboratory strains and field isolates from GabonMalar. J.7200818718816382

51. NanniniC.Effects of cyclophosphamide on pulmonary function in patients with scleroderma andinterstitial lung disease: a systematic review and meta-analysis of randomized controlled trials andobservational prospective cohort studiesArthritis Res. Ther.102008R12418937831

52. PrefontaineE.Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn'sdiseaseCochrane Database Syst. Rev.2009CD00006719160175

53. WuJ.J.Thalidomide: dermatological indications, mechanisms of action and side-effectsBr. J.Dermatol.153200525427316086735

54. MateosJ.Vincristine is an effective therapeutic approach for transplantation-associated thromboticmicroangiopathyBone Marrow Transplant.37200633733816341229

55. BalasegaramM.Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiensesleeping sickness in nine Medecins Sans Frontieres programmesTrans. R. Soc. Trop. Med. Hyg.103200928029018947846

56. HickmanJ.G.Human dermal safety studies with eflornithine HCl 13.9% cream (Vaniqa), a noveltreatment for excessive facial hairCurr. Med. Res. Opin.16200123524411268707

Nzila et al. Page 6


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

57. BermanJ.J.Treatment of leishmaniasis with miltefosine: 2008 statusExpert Opin. Drug Metab.Toxicol.420081209121618721114

AcknowledgmentsWe thank the director of the Kenya Medical Research Institute for permission to publish this manuscript. This studywas supported by Pfizer-Royal Society Award, UK, the EU Commission under Framework 6 as part of the AntiMalIntegrated Project 018834, and the European and Developing Countries Clinical Trials Partnership (EDCPT) to A.N.We also thank Andrea Groth for reading and editing the manuscript.

Nzila et al. Page 7


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

Figure 1.Dose–response effect of drugs in humans, as per Paracelsus’ law, using methotrexate (MTX)as an example. For any drug, there is a dose range (concentration) that is without any effect,one with a pharmacological effect but with minimal toxicity (or acceptable safety profile) andanother with pharmacological and toxic effects. Most drugs used in the treatment of humandiseases fall within the middle group. In the case of MTX, experience in multiple sclerosisindicates that a dose of 7.5 mg per week for up to 2 years is not associated with toxicity [21].The use of 7–30 mg per week LD–MTX in the treatment of rheumatoid and juvenile arthritisand psoriasis is associated with an acceptable toxicity profile [19]. Higher doses (<100 mg)are associated with toxicity, as shown in the treatment of cancer [18].

Nzila et al. Page 8


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

Nzila et al. Page 9

Tabl

e 1

Sele

cted

onc

olog

ic d

rugs

use

d in

the

treat

men

t of n

on-n

eopl

astic

dis

ease

sa

Dru

gM

echa

nism

of a

ctio

nN

eopl

asm

(onc

olog

y)N

on-n

eopl

asm

Ref

s

Dos

e ra

ngeb

and

indi

catio

nsT

oxic

ity p

rofil

ecD

ose

rang

eb a

nd in

dica

tions

Tox

icity

pro

filec

MT

X20

0–20

00 m

g pe

r do

seG

rade

37.

5–35

mg

per

wee

kG

rade

0–1

[19,

20,2

2]Fo

late

ant

imet

abol

ite, i

nhib

its D

NA

synt

hesi

sA

LL, b

reas

t can

cer,

head

and

nec

kca

ncer

, NH

L, lu

ng ca

ncer

, ost

eosa

rcom

a,Tr

opho

blas

tic n

eopl

asm

Neu

rolo

gica

l, ga

stro

inte

stin

al a

ndde

rmat

olog

ical

sym

ptom

s. Pu

lmon

ary,

bon

em

arro

w, r

enal

and

hep

atic

toxi

city

Cro

hn's

dise

ase,

rheu

mat

oid

arth

ritis

, JIA

, pso

riasi

s,ps

oria

tic a

rthrit

isG

astro

inte

stin

al sy

mpt

oms,

trans

ient

elev

atio

n of

live

r enz

ymes

, liv

erdy

sfun

ctio

n

Cyc

loph

osph

amid

eD

NA

alk

ylat

ing

agen

t, in

hibi

ts D

NA

synt

hesi

s25

0–13

00 m

g pe

r do

seG

rade

375

–250

mg

per

dose

Gra

de 0

–1

[51]

ALL

, bre

ast c

ance

r, B

urki

tt ly

mph

oma,

HD

, NH

L, M

M, o

varia

n ca

ncer

,re

tinob

last

oma

Gas

troin

test

inal

, der

mat

olog

ical

and

cata

rrha

l sym

ptom

s. B

one

mar

row

, ren

al,

hepa

tic, p

ulm

onar

y to

xici

ty. A

cute

haem

orrh

agic

cys

titis

, inf

ertil

ity

Beh

cet's

synd

rom

e, id

iopa

thic

pul

mon

ary

fibro

sis,

ITP,

JIA

, lup

us n

ephr

itis,

NS,

SLE

, tra

nspl

ant r

ejec

tion

prop

hyla

xis,

mul

tiple

scle

rosi

s, W

egen

er's

gran

ulom

atos

is

Fatig

ue, g

astro

inte

stin

al, c

atar

rhal

and

derm

atol

ogic

al sy

mpt

oms

6-M

erca

pto-

puri

nePu

rine

anta

goni

st, i

nhib

itor o

f DN

A a

ndR

NA

synt

hesi

s15

0–35

0 m

g pe

r do

seG

rade

310

0–15

0 m

g pe

r do

seG

rade

1–2

[52]

ALL

, AM

L, C

ML

Gas

troin

test

inal

and

der

mat

olog

ical

sym

ptom

s. B

one

mar

row

, hep

atic

and

rena

lto

xici

ty

Cro

hn's

dise

ase,

ulc

erat

ive

colit

isG

astro

inte

stin

al sy

mpt

oms,

bone

mar

row

supp

ress

ion,

ele

vatio

n of

live

ren

zym

es

Tha

lidom

ided

Mec

hani

sm o

f act

ion

is n

ot c

ompl

etel

yun

ders

tood

. Sel

ectiv

ely

redu

ces l

evel

s of

TNF

200–

1200

mg

per

dose

Gra

de 2

–325

–100

mg

per

dose

Gra

de 0

–1

[53]

Kap

osi's

sarc

oma,

MM

, mal

igna

ntgl

iom

a, m

yelo

dysp

last

ic sy

ndro

me,

rena

lce

ll ca

ncer

Neu

rolo

gica

l and

der

mat

olog

ical

sym

ptom

s.B

one

mar

row

supp

ress

ion,

incr

ease

d ris

k of

thro

mbo

sis

Beh

cet's

synd

rom

e, C

rohn

's di

seas

e, S

LE, D

LEN

euro

logi

cal s

ympt

oms

Vin

cris

tine

Vin

ca a

lkal

oid:

inhi

bito

r of m

icro

tubu

lefo

rmat

ion,

stop

ping

cel

l div

isio

n2–

3.5

mg

per

wee

kG

rade

32

mg

per

mon

thG

rade

0–1

[54]

ALL

, HD

, mal

igna

nt g

liom

a,ne

urob

last

oma,

NH

Lrh

abdo

myo

sarc

oma,

Wilm

s’ tu

mou

r

Neu

rolo

gica

l, ga

stro

inte

stin

al a

ndde

rmat

olog

ical

sym

ptom

s. B

one

mar

row

supp

ress

ion,

neu

roto

xici

ty

ITP,

TTP

Neu

rolo

gica

l sym

ptom

s

DFM

Oe

Inhi

bito

r of o

rnith

ine

deca

rbox

ylas

e

>10

g pe

r do

see

Gra

de 4

0.4–

0.8

g pe

r da

y fo

r a

year

Gra

de 0

–1

[55,

56]

Pros

tate

can

cer

Dia

rrho

ea, a

bdom

inal

pai

n, a

lope

cia

and

otot

oxic

ity

Che

mop

rote

ctio

n ag

ains

t pro

stat

e ca

ncer

, act

inic

ker

atos

is

>0.4

g p

er d

ay fo

r se

vera

l mon

ths

Gra

de 0

–1

As a

cre

am H

irsut

ism

(fac

ial h

air)

>5 g

per

day

for

15 d

ays

Gra

de 1

–2

Slee

ping

sick

ness

(try

pano

som

iasi

s)G

astro

inte

stin

al sy

mpt

oms

Milt

efos

inef

Inhi

bito

rs of

phos

phol

ipid

bios

ynth

esis

ofce

ll m

embr

ane

xx

1.5–

2.5

mg

per k

g fo

r 28

days

Lei

shm

ania

sis

Gra

de1–

2[5

7]


Sponsored Docum

ent Sponsored D

ocument

Sponsored Docum

ent

Nzila et al. Page 10

Dru

gM

echa

nism

of a

ctio

nN

eopl

asm

(onc

olog

y)N

on-n

eopl

asm

Ref

s

Dos

e ra

ngeb

and

indi

catio

nsT

oxic

ity p

rofil

ecD

ose

rang

eb a

nd in

dica

tions

Tox

icity

pro

filec

Nau

sea,

vom

iting

, dia

rrho

ea

a Abb

revi

atio

ns: A

LL =

acut

e lym

phoc

ytic

leuk

aem

ia, A

ML

= ac

ute m

yelo

geno

us le

ukae

mia

, CLL

= ch

roni

c lym

phoc

ytic

leuk

aem

ia, C

ML

= ch

roni

c mye

loge

nous

leuk

aem

ia, D

LE =

dis

coid

lupu

s ery

them

atos

us, H

D =

Hod

gkin

's di

seas

e, IT

P =

idio

path

ic th

rom

bocy

tope

nic p

urpu

ra,

JIA

= ju

veni

le id

iopa

thic

arth

ritis

, MM

= m

ultip

le m

yelo

ma,

NH

L =

non-

Hod

gkin

's ly

mph

oma,

NS

= ne

phrit

ic sy

ndro

me,

SLE

= sy

stem

ic lu

pus e

ryth

emat

osus

, TTP

= th

rom

botic

thro

mbo

cyto

peni

c pu

rpur

a.

b Adu

lt do

ses.

c Gra

de 0

= n

o ad

vers

e re

actio

n, G

rade

1 =

mild

adv

erse

reac

tions

, Gra

de 2

= m

oder

ate

adve

rse

reac

tions

, Gra

de 3

= se

vere

adv

erse

reac

tions

, Gra

de 4

= li

fe-th

reat

enin

g to

xici

ty.

d Not

use

d in

pre

gnan

cy b

ecau

se o

f its

eff

ect a

gain

st fo

etal

gro

wth

tera

toge

nici

ty.

e DFM

O (D

ifluo

ro-m

ethy

l-orn

ithin

e) w

as u

sed

as a

n ex

perim

enta

l dru

g in

can

cer b

ut w

as a

band

oned

bec

ause

eff

icac

y co

uld

only

be

achi

eved

with

dos

es a

ssoc

iate

d w

ith se

rious

life

-thre

aten

ing

toxi

city

. How

ever

, the

dru

g w

as re

vive

d fo

r can

cer c

hem

opro

tect

ion,

hirs

utis

m a

ndtry

pano

som

iasi

s tre

atm

ent a

t low

dos

e.

f Milt

efos

ine

was

initi

ally

dis

cove

red

as a

n an

tineo

plas

tic d

rug;

how

ever

, few

stud

ies w

ere

carr

ied

out i

n hu

man

s to

treat

can

cer,

thus

det

aile

d in

form

atio

n on

its t

oxic

ity a

nd d

ose

rang

es a

s an

antin

eopl

astic

is n

ot a

vaila

ble.


Anticancer agents against malaria: time to revisit?

Documents