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(1)

THE

EFFECT

OF

ACTINOMYCIN

D ON

CANCER

IN

CHILDHOOD

Charlotte 1. C. Tan, M.D., Harold W. Dargeon, M.D., and

Joseph H. Burchenal, M.D.

Division 01: Clinical Cheniothierapy, Sloan-Kettering Institute, Departnents of Pediatrics (11(1 Iedicine,

\femorial Hospital, Memorial Center for Cancer and Allied Diseases’, New York, and

Cornell UniversIty Medical College

(Accepted April 27, 1939; stibniitted March 1:3.)

The work reported in this paper was supported in part by grants from the National Cancer Institute

(grant CY-:3215), PtIl)liC i-Ieilth Service, and institutional grants from the American Cancer Society, the Damon Runyon \Iemoriai F’und for Cancer Research, Lasker Foundation, the Black-Steve:lsoII Foundation, and the Children’s Cancer Fund of Anierica, American Legion Auxiliary, I)epartinent of

New York.

ADDRESS: (C.T.C.T.) Sloan-Kettering Institute, 444 East 68th Street, New York 21, Ness’ York. PEnIATIIIcs, October 1959

544

T

HE ACTINOMYCIN5 are a group of

anti-hiotics, the first of which was isolated

from a culture of a soil actinomyces in 1940

by Waksman and Woodruff.1 This

organ-ism was described as Actinomyces

(

Strep-tomyces) u2

THE ACTINOMYCINS

The first actiiiom’cin isolated was designated

actillonlycin A. During the intervening ears, a variety of actinomycins was isolated and studliedi, and each investigator gave thenl a iame such as “C”, “X”, and “I” b\ Brockmann et al. :-is “B”,’4-’7

“J”,15’

I “D”2 and others.21 On h’droivzing preparations of actinomvcill A and B, sarcosine, D-valine, L-threonine,

L-proiine, and N-methyl-L-valine were Brockmann and Grubhofer’#{176} demon-strated that actinom’cin

C

was a mixture of very similar substances and that the actino-mycins are composed of a chromophor group

and 2 polypeptide chains. Upon hydrolysis,

D-alloisoleucine was preseiit in the hydrolvsate

in addition to the above five amino acids found

ill A and B. These complex mixtures were sepa-rated illtO three substances, C1, C2, and C3. I

Brockmann et al. determined their structures.

C1 contained D-valine in both peptides, C2 contains D-valine in one and D-ailoisoleucine

Ill the other pe1)tide, and C: d0I1tliI15

D-allo-isoleucme ill both peptides. The structure of actinomycin D was shown by Bullock et al.22

to be identical with that of actinomvcin C1.

The various preparations produced by the different species of actinomvcetes were com-posed of a mixture of actinomvcins, and the

components of the mixture varied with tile

Cill-ture method, the age of culture aii composi-tion of medium.232 Thus, the problem in nomenclature of the actinonlycins is first

ciiemi-cill’ to ch::racterize each actinonlycin and

secolldlly to determine the relative amount of

each type of actinom”cin as a pure sui)stance

ill a given filtrate. Waksman et 27 have given

each chemically distinct actinom’cin a Roman

numeral designation. At present, only actino-mvcill D, composed of actinomvcin IV27 (Fig.

1) is available in a relatively pure form, aiid

this was used 111 the present study. Actinom’cin

C (Sanamycin’( ), used widely in Europe, is

composed of C1, (actinom’ciii IV or D) C2 and

C (actinolllycili VI andl \TII).

PREVIOUS

STUDIES

OF

EFFECTS

OF ACTINOMYCINS

Waksman et al.25 ll 1941 and Robinson and Waksman2o ill 1942 reported the pharmaco-logic effect of actinomvcin A in mice, rats,

guinea pigs, and rabbits. At necropsY, the most striking phenomenon was the marked

diminu-tiOll ill the size and weight of the spleen.

Actinomycin A at 0.125 mg/kg given

intra-venously, disappeared from the blood within 15 minutes, l1ld 10 to 20 ‘as excreted! in the

urine within 6 hours.

In 1950, Stock and later Reilly et Cl.

reported tilat actiiiom’cms exerted sone

inhi-bition UO1l the growth of experimental tumors

in mice. In 1952, Hackmann2 reported that actinomcin C had some inhii)itory effects in a

number of animal tumors and! its cytostatic

(2)

FIG. 1. Structure of actinoniycin D.

Systeill. Others reported similar effects.5)9

Actinom’cin D was reported b’ Farber et

al.4_42 and other investigators to inhibit the growth of transplantable tumors in animals.13_)2

suggested that actinomvcin D inter-ferred with the synthesis of pantothenate in

lactobacillus test organisms. This mode of ac-tion \Vl5 not supported by other investiga-tors1’ 21 using Bacillus subtilis alidi

tumor-bearing animals.

Schulte2l ill 1954 summarized his experience with actinomnvcin C in 1CO patients with

Hodg-kin’s disease. Twent’s-eight of 43 patients who

received actinomycin

C alone

had

an objective response and 34 of 57 patients s’ilo received a combination of actinomvcin C and x-ray

therap’ were benefited. In some 55 patients with other types of cancer treated with actino-mycin C there was no regression of the tumor

noted. Schmidt2 amid 12576S other groups

re-ported

their

results with actinomvcin C in

ap-proximatel 140 patients. Of these, 100 had

Hodgkin’s disease. Actinomvcin C had a transient belleficial effect in an occasional

pa-tient with Hodgkin’s disease.

Farber et al. 40-42 reported that actinomycin

D in some children produced regression of Wilms’ tumor, rhabdomvosarcoma and

Hodg-kin’s disease.

0thers have reported experiences with

actillOmycill D in patients with cancer.

The present report is an evaluat:on of

actinomycin D which was initiated in

Dc-cember, 1955, in the treatment of children

with metastatic cancer and includes 111

cases.

MATERIALS

AND

METHODS

OF

PRESENT STUDY

Actinomycin D was supplied as a red

crystal-line powder which was dissolved in absolute alcohol at a concentration of 1 mg/mi for

intravenous use, and as 1 mg oral tablets. The

calculated single dose was taken from the stock

solution with a 1-mi syringe calibrated in 1/100 sui)divisions, diluted with 20 ml of normal

saline, and mixed thoroughly before injection. Special precaution was exercised to avoid

cx-travasation of the drug which might cause celluiitis.

A single course of intravenous

administra-tion of actinomycin D consisted of 15 .g/kg

of body weight per day for five doses or a

total

of

75 sg/kg. If, after 2 weeks, there were

110 signs of toxicity and no therapeutic effects

were obtained, the same dosage was repeated.

Some patients have received two to five or

more separate courses over a period of several

months.

The oral dosage of actinomvcin D was 3 to

10 mg daily Ill three divided doses.

Table I summarizes the data concerning the

type of neoplastic disease, number of patients

studied, and the objective response of the

disease. Of these patients, 109 had had pre-viotis conventional therapy, i.e.

,

surgery, x-ra’

therapy or aikvlating agents. During therap’,

patients were examined daih’ for signs of

toxicity and evidences of therapeutic response.

The concentration of hemoglobin and the

leukocyte count were determined daily and

platelet counts twice weekly. Concentration of

urea

nitrogen

in blood and uric acid in serum

were determined at intervals of 1 to 2 weeks

and, in some I)atients, aspirations of sternal

marrow were performed and other chemical

examinations of the blood as indicated.

Roent-genograms of chest and bones were made

serially when the pretreatment studies showed

lesions caused by the neoplastic process.

For various reasons not all the patients

started on actinomvcin

D

received an adequate

trial of therapy and these were not included

ill the evaluation of the therapeutic results.

H3C. H

H3C”

I

I

. C-CH

FH3NSARCOSINE SARCOS1NEP1-.CH3

0 L- PRLINE L-PIkLINE

D-VALINE 0-VALINE

oi4

II3CHC-CH

Hl1 l4H

NH

CH3 CH3

(3)

0 ORAL

S IV

I-z

Lu C)

a:

Lu

a.

- MOUTh GI SKIN AWPEIA WBC PITh

tic. 2. Percentage of 1)Itients shosving various toxic nianifestations after oral mud intravenous

1(1-niinistration of actinonsvcin I). Of the 108 patients Who receive(i a(lequite therapy svith actinonlycimi D, 102 received it intravenously, :32 received oral (lOS(’S (this included six who received actinonlycill

1) orally 0111%’ and 26 ‘s’ho received it by both the intravenous 111(1 oral routes l)ut with a period of at

least 4 ‘seeks separating the imitrasemious s1l(l oral

courses so that toxicity could ie attril)nted to the specific route of ac!ministration). Sixteen patients wlio received the drug 1))’ both routes within 4

weeks were not inclu(le(l here for (‘5’lllIatiOfl of

toxicity.

546 ACTINOMYCIN D

‘i’ABIE I

NI\11F:II .SNI) I)I.s;NosF” 01’ P.STIIN’I’s ‘IlOWING OnjF:’TIvF: ItF>1oNsF: TO A(TIXUS1Y(’IN I)

.IOXI .%NI) A(’TINOMY(’IN 1) i’Ll’ X-I sv i’IIF: sl

lelinoniIein I) .1/0fl(’ .te/inornycin I) /111.5.V-ray 1’/ierajiy

I)iagnosex Total . , . . . . .

.\0. “uiIablc for Objeehre .\ o. ‘ table/or ()bjeelre

Eralnation Response km/nation lies/ooze

%iIII15 t uiimor 38 1 (; 6 1 7 1 l

Neurol)lastolna () 7 3 11 3

ithahdonmvosar(oI1Ia 1’, .5 1 7 5

HoII sar(oIIla 1.? 3 (1 9

ar(oI11mL hotryoi(Ies 4 1 0 3 3

En11)rvollal (areilloIlla 4 1 1 1 0

‘oft tissue sarcona ‘2 1 (1

ie(IL1IlII})IastoI1ma 2 1 0

ilepatonia 1 1 (I

Carcinonma of kidney 1 1 0

llodgkins (lisease S .1 1 1

lteti(uhiln eiI sarconia 4 i I

Lylnpllosar(omlla 3 1 1

A(llte 1(’tlkeIIlia I 2 (1

( i11OIIi( leukemia I 1 0

lotal 1 1 1 49 0; So

RESULTS

Toxic Effects of Actinomycin D

Tile toxic effects of actinomycin D (Fig.

2) were: 1) Redness and ulceration of the

tongue and! th(. huccal mucosa, usually

de-‘eloping within 1 to 3 clays after the

comnple-tion of tue course of intravenous therapy

and lasting for 3 to 5 clays. 2)

Gastrointes-tinal dlisturi)ances: vomiting 4 to 5 hours

after each injection and nausea, anorexia,

aild occasionally abdominal I)clifl or diarrhea

(luring tile course of tilerapY. 3) Skin

re-iction over previtisly irradiate(I areas,

con-sisting of ervthema and, occasionally,

vesi-culation illdl exfoiittion (Fig. 3).

Twenty-seven of 57 patients had skin reaction after

intravenous administration of actinomycin

D at 1, 2, 3, tild! 4 months in one patient as

long as 17 months after radiation therapy.

Sixty-seven per cent of the patients

receiv-ing actinomycin D had this reaction at 1

montil, and 50 silowed this reaction at 2

months after radiation therapy. When

(4)

FII:. :3. Photograph of l)dck of SB., a 9-year-old boy vith Ewing’s sarcoua of the left hip with

involve-imiemit of tile left knee 111(1spine; tiicse httter ares svere given lOOt) r and 1750 r tumor (lose, respectively, alx)11t 1 sve’ek’ l)efore admuinistration of actinoni”,’ciii I). The extent of skin reaction ssts ninch nore

tildIl 550111(1 l1d’(’ l)((Il antici1)atc(l froul these (105(5 of x-ray therapy alone.

x-ray tiierapv, the skimi reaction ‘as greater

than that eX1)ected fronl x-ray therapy alone.

4) Tue ilair amid! sollletimes tile eyebrows

began to fall out in ‘arying severity at 7 to

10 (lays after the intravenous course. Loss

of ilair continued for 2 to 4 weeks and then regrowth occurred. 5) Depression of the

leukocvte count ustialiy was ten)porary an (I

consisted of decrease from nornial to 2000/

111111 imid occasionally to less than 1000/

111111, particularly if the I)ltie1lts ‘ere

re-ceiving irradiation simultaneously. 6) Dc-crease of platelet count fronl normal to less

than 100,()00/II1l \y55 cOllSid!ered! signifi-(tflt ctll(! occurred in 30 of the patients.

A total of 108 I)ttiellts received! adequate

therapy with actinomycin D. Sortie fornl of

toxicity was observed at different tinles

diur-rug or after til(’ course of therapy. The

I)er-centage of 1)ttie11ts showing each type of toxicity when given the drug orally or

intra-venously is shown in Figure 2. The local gastrointestinal toxicity was greater Witil tile

oral route, \Vilile

tue

intravenous route

pro-duced greater systemic toxicity.

Tile toxicity after intravenous adllllillistra-tion of actinomycin D usually developed!

within the first 2 weeks audi di5a)peared1

xvithin tile next 2 weeks; vitii oral

adlIllillis-tration, patients developed toxicity in ap-f)rOxinlately 10 weeks and it dlisappeared

when tile drug was stopped. AI)Out 5% of

the dose of actinomvcin

D

given orally was

ai)sOrbed as evidenced! by the 1)ro!uction of

systemic toxicity.

Aspirations of bone marrow were

cx-anlifled 111 42 pttients before and after

actinonlycin

D

therapy. Of the 30 suitable for evaluation, 15 silo\Ved no cilange;

11, a

decrease in tile nuniher of nlegakaryocytes

amid 1)iatelets; four, evidence of myeloid arrest; and eigllt, slight to moderate

megalo-blastosis. Patients with marked alteration in

tile l)one marrow of tile tyl)eS Iloted above

invariai)ly showed a decrease in the

formed

elements of the peri)ileral blood.

After adnlinistration of actinomycin

D,

concentrations of uric acid in the serum rose

in 24 of 9:3 patients and excretion of uric acid

tls() increased! for :3 to 5 days in 8 of 10

pa-tieiits studied. This increase of urinary

cx-cretion of uric acid was associated witil re-gression of tumor in t\V() patients Witil

Hod!g-kin’s dIisease, two with lymphosarcoma and

01W Witll neuroblastonia. This suggested that

(5)

548 ACTINOMYCIN I)

uI’

FI(;. 4. i0e11tgefl0gra11l of chest of CF. (Case 1) made on I)eceiiiber 27, 1956, before therapy witi#{236}

dctinOIllVciIl I) (left) miel (right) on August 7. 1958. showing 10 r(C’llrreflc(’.

to destructioll of tumor. Tile otiler tilrec

a-tients \vitil increased excretion of uric acid

indludledi one Witil Hodgkin’s disease who

iladi subjective improvement, one with

Wilms’ tumor wilo received x-ray therapy

simultaneously and showed regression of

pulmonary metastascs, and one dilildl witil metastatic hepatomna who

showed

no

meas-urable regression of the tumor.

Therapeutic Response

Tile oi)jectix’e response in patients treatedl

with actinomycin D alone and with

actino-mycin D and x-ray tilera)y is silown in

Table I. These objective responses

repre-sented a decrease in size of the tunlor by

actual measurements or roentgenograms,

and lasted for a ieriod! of at least 4 weeks.

The first group of patients with tile

excep-tion of C. F. (Case 1) had eitiler not

re-ceived x-ray tilerapy or had been irradiated!

at least 2 montils before receiving

actiilOmv-cm D. Tilerefore, the objective repose

shown was considered to be due to

actino-mycin

D alone.

The

second

group

receivedl

actinomvcin

0

either

simultaneously

or

within a period of 1 to 2 weeks before or

after x-ray tilerapy.

CASE REPORTS: THERAPY WITH ACTINOMYCIN D ALONE

Wilms’ Tumor

Of the sixteen patients with Wilms’

tu-mor treated with actinonlycin D alone, and

suitable

for

e’a1uation,

six

had (lefimte

evidence of objective response.

Case 1

HISTORY: G.F., t 2-year-old male, had left ne1)hrectonl\’ and! diagnosis of WillllS tumor made in August, 1956. Post-operativei, x-ray therap’ to the di)(iOIlleIl “as giveli. Three

IllOIlths later, d no(lular (leIlSitV most likely

nletastatic, (levelo1)e(l in the lower libe of the right lung, although he ssaS aSvlilptOfllatic,

and had no evidence of (lisease elsewhere. He

was given a total tumor (lost’ of 1 60() r to the

right lower lol)e, from November 26 to

1)ecem-her 5, 1956. However. after irradiation the nodule increased in SIZ(’ fronl 1 to :3 diii iii

diameter as shovn in the roentgenograni of the chest taken on December 27, 1956.

THERAPY WITH AcTINor1YcIN D: He was

given a single course of actinonlycin D intra-venously from December :30, 1956, to January 2, 1957. Three weeks later tile nodule (lisa1)-1)eared completely . He continued to receive actinom’cin D orally, at first 1 to 2 mg dail’ and later increasing to 3 to 4 mg daily fronl

February, 1957, to Septenlbcr, 1958; there has been no recurrence in 2 ‘ears (Fig. 4). Physical

growth has been normal.

COMMENT: The inten’al l)etween the x-ray therapy and adnlinistration of actinonivcin D xvas about 1 month. It is CDIlceiVal)le that the conq)lete regression of the 1)uinlonarv

nietasta-sis might i)e dela’ec! effect of x-ray thera1)V or due to the combination of effects of actinomycin

D and x-ray therapy. The fact that tile nodlule

(6)

HEIGHT

(inches

WEIGHT(IbS)35

aE;3f

41V2

42Y2

_____

36

37

37

3836

37

35

NODULE, LT.SUBSTERNAL

2000r AREA

J

Sept

Oct

1955

2-7mg /d

Mcmy

1956

LT. CHEST WHOLE CHEST Li CHEST Li QIEST 2OOOr l000r gOQQr 12OOr

I I

..‘,.

4-LV-MEDROL P0.

I I I I I I I I I I I I I

Jan

Jan

1957

1958

B.C., 3 YRS.,

cf,

WILM’S TUMOR

BIRTHOATE 11-13-52

/J(\\

I(:

\

m-\

7#{231}\ 1)(\

:L

:TL:

L]L

(JL

Expired-,

___

44

36

xl000

600

ABD

CHEST 2000r

-Lt Nephrectomy

TOTAL 7/ KG 90 125 103 i

Actinomycin

0

[

-

-I.V.

on-I I I I

FIC. 5. Temporary regression of pulmonary nietastases of B.C. (Case 2) after therapy with actinomycin I).

d11i Ilot l)(.’ definitely attributed to tile con-tiiiuous a(lmninistration of actillofli\’cill D orally. ActiIloIil’cin D did not seem to imihibit physical groxvth.

Case 2

HISTORY : B.C., a 3-year-old boy, had a \Vil Ills’ tunior renloved in September, 1955

(Fig. 5). Pulmonary mnetastases were present

at that time. Post-operatively, he received 003 r timnior dose to the right lung aIld! 20G0 r to tile dl)d!olllen. The pulmonary metastases

dis-11)l)’lre(! i)ut recurred 6 ni:nths later.

THERAPY WITH ACTINOMYCIN D: Five (fl5(5 of actmonl’cin D xs’ere givems

intra-venously and! actinomnycin D xvas given orally,

2 to 7 ng (hilly for a periol of 1 ‘ear.

COURSE: Three months after the start of

tilerapy with actinomvcin D, the pulnionar’ metastases regressed! except for the presence of one nO(lIli(.’ i)ChiIl(! the sternum, which xvas later givemi x-ray’ tllerapv. After this, he

(Ic-\‘(‘iOI)C(l niother slllaii llOdltli(’ ill tile left lung, Wilile receix’ing actilloln\’cin D oralk’. There xs’ere OCClsiOIldl episodes of Imausea, anorexia dud! (‘1)iStdXiS l)tlt 110 Iiltrk(’(l cilalige in the plat(’let coillit (luring the course of treatmnent.

J)cspite fuither courses of intravenous thertj)y

xvith actinoniycin D and x-ray therapy, the ptII-monary metastases contmuedl to progress and he diiedl 21 months after the start of

actino-Illycill D therap’.

COMMENT: This child, with pulmonary mc-tastases at the onset (If the disease, survived for

27 nlonths. Actinom’cin D, which causedi re-gression of pulmonar’ metastases, may have sloved the progression of the disease.

Case 3

HISTORY: A.V.,#{176}a 5-year-old l)oy, had a left nephrectom for \7ilms’ tumor in juk’, 1957.

Post-operatively, lie received :300() r tumor close to the abdomen. He developed massive bilateral l)uhlnollary metastases svith dspnea

dlldl fever in Max’, 1958.

THERAPY WITH ACTINOMYCIN D: Actinomy-cm D, 75 i.g /kg of body x’eight was given

in-travenously to the point of toxicit’ from May

19 to May 23, 1958.

COURSE : Pulmonary rnetastascs began to

recede 01) tile fifth clay’ of therap’ audi almost

completely regressed in 4 weeks (Fig. 6). Eight weeks later three flo(lUles reappeared in the

right lung field. This rcspon(l(’(l to a second

(7)

I

6-19-58

550

ACTINO\IYCIN

D

COMIENT : hid’ ttllllor l’S1)0n(le(! to

intra-L

F’ic. 6. Appearance of tlu roentgenogranl of the chest of A.V. (Case :3) lwforc aP(l after the initial

ultra-venous (ourse of actiIlOIllVciI1 I).

course of actiIlOlll\ciu D, i)tlt this tiiiie

tue

remission Ollly lasted! for :3 seeks. A tilird course of actmomycin D resulted! in severe toxicity l)Ut no regression of tunlor, although some s\lilptolllatic relief was obtained after tumor (lose of 1800 r to the chest given silortlv after the third! course of actillolilycill D.

COMMENT: Tile m(i’5Ph15 obtained in this 1)atiellt were striking although the remissions were short. Since no previous x-ray therapy had

i)een givell to tile area of the tulTior, this

regres-sioll seemedl definitely attrii)Utal)le to

actinomy-dill D.

Neuroblastoma

Of the seyen

I)atieflts

witii neuroblastoma, suitai)le for evaluation, treated \vitil

actillo-mycin

D

alone, one patient had decreased joint swelling (Inc to metastasis in

associa-tion with increased! serum concentration and urinary excretion of uric acidi. Two had regression of metastatic subcutaneous scalp

nodiules associated \Vitll markedi improve-ment in general condition. These regressions lastedi for 1 to 3 months. There were no cilangeS ill other lesions.

Other Types of Tumors

Three 1)Utiellts Witil sarconia of bone, one

Witil sarcoma botryoides, two with sarcomas

of soft tissues, two with uleduhid)hlaStOlilas and one vitii carcinoma of kidiiev, suital)le

for evaluatioll, (lid! not show objective

re-after tileral)v with actiflolllycill

D

alone.

Case 4

Embryonal Carcinoma

HISTORY : \I.C., a 23-year-old girl, had em-l)1’’Oildl carcinonia of tile IllesoCOiofl renloe(l

in March, 1956, dll(I P5t-Per1ti\’’lY received! x-ray therapy to the al)(lonlen. Ts’o liloIltilS

later, she dieveloped 1)u1lli1llrY nietastasis in the left lung field.

THERAPY WITH ACTINOMYCIN D: After a smigle course of actinoni’cin D intravenousl\’, there vas (Onll)lete regression of tile nletastatic nodlule ill

tue

lung (Fig. 7). Oral administration

of actinomycin D, 2 to :3 mug daily, sas

comi-tinned for 7 lllollths; (loses s’ere occasionally

oniitted because of toxicity . \Vhen recurrence of

)t1l111111ry and ai)dOlliiIldl tunlors occurred

after 7 IllolithS, six separate courses of actino-nivcin D intravenously in ad(!itiofl to local x-ra’ therapy u1’ Pr!llcd’(l yc’r\ transient dll(l

sligilt regression (If tile tunlor. She die(l of

ic-currenc(’ of til(’ pulmonary all(I al)(ionlinal

tunior 16 fllolitilS aftem’ tile onset of her

(8)

FIG. 7. Roentgenogram of chest of MC. (Case 4). Embryonal carcinoma with metastatic nodule

2.5 cn in (hianieter in left lung field which developed 2 months after abdominal surgery. There was

complete regression of this nodule for a period of 7 months after a single course of actinomycin D intravenously and orally.

%‘eIlOtl5 adlministration of actinomycin

D

and

maintenance therap with oral actinomycin D nlight have been responsible for the apparent

inhibition of recurrent disease for 7 months.

Recurrences were resistant to further therapy

s’ith actinonlvcin D.

Lymphoma

Of the 12 patients with lymphomas, 8

were suitable for evaluation. Objective

cvi-dence of improvement was found in 2 of 4

patients with Hodgkin’s disease, 1 of 2 with

reticulum cell sarcoma and 2 with

lympho-sarcomas.

Hodgkin’s

Disease

Two boys, 8 and 13 years of age,

re-spectively,

with

Hodgkin’s

disease

had

no

previous

therapy;

both

patients

had

large

cervical nodes, and the older had

enlarge-ment

of mediastinal

nodes

in addition.

Mod-crate regression of the enlarged cervical

nodes was seen after a

single

course

of

intra-venous administration of actinomycin D in

both cases. These patients had complete

re-gression of disease when later given x-ray

therapy and have had no recurrence after a

period

of 23 months.

Two other patients had decrease in fever

alld improvement in general condition for

2 to

4

weeks.

Case 5: Reticulum Cell Sarcoma

HISTORY: R.S., a 14-year-old boy with

reticulum cell sarcoma and multiple metastases

of skin and bone, received inethvl-bis-(beta

chloroethyl) amine hydrochloride (Mustar-gen#{174}), triethylene melamine (TEM), cortisone, 6-mercaptopurine (Purinethol#{174}) and

o-diazo-acet\lLserine (azaserine) with no beneficial

response. The skin nodules (lisappeared

mi-tially after x-ray therapy, and when they re-curred, he was given chlorambucil (CB 1348) (p-bis (2-chloroethvi) aminophen’lbut’ric acid),

(Leukeran#{174}), for 4 months to the point of marked depression of the platelet coullt, again

with no response.

THERAPY WITH AcTIN0MYcIN D: After a

single course of actinomycin

D intravenously

there was marked regression of the skin nodules within 1 week; they recurred, however, after

3 weeks. Skin nodules regressed again when

actinomycin

D

was given orally in dosage of 16 mg/kg in 13 weeks. Because of persistent

gastrointestinal symptoms, the oral dose then was interrupted for 2 weeks amid the nodules

recurred. Repeated administration of

actino-mycin D both orally and intravenously caused

no further improvement. The skin nodules

sub-sequentl\? disappeared after x-ray therapy.

COMMENT: This patient presented an

un-usual picture of reticulum cell sarcoma with

multiple

subcutaneous and osseous involve-ment. The generalized process has continued

for 43 years. The disease was responsive to

x-ray therapy but did not respond to

Purin-ethol#{174}, cortisone, or alkylating agents.

Actino-mycin D caused a striking response in

(9)

ACTINOMYCIN D

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Fic. 8. G.C. (Case 6). Response of the elevated leukocyte count of the cerebro-spinal fluid (protein changes not shown in graph) after each course of actinornycin I) administered. Also shown are the concentrations of uric acid in the serum and

the levels of urinary excretion of uric acid.

oral routes. There was no change in the roent-genographic appearance of the metastatic bone

lesions. However, he has no evidence of

dis-ease elsewhere.

Forty-eight patients received actinomycin D

orally to the point of toxicity. Of these, six

re-ceived actinomycin D only by the oral route and

42 also received it intravenously but at a

dif-ferent time. This was the only case in which there was an objective response.

Case 6: Lymphosarcoma

HISTORY:

G.C.,

a 9-year-old boy, had

lvm-phosarcoma with a mediastinal mass which

was given x-ray therapy and did not recur.

However, subsequently, lie developed

metas-tases to testes and central nervous system.

THERAPY WITH ACTINOMYCIN D: After a first

course of actinomycin D, the testicular mass

decreased

in size and did not recur. After each

of the five intravenous courses of actinomvcin D (Fig. 8), the elevated leukocvte count and

concentration of protein of the cerebrospinal

fluid returned to normal and he improved

clini-cally for several weeks. This response was

as-sociated

with a temporary elevation of serum

concentration and urinary excretion of uric acid

on two occasions. The responses i)ecanle

pro-gressively less satisfactory, and he later showed improvement after administration of

Mustar-gen#{174}and x-ray therap’ to the skull and spine.

He

died

20 months after the clinical onset of

the disease.

COMMENT: It is of interest that the response

of the mediastinal mass to x-ray therapy and

the testicular mass to actinomycin D lasted for

16 and 12 months, respectively (before death).

There was no clinical evidence of recurrence

of disease at these sites. However, the response

of the central nervous system involvement both

to x-ray therapy amid to administration of

actinomcin

D

was of short duration, and he

died of the disease of the central neryous

(10)

.

6-

I3

51

Fic. 9. G.S. (Case 7). Roentgenogranl of the chest made before and after tllerapy with actinomycin, showing disappearance of the mediastinal mass and left pleural effusion.

IhId’l( \s’as 110 cross-resistance l)etween

ac-tii(Olliy(ill 1) dll(l \tustargcn in this patient.

Case 7: Lymphosarcoma

HIsToRY: CS., a 5-year-old boy, developed niediastinal and cervical adenopathy in April,

1958; biopsy of the cervical node showed

lym-phosarcoma. No aspiration of the bone marrow

was done. He was given a total tumor dose of 900 r to the mediastinuni in addition to

Mus-targen#{174} intravenously followed by thio-TEPA

(trieth’lenethiophosphoramide) orally for 2

months with no depression of the leukocyte

count or Platelet count. There was regression of the mediastinal nodes initially, but enlarge-ment recurred while receiving thio-TEPA oralh.

PHYSICAL AND BONE MARROW FINDINGS: In

J

umne, he was seen at Memorial Hospital. He

had enlargement of cervical and mediastinal

nodes, swelling of the right side of the hard

palate, and aspiration of the bone marrow

showed 50% stem cells.

THERAPY WITH ACTINOMYCIN D: Two courses of actinomycin D intravenously, 75

i.g/kg were given from June 9, 1958, to June 13, 1958, and June 17, 1958, to Juiie 20, 1958,

respectively. Roentgenogram of the chest made

oIl July 21, 1958 (Fig. 9) showed complete

regression of the mediastinal mass. The

swell-ing of the hard palate disappeared and the

appearance of sniears of bone marrow returned

to normal.

COURSE : However, there was recurrence of the mediastinal mass 9 weeks later and further

response, though less satisfactory, was ob-tamed after two more courses of actinomycin D

intravenously. X-ray therapy to the chest

mi-mediately after the last course of actinomycin

D resulted in regression of the mediastinal mass

which has not recurred in 4 months. Leukemic

cells which reappeared in the peripheral blood disappeared after treatment with

6-mercapto-purine.

COMMENT: Actinomycimi D alone produced complete regression for only 9 weeks. The re-gression of the mediastinal mass after x-ray

therapy, Mustargen#{174} and thio-TEPA was also

of short duration. This disease is usually

char-acterized by rapid recurrence and frequently

terminates in leukemia.

Acute Leukemia

Two children with acute leukemia who

had received conventional therapy,

Purin-ethol#{174},Methotrexate#{174}, and adrenal steroids

and had become resistant, were given

ac-tinomycin

D.

Case 8

One patient received a single course of

actino-mycin D intravenously. The total dose was

given in 21 days because of the

thrombocyto-penia due to the disease. The patient was also

receiving prednisone because of the bleeding tendency. After administration of actinomycin D, the leukocyte count dropped from 82,000 to

1200/mm3, but there was no change in the

progress of the disease. She died 1 week after the completion of therapy with actinomycin D.

Case

9

(11)

554 ACTINOMYCIN D

a total dose of 22.5 mg/kg of body weight in

I 4 (lays. At that time, the bone marrow showed

rapid relapse followed by thrombocytopenia

and the kukocyte count decreased from 4000 to 900/mm3. Because of the rapid progression

of the disease, therapy was changed to adrenal

steroids and she died of the disease 2 weeks

later.

Chronic Granulocytic Leukemia

Case 10

A 15-year-old girl with chronic granulocytic

leukemia with marked splenomegaly who had

become resistant to Purinethol#{174} and Myleran#{174},

received a single course of actinomycin D in-travenously in 19 days, to the point of toxicity.

There was no change in the size of the spleen;

later, x-ray therapy at 600 r tumor dose to the

spleen did not alter the size of the spleen. She

died of the disease 6 months after the therapy

with actinomycin.

CASE REPORTS: ACTINOMYCIN D AND

X-RAY

THERAPY

The

additive

effects

of

actinomycin

D

and x-ray therapy are difficult to evaluate

because of the inability to predict

accu-rately the degree of response of the tumor

in individual patients with various doses of

these agents, given separately. Patients

were treated with approximately 50% of

the estimated therapeutic dose of x-rays

and one or more courses of actinomycin D

intravenously. Wilms’ tumor and

neuro-blastoma are considered to be

radiosensi-tive, and actinomycin D in 18 of 28 patients

(Table I

)

appeared to have enhanced the

predicted degree of response to x-ray

ther-apy. In more radioresistant tumors, though

some were relatively radiosensitive, such as rhabdomyosarcoma and bone sarcoma,

actinomycin D sometimes appeared to

in-crease the response to x-ray therapy. This

suggests that the effect of actinomycin D

and x-ray therapy are additive in certain

responsive tumors, but we had no

convinc-ing evidence that actinomycin D sensitizes

radioresistant tumors to the action of x-ray

therapy.

Case

11

Embryonal Rhabdomyosarcoma

HISTORY: A 5-year-old boy developed a swell-ing over the right perineal region, which was

diagnosed as embryonal rhabdomyosarcoma in

July, 1957. From September 17 to October 29,

1957, he was given a total tumor dose of

3000 r to the pelvic region. During x-ray

therapy, he developed hepatic enlargement

which regressed after treatment with

Mustar-gen#{174}and Methotrexate#{174}. In May, 1958, while receiving Methotrexate#{174}, he developed bilateral

pulmonary metastases, recurrent enlargement of the liver, ascites and edema of the lower cx-tremities.

THERAPY WITH ACTINOMYCIN D: He was

then seen at Memorial Hospital; a course of

actinomycin

D intravenously

at 91 hug/kg of body weight was given to the point of toxicity,

from May 2 to May 8, 1959.

X-RAY THERAPY: A total tumor dose of 1700

r was given to the abdomen from May 12 to

May 29, 1958, and resulted in complete

regres-sion of the hepatic enlargement, ascites, and

edema.

COURSE : Although no x-ray therapy was given to the lungs, there was marked regression

of pulmonary metastases bilaterally as shown

in Figure 10, but this recurred within 4 weeks

and later responded to x-ray therapy for about

2 months. He died of the disease 5 months after

the start of therapy with actinomycin D.

COMMENT: The therapeutic dose of 3000 r

to the pelvic region produced temporary and

partial regression of the tumor while hepatic

metastases were appearing concurrently.

Sub-sequent treatment with Mustargen#{174} and

Metho-trexate#{174} again produced regression of the

he-patic metastases but pulmonary and abdominal

metastatic disease appeared during therapy

with Methotrexate#{174}. A combination of x-ray

therapy to the abdomen and administration of

actinomycin

D produced

regression

of both ab-dominal and pulmonary metastases. There is the suggestion from this latter course of therapy

that the regression of pulmonary disease might

have been due to the actinomycin D, since x-ray

therapy was not given to this area. The

sponse of the local abdominal disease at a

dose of 1700 r was approximately the same as that previously seen with 3000 r, suggesting an

(12)

Fic. 10. Roentgenograni of the chest in Case 11 showing the bilateral decrease in number and size of

pulmonary lll(’taStases; this effect was probably (hue to actinornycin I) alone, since x-ray therapy was not given to this area.

Case 12

Neuroblastoma

HISTORY: J.L., 4l years of age, had swelling of the right jaw in October, 1956 (Fig. 11), and

was treated with antibiotics with no response.

The first biopsy of the right side of the jaw was

negative; the second biopsy showed malignant tumor cells.

PHYSICAL AND LABORATORY FINDINGS: In

December, 1956, at the age of years, he was seen for the first time at Memorial Center. The

abdomen was large and the intravenous

pye-logram showed that the left kidney was de-viated and depressed by a tumor mass with

calcification. Roentgenogram of the chest showed infiltration of the right lung and

widen-ing of the superior mediastinum; the right side of the mandible showed a destructive bone

lesion.

FINDINGS AT LAPAROTOMY: Laparotomy on January 3, 1957, showed a large, firm, lobulated

mass oIl the left extending from the sub-diaphragmatic space to below the level of the

umbilicus and attached to large vessels. Only

three-fourths of the mass was removed.

THERAPY WITH X-RAYS AND ACTINOMYCIN D:

Postoperatively, he was given x-ray therapy to

the paraortic lymph nodes from the level of the

seventh dorsal vertebra to the lumbar vertebra; and to the left renal area (21 by 12 cm), a

total tumor dose of 2190 r in 2 weeks, and to

the right side of the mandible, a tumor dose of

1 160 r in 1 week. At the same time, he received two separate courses of actinomycin D

intra-venously, and from February, 1957, to

Feb-ruary, 1958, he ‘as given actinonicin D oralh 2 to 4 mg daily.

COURSE: In April, 1957, roentgenogram of

the chest showed clearing of the infiltration of

the lung and decreased mediastinal widening.

Since September, 1957, repeated roentgeno-grams revealed normal chest findings, and the

right side of the mandible showed recalcifica-tion of the metastatic lesion. Intravenous

pye-logram showed extensive calcification in the

left upper quadrant. He has no evidence of ac-tive disease 2 years after the onset of metastasis

to bone due to neuroblastoma. He received

actinomycin D during the first 14 months of the

disease and is now receiving no therapy

COMMENT: Metastases to bone in patients

with neuroblastoma are usually considered to

indicate poor prognosis. This child had a lesion of bone as a presenting sign of the disease and is now without evidence of disease 2 years

after therapy. Because of the multiple sites of

involvement and poor prognosis, he was given

both x-ray therapy and actinomycin

D. He

de-veloped toxic effects after both intravenous

courses and after oral doses. During the 1-year

period while he was receiving actinomycin

D

orally he had occasional episodes of nausea,

vomiting, and diarrhea. The concentration of hemoglobin remained between 8 and 9 gm/100

ml and the body weight remained 13.5 kg.

Ad-ministration of actinomycin D was then

discon-tinued. He was given iron orally for a period of

6 months. In the past months, the concentration

of hemoglobin rose to 10 to 1 1 gm/100 ml. He

has gained 6 kg during the last year. The lack

(13)

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JAN

1958

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556

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1957

Fic. 11. Diagnosis of neurobiastoma was made at 23 years of age in patient J.L. ( Case 12), with metastasis to bone at the onset. After partial removal of the adrenal tumor, the patient received 2190 r

and 1160 r to the abdomen and right side of the mandible, respectively. He had two courses of

actinomycin D intravenously and maintenance therapy with actinomycin I) orally for 1 year. He is now

4l years of age with no evidence of disease.

hemoglobill previously may have been due to nutritional deficiency because of gatrointesti-nal disturbances caused by oral administration

of actinomycin D.

It is difficult to determine whether this pro-longed arrest of the disease was due to the

effect of x-ray therapy alone or combination

with actinomycin D or possibly spontaneous

re-gression.

DISCUSSION

Actinomycin D is highly toxic clinically.

The therapeutic intravenous dose per

course of treatment is approximately 75

bug/kg in children. Its mechanism of action

is unknown. It has produced a consistent

pattern

of

toxicity

in humans,

including

a

local

effect

on

the

digestive

tract,

depres-sion of

the

formed

elements

of the

periph-eral

blood

and,

sometimes

of

the

bone

marrow,

exacerbation of

skin

reaction

in a

previously irradiatedi area, and nonspecific

effect on the hair follicles. Oral

adminis-tration of actinomycin D caused a more

severe local effect on the digestive tract.

The duration of improvement after a single

course of actinomycin D was usually short.

It would be desirable to have a suitable

preparation for oral maintainance therapy,

but such is not yet available. Actinomycin

D does not have a wide spectrum of

ther-apeutic activity in childhood cancer, but

its use seems indicated, on the basis of our

experience, in the following situations.

Wilms’

Tumor

In

metastatic

Wilms’

tumor,

6 of

16

pa-tients receiving actinomycin D alone showed

an objective response and in five of these

pa-tients

there was substantial clinical benefit.

(14)

age md is now 4 years of age and has no

evidence of disease. Another child, who had

pulmonary metastases at the onset at the

age of 3 years, survived 27 months. One

had no recurrence for 7 months; the other

two showed remarkable regression of

pul-monary metastases for 6 to 8 weeks.

Actinomycin D, therefore, appears to

have an appreciable degree of therapeutic

activity in about one third of the patients

in this series with metastatic Wilms’ tumor.

We believe that it deserves an adequate

trial in patients with metastatic Wilms’

tumor not satisfactorily controlled by x-ray

therapy.

The role of actinomycin D in connection

with local x-ray therapy has not been

defi-nitely established in Wilms’ tumors.

One suggestion would be to use

acti-nomycin D as the initial form of therapy

in patients with pulmonary metastases. If

there is evidence of complete regression of

pulmonary metastasis by roentgenogram,

no further therapy should be given until

signs of recurrence are present. Then more

courses of actinomycin D are administered.

When the disease recurs despite further

therapy with actinomycin D x-ray therapy

to the pulmonary metastasis would be

in-dicated. If only partial regression can be

obtained by a course of actinomycin D,

more actinomycin D should be given to the

point of toxicity. If again, the regression

is still incomplete, it should be followed by

x-ray therapy.

Another approach is to give x-ray therapy

first and later actinomycin D when

metas-tases recur. The simultaneous administration

of x-ray therapy and actinomycin D may be

considered, particularly if the patient has

had a previous course of x-ray therapy to

the lungs. In combination with actinomycin

D, regression may be produced with smaller

and less hazardous doses of irradiation.

Neuroblastoma

En patients with neuroblastoma, our

ex-perience has not been as favorable. When

the (lisease is far advanced there is usually

infiltration of the hone marrow with

extrin-sic cells; therefore, in these patients the

disease behaves somewhat like leukemia and

further

depression

in the platelet count

re-suiting from actinomycin D may be

suffi-cient

to

cause severe hemorrhage and

pre-vent

adequate further therapy. However, in

two of the three patients with

neuroblas-toma, when there was no infiltration of the

bone

marrow, there was remarkable

regres-sion of the nodules in the scalp and

improve-ment in the general condition for several

months. In cases of extensive involvement

without infiltration of the bone marrow,

ade-quate courses of actinomycin D

intravenous-ly, either alone or in combination with x-ray

therapy, should be considered. With

involve-ment of the bone marrow, the total dose of

actinomycin D may be given in 8 or 10 days;

thus, therapy can be stopped if there is

depression of the platelets. If there is

in-filtration of the bone marrow and local

metastases to the abdomen or lung, then

local x-ray therapy is more desirable.

Rha bdomyosarcoma

In patients with rhabdomyosarcoma and

pulmonary metastases, actinomycin D may

be a useful agent. Pulmonary metastases

have shown regression with actinomycin

D

alone. If the metastases involve a larger

area, such as an abdominal tumor, x-ray

therapy at a smaller dosage and actinomycin

D intravenously may produce favorable

re-suits. This may be especially helpful if such

an area has had previous x-ray therapy.

Bone Sarcoma

In patients with osteogenic sarcoma or

Ewing’s sarcoma who have developed

pul-monary metastases in one lung, actinomycin

D intravenously may be tried alone; if no

response occurs, then the combination of

actinomycin D audI x-ray therapy may he used.

In bilateral pulmonary mnetastases, a

rela-tively large dose of x-ray therapy is usually

required to produce an effect with the

at-tendant

hazard

of irradiation-induced

pui-monary fibrosis. Therefore, in this situation,

(15)

558 ACTINOMYCIN D

may be tried in combination with a smaller

dose of x-ray therapy.

Sarcoma Botryoides and Other

Metastatic

Sarcomas

and

Carcinomas

This group is usually considered

radio-resistant. Irradiation alone may produce

partial, temporary regression of the tumor.

Actinomycin D in these situations should be

given in addition to x-ray therapy in an

attempt to achieve an additive effect.

Lymphomas

The two patients with acute leukemia

who were treated did not respond because

of the rapid progression of the disease and

accompanying

hemorrhagic

tendency.

The

therapy given was, therefore, not adequate.

More studies should be done in patients

with leukemia whose disease is not too far

advanced.

There did not seem to be cross-resistance

between actinomycin D and the alkylating

agents; therefore, when patients with

lym-phoma become unresponsive to the

alkylat-ing agents, actinomycin

D might

be a useful

agent in producing further regression of the

tumor.

SUMMARY

Actinomycin

D

has

a slight

but

definite

effect in producing regression of tumors in

patients with cancer. Wilms’ tumor and

lymphomas have shown better response

than other tumors. Although the effect of

the combination of actinomycin D and

x-ray therapy is difficult to evaluate, these

agents appear to be additive in producing

temporary regression of the tumor in some

patients.

The usual single course of actinomycin

D intravenously is 75 .g/kg of body weight

divided into four or five daily doses. The

oral dose of actinomycin

D is 3 to

10 mg

daily. About 5% of actinomycin D given

orally is absorbed as evidenced by

produc-tion of systemic toxicity. However, severe

local gastrointestinal effect usually prevents

adequate oral administration of the drug.

The toxic effects of actinomycin D are

local on the gastrointestinal tract with

ul-ceration of the mouth, nausea, vomiting,

anorexia,

occasional

abdominal pain and

diarrhea; exacerbation of skin reaction in

previously irradiated areas; alopecia;

de-crease in leukocyte and platelet counts. The

toxicity after intravenous administration of

actinomycin

D

usually develops within the

first 2 weeks and disappears within the

next

2 weeks.

The duration of improvement after a

single course of actinomycin D

intra-venously was usually from 1 to 10 weeks.

Two children, one with Wilms’ tumor and

one with embryonal carcinoma, had no

re-currence for 24 and 7 months, respectively.

Both received maintenance doses of

actino-mycin D orally.

Acknowledgment

We acknowledge with appreciation the

sup-ply of actinomycin D from Merck, Sharp &

Dohme, Division of Merck and Company, West

Point, Pennsylvania.

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Bacteriostatic and bacteriocidal

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Brockmann, H.,

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30. Stock, C. C. : Aspects of approaches in

ex-perimental cancer chemotherapy. Am.

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31. Reilly, H. C., Stock, C. C., Buckley, S. M.,

and Clarke, D. A. : The effect of

anti-biotics upon the growth of sarcoma 180

in vivo. Cancer Res., 13:684, 1953.

32. Hackmann, C. : Experimentelle

Unter-suchungen Ober die Wirkung von

actino-mycin C (HBF 386) bei bosartigen

Geschwiilsten. Ztschr. Krebsforsch., 58: 607, 1952.

33. Idem: HBF 386 (Actinomycin C) em

cytostatisch Wirksamer Naturstoff.

Strah-lentherapie, 90:296, 1953.

34. Hackmann, C., and Schmidt-Kastner, C.:

Uber die cystostatische Wirkung

ver-schiedener neuer biosynthetischer

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Ztschr. Krebsforsch.,

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:607, 1957. 35. Boric, F., Seemayer, N., and Ivankovic, S.:

Uber die Wirkung des Actinomycin C

auf em transplantables Lymphosarkom

der Maus. Ztschr. Krebsforsch., 62:239,

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36. Idem: Untersuchungen #{252}berdie Wirkung

des Actinomycin C auf das

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: Action antitumoraie

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#{233}tudecancer, 43 : 1 12, 1956.

38. Field, j. B., Costa, F., Boryczka, A., and

Sekely, L. I. : Experimental evaluation of

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antibiotic actinomycin C. Antibiotics

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39. Friederici, L. : Untersuchungen #{252}berden

Einfluss des Actinomycins C

(Sanamv-cm) auf das Blut und die blutbilden

Or-gane des Kaninchens sowie auf

(17)

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anti-biotics: puromvcin and actinomycin D.

Am.

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Path., 31:582, 1955.

41. Farber, S., Maddock, C., and Swoifried,

M.: Studies on the carcinolytic and other

biological activity of actinomycin D.

Proc. Am. A. Cancer Res., 2: 104, 1956.

42. Farber, S., Toch, R., Sears, E. M., and

Pinkel, D. : Advances in chemotherapy

of cancer in man. Advances Cancer Res.,

4:1, 1956.

4:3. DiPaolo,

J.

A., Moore, G. E., and

Wied-bala, T. F. : Experimental studies wth

actinomvcin D. Cancer Res., 17:1127,

1957.

44. Idem: The influence of actinomydin D on

animal and human tumors. Proc. Am.

A. Cancer Res., 2:195, 1957.

45. Fantini, A., Moser, L., Will, L., Partridge,

R., and Halliday S. L. : The effect of

actinomycin D on several mouse tumors.

Proc. Am. A. Cancer Res., 2:108, 1956.

46. Garattini, S., Costa, V., Murelli, B., Palma,

V., and Vegeto, N. : Richerche sughi

ef-fette antitumorale della actinomycina D.

Gior. ital. chemioter., 3:498, 1956.

47. Gregory, F.

J.,

Pugh, L. H., Hata, T., and

Thielen, R. : The effect of actinomycin D

on experimental ascitic tumors in the

mouse. Cancer Res., 16:985, 1956.

48. Handler, A. H., Adams, R. A., and Farber,

S.: The effects of actinomycin D on

transplantable human and animal tumors

iii golden hamsters. Proc. Am. A.

Can-cer Res., 2:210, 1957.

49. Merker, P. C., Teller, M. N., Palm,

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E.,

and Woolley,

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W. : Effect of

actinomv-cm D on two human tumors growing in

conditioned rats. Antibiotics &

Chemo-ther., 7:247, 1957.

50.

Sugiura, K. : Merits of ascites tumors for

chemotherapeutic screening. Ann. New

York Acad. Sc., 63:962, 1956.

51. Sugiura, K., and Schmid, M. S.: Effects

of antibiotics on the growth of a variety

of mouse and rat tumors. Proc. Am. A.

Cancer Res., 2:151, 1956.

52. Sugiura, K., Stock, C. C., Reilly, C. C., and

Schmid, M. M. : Studies in a tumor

spectrum. XII. The effect of antibiotics

on the growth of a variety of mouse, rat

and hamster tumors. Cancer Res., 18:

66, 1958.

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the mechanism of action of actinomycin D in microbiologic systems. Antibiotics

Annual 1955-1956, p. 432.

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J.

: Studies on the mechanism

of actinomycin D inhibition of Bacillus

subtilis. I. Failure to demonstrate

pan-tothenate relationship. Antibiotics &

Chemother., 7:387, 1957.

55. Schulte, C. : Resultados ulteriores en los

pacientes con linfogrunulomatosis tra-tados con Sanamicina (actinomycin C

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: Essais de

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S.: Experimentation de l’actinomcine. Presse med., 62:740, 1954.

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P. : Premiers

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: Essais de traitement de

cer-tames hemopathies malignes par

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Lymphogranulo-matosen und Leukamien. Ztschr. ges

inn. Med., 10:913, 1955.

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chimiotherapie anticancereuse. Gior. ital. chemioter., 3:417, 1956.

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Agranulocytoses mortelles par traitement

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ERIC DENHOFF, M.D,

effect of actlnolliycin D treatment in

three cases of Hodgkin’s disease. Anti-biotic Med., 1:474, 1955.

70. Maney, B. E., and Shen, S. C. : The

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Cancer Res., 2:254, 1957.

THE CHILD WITH A HANDICAP, edited by

Edgar E. Martmer, M.D. Springfield,

Illi-Ibis, Charles C Thomas, Publisher.

Occasionally, a simple, heart-warming

docu-ment appears unexpectedly to win the public’s

heart. In the parlance of show business, such

a presentation is called a “sleeper,” i.e., a film

or play that makes a hit.

The Child with a Handicap, edited by Dr.

Martmer, a past-president of the American Academy of Pediatrics, deserves the right to

be called a “sleeper.” Those of us who devote a major part of our practice to the handicapped

child are often exposed to articles and

text-books which more often complicate an already

complicated subject. The Child with a

Handi-cap helps neutralize material which tends

to-wards frightening pediatricians away from

knowing more about an important phase of

pediatric practice.

Dr. Martmer was able to gather material

from experts who were interested in children

rather than diseases. He put his book together like a sandwich: 15 chapters of meaty material

on 15 different chronic disabilities of children,

are held together on topside by material

deal-ing with various roles of the rehabilitation team

and on the bottom by guides for pediatricians

and families about important aspects of

handi-capping conditions of childhood.

At the top of the batting order, Dr. Samuel

Wishik describes 25 basic philosophies for

physicians who deal with children with

crip-pling conditions. These principles should be

imprinted on the top of every pediatrician’s desk blotter.

The next batter is a parent of a retarded

child who punches through a hit when she

emphasizes some points on pediatrician-hmiI relationships that makes one pause for thought.

To quote:

“Confidence

in

Professional

Corn-Petence is Often Lost. Why doesn’t this bab’

have a soft spot?, I asked my pediatrician when

the child was very young. ‘Oh, you just had a

lot of good calcium when you were carrying him,’ he replied. Such supposed to be satisfying

but incompetent answers onh’ served to

bul-wark my natural defenses towards the truth

when it was finally given us by a physician

skilled in diagnosis, a skill which I had

ex-pected of my pediatrician.”

Such succulent yet pertinent comments are

found in each of the successive sections which

deal with the role of the psychiatrist, the social

worker, the teacher, adoption agencies, and the

counselor in medical genetics.

As to the meaty center of the sandwich, for

the first time the pediatrician can find in one

place pertinent practical information about the

pediatric approach to most of the childhood handicapping conditions.

Each chapter is written to fulfill the special

needs of pediatricians and is written in a way

which can guide the pediatrician towards the

“next step.” Each chapter has good reference

material for additional help or more specialized

inforniation.

The bottom side of the sandwich includes

guides for discipline for parents, for play

ma-terial, for reading material, for health

educa-tion material, for community programs, and

directories for camps, school services, and other

References

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