THE BIOMEDICAL SCIENCE SCIENCE THE BIOMEDICAL 30 SCIENTIST The big story The big story SCIENTIST 31

“These advances could not have been achieved without a vast amount of dedicated research over the WAR ON last 70 years” CANCER PT.1 THE DEVELOPMENT OF CHEMOTHERAPY TO 1950

A review of the early historical development and use of chemotherapy to treat different cancers. The phrase “war on cancer” refers to the recognition of cancer as a major cause of death and the need to act, resulting in increased funding, clinical trials and the development of more effective treatments.

he Nobel laureate, animals. In addition, he also experimented German scientist Paul Ehrlich with aniline dyes and simple alkylating (1854-1915) pioneered agents in cancer treatment. chemotherapy during the Cancer chemotherapy may be broadly early 20th Century. He coined defined as often a cyclical process to the term “chemotherapy” deliver a chemical agent (CA) or cocktail and researched a large of chemical agents to selectively target number of chemicals to screen and destroy cancer cells. At this time a their effectiveness in the treatment of vast range of CA have been developed to Tinfectious diseases, those succeeding he optimise this process in different modes, described as “magic bullets”. such as adjuvant chemotherapy, based He was also one of the first to use animal on the type and stage of cancer, response models for chemical research, which would rate, individual patient status and much later be used to screen chemicals tolerance and with a view to minimise using transplantable tumours in a range of toxic side effects. Standard protocols have and haematological results inacute in 1996,which show successful clinical generated byreports from Chinesestudies reduced the useofarsenicsalts. radiotherapy intheearly 20thCentury skin andbreast. Theintroduction of arsenical pasteswere usedfor cancers of this regime. Duringthenextdecade showing areduced white cell count with includes somehaematology results arsenic trioxide treated patient with CML from BostonCity hospital in1878ofan myelogenous leukaemia(CML).Areport improve apatient with chronic sodium bicarbonate (1% w/v),toclinically Fowler’s solution ofarsenictrioxide in as 1865byLissauer, usingThomas Most literature sources record its firstuse used therapeutically for over 2,000years. surprising that arsenicsalts have been In viewoftheirtoxic nature it isperhaps Arsenic salts and nonHodgkin’s lymphoma. positive responses inprostate, lung cancer noted that somestudies have demonstrated complementary treatment. It shouldbe cancer patients asalternative or preparations, which continues today in ofherbal showalonghistory Surveys herbal remedies for cancer treatment. Chinese medicalprocedures were using for thetopicaltreatment ofcancer. minerals, including somewhich were used of themedicinalproperties ofplants and around 70AD–afive-volume compendium Dioscorides produced DeMateriaMedica The Greek physician andpharmacologist, were usedtopically inmalignant diseases. papyri that suggestsherbalpreparations There issomeevidence from Egyptian Ancient medicine dedicated research over thelast70years. been achieved without avastamount of oncologist. Theseadvances could nothave of cancer managedbyaconsultant now beendeveloped for mosttypes 32 However, great interest hasbeen Around thesameperiod,traditional SCIENTIST THE BIOMEDICAL The bigstory SCIENCE hydrocarbons with asulphur or of toxic chlorinated collective namefor agroup Mustard gas(MG) isthe Mustard gas triple negative breast cancer. acid, may beofclinicalvalue in pathways andusedwith retinoic – akey regulator inoncogenic signalling trioxide inhibits anenzyme(PIN1) studies in2015propose that arsenic complex mechanisms.More recent cancer, provide more detailsonthese their 2001review ofarsenicderivatives in Waxman andAndersonfrom theUSin bone marrow ofapatient with APL. specific cell line(NB4)derived from the and inhibition ofangiogenesisusinga induction ofapoptosis,antiproliferation arsenic trioxide incancer. Theseinclude proposed for themechanismofaction for orrelapsed refractory APL. for usebyFederal Drug Agencyin2000 commercial form, Trisenox, wasapproved randomised clinicalstudiesandthe These findings were confirmed byUS marrow suppression andfew sideeffects. low dosearsenictrioxide, without bone promyelogenous leukaemia(APL) with A number oftheorieshave been counts andthat autopsy revealed of Pennsylvania who reported lowwhite leading aresearch teamat theUniversity US Pathologist Edward BellKrumbhaar, and wasmore fully examinedin1919 by MG causes suppression ofhaemopoiesis suffered long-term mental health issues. an inestimable numbers ofsoldiers 185,000 injuriesdue tomustard gasand there were 6,000warfatalities and to potentially fatal bronchopneumonia. tractdamagewhichrespiratory may lead painful skinblisters andsevere irritant tomucous membranes,may form attack occupied trenches. It isextremely a dispersedmistduring World War 1to in 1860,andthesulphur form wasusedas mechlorethamine. It wasfirstsynthesised hydrochloride) ormore simply is (methyl bis)(beta chlorethyl) (amine nitrogen atom, thus nitrogen mustard Imperial War Museum records estimate lymphoid atrophy andbone Halsey Bagg in 1931 to test its Halsey Baggin1931 totestits marrow hypoplasia. Ewing, and also Frank Adair and Ewing, and also FrankAdairand studies were madebyJames recognised for cancers myeloid proliferation, further affecting lymphoid and Thus its potential was Thus its potential was

IMAGES: GETTY/ALAMY/ISTOCK combination chemotherapyfor notably range ofcancers andmay beusedtoday in approved bytheFDA in 1949for adefined serious limitations for othercancers. conditions but it wasfound there were reported cautious optimismfor these various typesofleukaemia.Theauthors Hodgkin’s disease, lymphosarcoma and patients with different cancers-mainly at several centres intheUSonarangeof remission andtumoursreturned. However, it proved tobeatemporary symptoms due totumourmasses. improvement with easingofobstructive Kg i.v. daily, who showed adramatic patient with lymphosarcoma given 0.1mg/ in 1942at Yale onaradiation-resistant experimentation results with mustard gas. toxicological characteristicsandanimal reviewed thechemical,pharmacological, published until 1946.GilmanandPhillips security thereports oftheirwork were not Philips andRoberta Allen.Duetowartime Goodman andtheirco-workers Frederick pharmacologists Alfred Gilman,Louis undertaken, mostnotably byyoung US advent ofWorld War 2more research was suitability for othercancers. With the The nitrogen mustard, mustargen was Further clinicaltrialswere conducted The firstclinicalapplication took place and “Records estimatethere were Left. WorldWarIGasattack,circa1916 Page 31.PaulEhrlichinhisworkroom(1910) root forDeMateriaMedica Page 30.Dioscoridesstudyingamandrake conducted a clinical conducted aclinical cells inleukaemia. proliferation ofcancer acid allowed further even suggested that folic treatment failedandresults features toALL,however, folic acid with somesimilarhaematological the clinicalvalue offolic acidinanaemia prognosis. Previous studieshadshown childhood, toimprove poor thevery lymphoblastic leukaemia(ALL)in had many clinicalinterests, notably acute School andBostonChildren’s Hospital, paediatric pathologist at Harvard Medical physiological role andmetabolism. opportunity for furtherresearch into its availability offolic acidprovided an its structure determinedin1945.The isolation from spinach leaves in1941and vegetables andidentified as folic acidby present inanimalliver andgreen leafy established. Thiswasalsoshowntobe marrow was functionanderythropoiesis newfactorandbone between adietary human pregnancy. Thus anassociation found tocorrect macrocytic anaemiain (“Marmite”) addedtothedietwasalso it wasshownthat afactorinyeast extract lacking Bvitamins. Insubsequent studies adding yeast extractstoadietotherwise anaemia andfound it wasprevented by albino rats with induced macrocytic assessed theeffect ofdietchangeson English haematologist Lucy Wills In landmark studiesreported in1931, Folic acidantagonists with enzymesinvolved inDNA replication. proteins forming crosslinks andinterferes covalent bondswith nucleic acidsorkey agent andisaneffective CTA by forming Hodgkin’s lymphoma. MG isanalkylating In 1947 Farber In 1947Farber Sidney Farber, aleadingpioneer US 185,000 injuriesduetomustard gas” online atthebiomedicalscientist.net To seethereferences,viewarticle Stephen ClarkeisaretiredIBMSFellow. for thefuture ofchemotherapy. Century andthere wascautious optimism chemotherapy inthefirsthalfof20th Sidney Farber laidthefoundations for collaborators,Lederle Laboratory and Goodman with theirYale colleagues and Krumbhaar, Alfred GilmanandLouis with theseearly agents. remissionsonly were temporary achieved with ALL.It isalso worthy tonotethat to usefolate antagonists totreat children providederythropoiesis theinspiration acid andbonemarrow functionand ofthelinkbetweenThe discovery folic War Isoldiers exposedtomustard gas. follow-up ofautopsy evidence from World extreme. Thelatter wasabelated mustards incancer treatment nowseems substances asarsenicsalts andnitrogen The principle ofusingsuchtoxic Concluding comments bone marrow function. of malignant cells andre-establish normal antifolates could suppress theproliferation methotrexate, anddemonstrated that to produce otherfolate antagonists, notably with HarrietKilte ofLederle Laboratories remission. Farbertemporary collaborated acid and10of16children showed a in anattempt toblock theactionoffolic trial with thefolate antagonist aminopterin Nevertheless, Paul Ehrlich, Edward fatalities fatalities 6,000 The bigstory SCIENCE

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