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EPPECT OF 1, 3-BIS(2-CHLOROETHYL)--1-NITROSOUREA (NSO-@962) AN@TWO REL&TED COMPOUNDS ON A SPECTRUM OP RB12

Kanematsu Sugiura3

SUMMARY

1, 3-Bis (2â€”chioroethyl) - 1â€”nitrosourea (BCNU), 1-@methyl- 1â€”nitrosourea (NSC -2 39 09), and hydroxy-.urea (NSC-32065) were tested for antitumcr activity against 31 transplantable animal tumors. BCNU, themost effective, produced complete inhthltlon of tumor growth In 16 tumors. Its antitumor action was generally the greatest at the maximum tolerated dose (MTD). Four rat tumors were completely inhibited byone-half the MTD and 2 of these tumors by one-fourth the MTD.

INTRODUCTION

It has been reported (2, 3, 5-7, 16) that BCNU has strong antileukemic activity in experimentalanimals, and Reltemeler et ad. (4) obtained good regression of advanced gastrointestinal carcinoma Inpatients. This led us to investigate further Its antitumor activity in a spectrum of animal tumors and tocompare it with 2 closely related compounds, 1-methyl- 1-nltrosourea and hydroxyurea (Table 1).

MATERIALSAND METHODS

Saline solutions of the compounds were prepared fresh daily, and the usual volume for InjectIonswas 0. 5 ml. The agents were given at or near the MTD, I. e. , the dose at which at least 60% of the anlmals survived when started 24 hr after tumor Inoculation and given intraperitoneally (I. p. ) once daily for7 days. A twofold increase In this dose killed at least 60%. If a compound caused marked Inhibition ordestruction of the tumor by this procedure, it was tested against well-established, 7-day-old tumors.

The compounds were tested against 13 solid tumors, 4 ascltes tumxs, and 1 viral leukemia Inthe mouse and against 13 solid rat tumors.

The history, biologic properties, and cytologic descriptions of most of these tumors have beenpresented (12-14), as well as the methods used in the chemotherapy studies. The transplantable ratfthrosarcomas (Nos. 1, 4, 6, 7, and 10) were induced by xanthlne 7-N-oxide (1). Transplants of thesefibrosarcomas â€œtakeâ€•In 80-l00@ of Wistar rats, and 14 days after transplantation the tumors measureapproximately 4 . 2 x 2 . 1 x 1 . 6 cm . They are solid and show little necrosis.

For solid tumors (12), small pieces of tumor, each weighing approximately 8 mg and measuring2. 5 cu mm, were Implanted subcutaneously (s. c. ) into healthy young animals (mice, 18-22 gm, and rats,80- 100 gm). A single implant was made by trocar Into the right axillary region.

For ascites tumors (8), each mouse received 0. 1 ml of fluid containing 1-2 million cancer cells,I. p. In the inguinal region.

For the Friend mouse virus leukemia (9), 0. 2 ml of a 10% saline homogenate of leukemic spleenswas injected i. p. in the Ingulnal region.

The criteria for evaluating tumor inhibition are given in Table 2; the tumors and their abbreviationsare listed in Table 3,

Tumor-bearing animals were divided into 1 group of 10 animals for controls and 1 group of 5 animalsfor treatment. The data are averages of the results of multiple experiments.

Animals were maintained on a standard diet (Purina Laboratory Chow) and water@ libitum.

1 Presented in part at theAnnual Meeting of the A merican Association for Cancer Research, Philadelphia,April 7, 1965 (11).

@ Supported in part by grant CA-08748 from the National Cancer Institute, USPHS.@ Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New

York.

MARCH 1967 (Part 2) 179

on July 13, 2018. © 1967 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

Kanematsu Sugiura.

RESULTS

The results with BCNU (Table 4) show that i. p. injections of 8. 0 mg/kg/day had a completelyinhthitory effect on WOS, MLS, G26, Sl8Oa, EA, KCa, and TLTa in mice and FRC, JRS, YRS, Fl, F6,F7, FlO, FOT, and AT in rats. This compound had a marked inhibitoryeffect on Sl80, Cl025, BC,TLT, FVL, and W256. The effectiveness of the compound seemed proportional to the dose. However,complete destruction of JRS, YRS, F6, and F7 was obtained with one-half the MTD and the animals appeared normal. Histologic examination of the visceral organs and bone maxrow showed no abnormalities.There was no delayed toxicity.

The controls uniformly had 100% â€œtakesâ€•and low average tumor regression rates essentially similar to those reported elsewhere (10), except that In 2 rat tumors, FRC and YRS, there were 8 and 15%spontaneous tumor regressions, respectively.

The study of BCNU showed complete regression of well-established 7-day-old S 180a, MLS, JRS,YRS, and F 1 (Table 5) . Seven-day-old FVL and FRC were markedly inhthited, and C 1025, G26, and TLTwere moderately inhibited. No spontaneous regressions occurred.

Because BCNU had a distinct inhibitory effect on 7-day-old tumors, it was tested by oral administration (Table 6). S l8Oa and F 1 completely regressed following a dose of 15 and 10 mg/kg/dayrespectively for 7 days.

Fl was implanted In the anterior chamber of the eye of rats. About 100 mg of fresh tumor tissuewas minced with a scalpel and forceps and 10 ml of sterile saline was added; the cells were stained withmethylene blue and counted. An emulsion of 0. 02-0. 05 ml containing 0. 5- 1 million cancer cells was injected by an 0. 25-ml syringe fitted with a 27-gauge needle. Three days after transplantation, I. p. administration of BCNU (8. 0 mg/kg/day) was begun and continued for 7 days. The fibrosarcomas werecompletely destroyed In 8 of 10 rats. There was no evidence of lung metastases. Eight control animalsdied from ulcerated tumors and lung metastases, whereas the tumors In the other 2 animals regressedspontaneously a nd completely, without metastasizing.

Table 7 shows that the antitumor activity of 1-methyl- 1-nitrosourea was much less than that ofBCNU. 1-Methyl-1-nltrosourea at a dose of 20 mg/kg/day produced marked to complete inhthition ofS l8Oa, E1k, KCa, E077 1, C 1025, TLTa, FRC, F6, and FOT, or 9 of 29 tumors. At this dose animals lostconsiderable weight; a higher dose was toxic.

The results with hydroxyurea tested at or near the MTD (Table 8) show that 500 mg/kg/day had amoderate inhthitory effect on S 180a, EC, BC, WOS, MM, and TLTa, but failed to produce a complete ormarked inhibitory effect on any of the 18 tumors tested. Recently Tarnowski@ @j. (1 5) of our Institutetested hydroxyurea against sarcoma T24 1, TLT, EA, ROS, Cl025, MLS, E077 1, melanoma B16, and W256,and found that the first 4 were substantially retarded at the end of therapy.

DISCUSSION

The difference in the effectiveness of BCNU, depending on the tumor system, reemphasizes theusefulness of studies on a variety of tumors. 5180 was markedly inhthited by this compound but 537 wasnot affected. Both mammary tumors, C63 and E077 1, were only slightly inhibited. WOS, generally resistant to chemotherapeutic agents, was completely destroyed but ROS, relatively sensitive to compounds,was completely resistant. Growth of MLS was completely inhibited but MRLS was not affected. Injections of BCNU i. p. completely inhibited the growth of all 4 ascites tumors, 5180a, EA, KCa, and TLTa;but s. c. injections resulted In only slight or moderate Inhibition of growth (unpublished data).

BCNU was tested against 5 grossly and histologically Identical fibrosarcomas induced in rats byxanthlne 7-N-oxide to find out whether these 5 tumors respond to the agent in the same manner. The results showed that the compound had a complete inhthitory effect on Fl, 6, 7, and 10 but only a moderateinhibitory effect on F4.

180 CANCER RESEARCH VOL. 27



Effect of 1 ,3-Bis(2-chtoroethyl)-1-nitrosourea (NSC-409962) and Two Related Compounds on Tumors

REPERENCES

1. Brown, G. B. , Sugiura, K. , and Cresswell, R. M. Purine N-Oxides. XVI. Oncogenic Derivativesof Xanthine and Guanine. Cancer Res. , @:986-9 1, 1965.

2. Goldln, A. , Venditti, J. M. , Mead, J. A. R. , and Glynn, J. P. Antileukemlc Activity of Hydroxyurea (NSC-32065) and Other Urea Derivatives. Cancer Chemother. Rept. , @:57-74, 1964.

3. Johnston, T. P. , McCaleb, G. S. , and Montgomery, J. A. The Synthesis of Antineoplastic Agents.)oom. N-Nitrosoureas. I. J. Med. Chem., .@.:669-81, 1963.

4. Reitemeier, R. J. , Moertel, C. G. , and Hahn, R. G. 1, 3-Bis(2 -chloroethyl)-l-nitrosourea (BCNU)Therapy In Advanced Gasirointestinal Adenocarcinoma. Proc. Am. Assoc. Cancer Res. , Z: 59, 1966.

5. Schabel, F. M. , Jr. , Johnston, T. P. , McCaleb, G. S. , Montgomery, J. A. , Laster, W. R. , andSkipper, H. E. Experimental Evaluation of Potential Anticancer Agents. VIII. Effects of CertainNitrosoureas on IntracerebralL12l0 Leukemia. Cancer Res., j@: 725-33, 1963.

6. Skinner, W. A. , Gram, H. F. , Greene, M. 0. , Greenberg, J. , and Baker, B. R. PotentialAnticancer Agents. )OOCI. The Relationship of Chemical Structure to Antileukaemic Activity with Analogues of l-Methyl-3-n.ttro- l-nitrosoguanldine (NSC-9369). J. Med. Pharm. Chem. , @:299-333,1960.

7. SkIpper, H. E. , Schabel, F . M . , Jr. , and Wilcox, W. S. Experimental Evaluation of PotentialAnticancer Agents. XIII. On the Criteria and Kinetics Associated with â€œCurabilityâ€• of ExperimentalLeukemia. Cancer Chemother. Rept. , @:1-1 11, 1964.

8. Sugiura, K. Merits of Ascites Tumors for Chemotherapeutic Screening. Ann. N. Y. Acad. Sd.,j@: 962â€”73, 1956.

9. Suglura, K. Effects of Compounds on the Friend Mouse Virus Leukemia. Gann, @:251-64, 1959.

10. . Experimental Chemotherapy of Cancer--A Report of Progress. jj@: Progress of Expertmental Tumor Research, Vol. 2, pp. 332-76. New York: Karger, 1961.

11. . Effect of 1, 3-Bis (2 -chloroethyl) - 1-nitrosourea on a Spectrum of Tumors . Proc. Am.Assoc. Cancer Res. , &: 62, 1965.

12. Sugiura, K. , and Stock, C. C. Studies in a Tumor Spectrum. I. Comparison of an Action of Methylbis (2 -chloroethyl)amine and 3 -Bis (2 -chloroethyl) amino-methyl-4-methoxymethyl-5-hydroxy-6-methylpyridine on the Growth of a Variety of Mouse and Rat Tumors. Cancer, @:382-402, 1952.

13. . Studies in a Tumor Spectrum. II. The Effect of 2, 4, 6-Trlethylenimino-a-triazine onthe Growth of a Variety of Mouse and Rat Tumors. Cancer, @:979-9 1, 1952.

14. . Studies in a Tumor Spectrum. III. The Effect of Phosphoramides on the Growth of aVariety of Mouse and Rat Tumors. Cancer Res. , j@: 38-51, 1955.

15. Tarnowski, G. S. , Kreis, W. , Schmid, F. A. , Cappuccino, J. G. , and Burchenal, J. H. Effect ofHydroxylamine (NSC-26250) and Related Compounds on Growth of Transplanted Animal Tumors.CancerRes. (Suppl.), j@(No. 11, part2): 1279â€”1301,1966.

16. Vendltti, J. M. , Kline, I. , and Goldin, A. Evaluation of Antileukemic Agents Employing AdvancedLeukemia Ll2lO in Mice. Vu. Cancer Res. (Suppl. ), @.j(No. 6, part 2): 827-79, 1964.

MARCH 1967 (Part 9) â€¢ 181



ENTRY[ICOMPOUNDNAME*MOLECUlARSTRUCTURESOLVENT79637

79638

79 63 923909t

32065*

4 099 62tUrea,

lâ€”methylâ€”1â€”nitroso

Urea, hydroxy

Urea, 1, 3 -bis (2-chloroethyl)-l-nitroso

N3O2C2H6

N202CH4

N3 O@Cl3 C@H90

CH3

@ IH3Nâ€”Câ€”â€”Nâ€”NO

0

IH2 Nâ€”C â€”NHOH

I CH3CH2C1HNâ€”C â€”N â€”NO

ICH3CH2C1Saline

Saline

Saline*

Compounds were supplied by the Cancer Chemotherapy National Service Center, National Cancer In

stitute.t Original supplier was Southern Research Institute.$ Original supplier was The Squibb Institute for Medical Research.

TABLE 2

Criteria for Evaluating TumorInhibltlon*SYMBOL

-

Â±

+

-H-

+++DEGREE

OF TUMOR INHIBITION

None

Slight

Moderate

Marked

CompleteTUMOR

INDEXt

0.76-1.0

0.51â€”0.75

0. 26-0. 50

0. 08-0. 25

0-0.07

Kanematsu Sugiura

* Solid tumors were measured with calipers, in 2 dIameters, weekly for 4 weeks. Results in the fol

lowing tables are based on observations made 2 weeks after tumor implant except for Iglesias ovarianand adrenal tumors, which were measured at the times indicated In the tables.

Volume of ascites fluid was measured 10-li days after injection of ascites. The animals were killedwith ether and weighed, the fluid was removed by cutting the abdominal skin, the adhering fluid waswiped off with a paper towel, and the animals were reweighed. The weight difference was the fluidvolume. Grading of ascites tumors was calculated similarly to that of solid tumors but was based onthe relative weight (in grams) of the ascitic fluid in the treated animals compared with the weight ofthe fluid In the control group.

The spleens of mice with Friend virus leukemia were weighed at the end of the 3rd week.

t The tumor index was determined by dividing the average measurement in the treated animals by theaverage measurement in the control group.


TABLE 1

Compounds Tested Against a Spectrum of Tumors



MOUSE TUMORSRATTUMORSS

180 Sarcoma 180Sl8Oa Sarcoma 180, ascltes537 Sarcoma 37EC Ehrlich carcinomaEA Ehrlich carcinoma, ascitesKCa Krebs II carcinoma, ascitesC63 Bashford carcinoma 63EO77 1 Adenocarcinoma EO771Cl025 Carcinoma 1025BC Lewis bladder carcinomaWOS Wagner osteogenic sarcomaROS Ridgway ostÃ©ogenlc sarcomaMLS Mecca lymphosarcomaMM Harding-Passey melanomaG26 Glioma 26TLT Taper liver tumorTLTa Taper liver tumor, ascitesFVL Friend virus leukemiaFRC

Flexner-Jobling carcinomaW256 Walker carcinosarcoma 256JRS Jensen sarcomaYRS Yoshida sarcomaF 1 Fibrosarcoma No. 1F4 Fibrosarcoma No. 4F6 Fibrosarcoma No. 6F7 Fibrosarcoma No. 7FlO Fibrosarcoma No. 10MRLS Murphy-Sturm lymphosarcomaFOT Igleslas ovarian tumorAT Iglesias adrenal tumorBRK Babcock kidneytumorTA3LE

4

Effect of BCNU on a Spectrum ofTumorsTUMOR*

, D@S@@

@mg@icg@dayjRESULTS

AT END OF 2ND WEEK..__________RESULTSAv.

wt. changeTreated@Control

(gm)No.

ofdeathsAv.

tumor diam.,Treatea,'Control

(cm)TumorIndexResults

oftreatmentATMouse

5180

Sl8Oa

537

EC

EA

KCa8.0

4.02.0

8.04.02.0

8.0

8.04.0

8. 04. 02.0

8.04.02. 0+

1.5/+ 1,0

4 i.o/+ 1.0

4 s.o/+ 1.5

0/4 5.0+ 5.5/4 6.04 6.5/4 5.5

4 0.5/4 8.0

+ 2.5/+ 8.54 7.0/411.0

4 0. 5/+ 5. 5

4 3. o/+ 3. 5

+ 5.5/+ 2.0

4 1.0/4 7.5

+ 3. 5/4 7. S

4 5. o/+ 7. 00/15

0/150/15

0/101/101/10

0/10

0/100/ 5

0/is0/200/10

0/100/100/ 50.27/

1.590.99/ 1.591.28/ 1.20

0/ 8.715.5 / 9_st8.4 /ll.ot

1.47/ 1.91

0.77/ 1.801.70/ 2.17

0. 13/ 6. 5t1. 07/ 8. St8.4 / 9.2t

0/ll.8t1.01/ 9.9t6. 4 / 7. 2t0.17

0.621.07

00.580.76

0.77

0.430.79

0. 020. 130.91

00.100. 89++

Â±â€”

4+4

Â±â€”

â€”

4â€”

+4+

4+â€”

+4+

+4â€”4+

â€”

â€”

â€”

â€”

â€”

Effect of 1 ,3-Bis(@-chloroethyl)-1-nitrosourea (NSC-40996f2) and Two Related Compounds on Tumors

TABLE 3

Test Systems*

MARCH 1967 (Part @) 183



RESULTS AT END OF 2NDWEEKTUMORDOSE*

(mg/kg/day)RESULTSAv.wt. change

Treated/Control(gm)No.

ofdeathsAv.

tumor diam.Treated/Control


oftreatmentAT

Kanematsu Sugiura

Mouse

C63 8.0 + 5.0/-i-u.s 0/10 0.91/ 1.51 0.60 Â±4.0 + 4.5/+ 7.0 0/ 5 1.38/ 1.59 0.87 â€”

E0771 8.0 o/+ 6.5 1/16 1.31/ 2.03 0.65 Â±4. 0 + 1. o/+ 5. 5 0/ 5 i. 63/ 2. 06 0. 79 â€”

Cl025 8.0 o/+ 8.0 0/10 0.43/ 1.89 0.23 +4 Â±4.0 + 2.0/+ 5.5 0/10 1.09/ 1.63 0.67 Â± â€”2. 0 + 2. o/+ 3. 0 0/10 1. 12/ 1. 90 0. 59 Â± â€”

BC 8.0 â€”2.5/+ 2.0 0/10 0.22/ i.16 0.19 +4 +4.0 â€”0.5/i-2.0 0/10 0.86/ 1.35 0.64 Â± â€”2.0 + l.0/+ 2.5 0/ 5 1.21/ 1.35 0.90 â€” â€”

WOS 8.0 â€”1.5/i-4.0 0/20 0/ 3.06 0 -i-++ +4+4. 0 + 1. 0/-i- 3. 0 0/25 0. 79/ 2. 12 0. 37 + Â±2. 0 + 5. 0/-i- 5. 0 0/10 2. 39/ 2. 17 1. 09 â€” â€”

ROS 8.0 â€”1.5/+ 5.0 1/10 0.83/ 1.01 0.824. 0 â€”1. o/+ 2. 0 0/ 5 1. 07/ 1. 14 0. 94

MLS 8. 0 â€”1. 0/i- 3. 5 0/10 0. 13/ 1. 95 0. 07 +++4. 0 â€”1. 5/+ 3. 0 0/15 0. 60/ 2. 30 0. 26 +4 +2.0 + 2.5/+ 3.5 1/10 1.83/ 2.23 0.82 â€” â€”

MM 8.0 + 2.0/+ 5.5 0/10 0.77/ 0.82 0.94

G26 8. 0 â€”3. 5/i- 1. 5 o/io 0. 03/ 0. 83 0. 04 -i-++ +4+4.0 + 0.5/+ 2.5 0/10 0.56/ 1.24 0.45 + Â±2.0 + o.s/+ 1.5 0/ 5 1.05/ 1.21 0.87 â€” â€”

TLT 8.0 + 0.s/i-4.5 0/10 0.27/ 1.55 0.17 +4 +4.0 + 7.5/+ 7.5 0/10 1.04/ 2.31 0.45 + Â±2.0 +lO.0/+ 7.5 0/ 5 2.04/ 2.31 0.88 â€” â€”

TLTa 8.0 + 0.5/-f2.5 1/10 0/ 8.Ot 0 +444.0 + 2.5/+ 5.0 0/15 1.92/ 8.3t 0.23 +42. 0 + 3. o/+ 4. 5 0/10 7. 7 / 8. Ot 0. 96 â€”

FVL 8.0 â€”1.0/-i-8.5 3/10 0.50/ 2.48* 0.20 144. 0 + 1. 5/+lO. 0 1/10 0. 66/ 2. 26$ 0. 29 +2.0 +ll.0/â€”l3,5 0/10 1.00/ 2.00* 0.50 +

Rat

FRC 8.0 +11.0/1-49.0 0/10 0/ 2.37 0 14+ 44+4.0 +l7.0/+62.0 0/10 1.02/ 2.39 0.43 + Â±2.0 +29.0/i-44.0 0/ 5 1.21/ 1.74 0.70 Â± â€”1. 0 +32. 0/4-42. 0 0/ 5 1. 27/ 2. 26 0. 56 Â± â€”


TABLE 4

(Continued)



TUMORDOSE*(mg/kg/day)RESULTS

AT END OF 2ND WEEKRESULTS

AT3WEEKSAv,

wt. changeTreated/Control

(gm)No.

ofdeathsAv.

. tumor diam.Treated/Control


oftreatment

Effect of 1 ,3-Bis(P2-chloroethyl)-1-nitrosourea (NSC-409962) and Two Related Compounds on Tumors

TABLE 4

(Concluded)

Rat

W256 8.0 â€”11.o/+36.0 0/10 0.60/ 3.24 0.19 44 444.0 + 7.0/+47.0 0/10 0.61/ 2.96 0.21 44 Â±2. 0 +22. 0,1+55. 0 0/10 0. 56/ 3. 37 0. 17 14 Â±1.0 +32.0/+54.0 0/10 1.41/ 3.28 0.43 + â€”

JRS 8.0 + 5.0/+39.0 0/10 0/ 3.13 0 +++4.0 +ll.0/+43,0 0/10 0/ 3.63 0 +4+2.0 +34.0/+52.0 o/io 0.26/ 3.31 0.08 44 +1.0 +5l.0/+56.0 0/5 4.02/4.42 0.91 â€” â€”

YRS 8.0 +13.0/4-54.0 0/10 0/ 2.49 0 +4+ +4+4.0 +l6.0/+5l,0 0/10 0.02/ 2.38 0.01 +4+ +4+2.0 +34,0/4-46,0 o/io 0/ 2.79 0 44+ +4+1.0 +48.o/+53.0 0/10 0.86/ 2.95 0.29 +4 +

8.0 o/+47.o 0/is 0/ 2.20 0 44+ +4+4.0 +l5.0/+48,0 0/10 0.43/ 1.84 0.23 44 +2.0 +26.o/+44.0 0/ 5 1.14/ 1.77 0.64 Â± â€”1.0 +36.0/+4'4.0 0/ s 1.37/ 1.77 0.77 â€” â€”

F4 8.0 â€”12.0/+44.0 0/ 5 0.40/ 1.22 0.33 + Â±4.0 + 6.0/+38.0 0/ 5 0.40/ 0.61 0.66 Â± â€”2.0 +2l.0/+38.0 0/ 5 0.57/ 0.61 0.93 â€” â€”

P6 8.0 â€”6.0/+46.0 0/is 0.03/ 1.47 0.02 +4+4.0 + 8.0/+31 0/10 0/ 1.20 0 +++ 44+

F7 8.0 â€”7.0/+48.0 0/10 0/ 1.95 0 +++4.0 +14.0/+54.0 0/10 0/ 1.77 0 +++ 44+2.0 +20.0/+37.0 0/ 5 0/ 1.59 0 +1â€”i- 44+1.0 +25.0/+68.0 0/ 5 2.49/ 2.24 1.11 â€” â€”

FlO 8.0 â€”5.0/+5l.0 0/10 0/ 2.31 0 44+ +4*

MRLS 8. 0 â€”3. o/+38. 0 2/10 3. 43/ 3. 99 0. 864. 0 +12. 0/+30. 0 1/ 5 3. 55/ 4. 44 0. 80

FOT 8. 0 â€”11. 0/+35. 0 0/ 5 0/ 1. 82 Â§ 0 +4+

AT 8.0 â€”12.0/+106.0 0/ 5 0/ 1.5911 0 +4+

BRK 8.0 â€”l0.0/+43.0 0/is 0.68/ 2.05 0.33 + Â±4.0 + 5.0/+40.0. o/ s 1.35/ 2.03 0.66 Â± â€”

* Treatment (1. p. ) was started 24 hr after tumor inoculation and continued for 7 days.

t Volume in ml at 10-il days.4:Spleen weight in gm at 3rd week.Â§4th week results.II8th week results.

185MARC!! 1967 (Part 2)




AT END OF 2 ND WEEKRESULTS

AT@ WEEKSAv.


(gm)No.

ofdeathsAv.



oftreatment

Kanematsu Sugiura

TABLE 5

Effect of BCNU on 7-Day-Old Tumors

Mouse

5180 8.0 â€”5.0/â€”4.0 5/10 1.77/ 2.15 0.82

S180a 8.0 + 2.0/+ 8.0 4/10 o/ll.3t 0 44+

E1k 8.0 + 5.5/4-8.0 4/30 8.1 / 8.4t 0.96

KCa 8.0 + 6.0/+ 7.0 0/20 7.9 /ll.8t 0.67 Â±

C1025 8.0 o/+ 4.5 1/20 0.81/ 2.00 0.41 + Â±

BC 8.0 + l.0/+ 2.5 0/10 1.80/ 1.92 0.94

WOS 8.0 â€”1.o/+ 4.5 0/20 1.54/ 2.93 0.53 Â± â€”4.0 + 2.5/+ 4.0 o/io 2.53/ 3.01 0.84 â€” â€”

MLS 8.0 + 1.o/+ 2.0 0/30 0.07/ 2.11 0.03 +++

G26 8. 0 â€”1. 5/+ 7. 0 1/20 0. 63/ 2. 28 0. 27 + +

TLT 8.0 + 4.5/+ 6.0 0/10 1.42/ 3.32 0.43 +

TLTa 8.0 4 3.5/+ 6.0 0/20 8.2 / 8.40t 0.98

FVL 8.0 + i.o/+ 9.5 1/15 0.48/ 1.99* 0.24 44

Rat

FRC 8. 0 + 6. o/+62. 0 1/20 0. 22/ 2. 78 0. 08 +4 +44. 0 +28. 0/+66. 0 0/10 @.76/ 3. 60 0. 49 + â€”

W256 8.0 +ls.0/+82.0 0/20 2.38/ 4.43 0.54 Â±

JRS 8. 0 +15. o/+35. 0 o/io 0. 15/ 3. 27 0. 05 44+ 14+4.0 â€”8.o/+35.0 0/ 5 0/ 3.27 0 14+ +142. 0 +14. o/+72. 0 1/20 0. 52/ 3. 91 0. 13 +4- 14

YRS 8.0 +28.0/+58.0 0/20 0.07/ 3.37 0.02 +++ +14

Fl 8.0 + s.o/+52.o 0/20 0.02/ 2.75 0.01 14+ 14+4.0 +32.0/+73.0 0/10 i.60/ 2.50 0.64 Â± â€”

MRLS 8.0 +29.0/+33.0 0/10 3.52/ 3.18 1.11

* Treatment (I. p. ) was started 7 days after tumor inoculation and continued for 7 days.

t Volume in ml at 10-il days.4: Spleen weight in gm at 3rd week.






AT3WEEKSAv.


(gm)No.

ofdeathsAv.



oftreatmentMouse

5180

Sl8Oa

WOS

@iYRS

Fl15

15

is10

10

10+

0.5/â€” 2.5

0/+ 7.0

â€”5. o/+ 4. 0

â€”3. o/+ 4. 0

â€”2l.0/+38.0

â€”25.0/+35.00/10

0/10

2/10o/io

0/b

o/io1.22/

2.20

0.80/lO.7t

0. 69/ 2. 920. 84/ 2. 92

0.71/ 2.34

0/ 1.470.55

0.07

0. 240. 29

0.30

0Â±

14+

4*

+

+

44+â€”

+

Â±

Â±

44+*

Treatment was started 7 days after tumor inoculation and continued for 7 days.

t Volume in ml at 10-li days.

TABLE 7

Effect of l-Methyl-l-nitrosourea on a Spectrum ofTumorsTUMORDOSE*

(mg/kg/day)RESULTS


AT3WEEKSAv.


(gm)No.

ofdeathsAv.

tumor diam.Theated/Control


oftreatmentMouse

5180

Sl8Oa

537

EC

EA

KCa

C63

EO771

Ci02520

20

20

20

20

20

20

20

20â€”

1.0/â€” 2.5

â€” l.0/+ 6.5

â€” 3.0/+ 8.0

â€” 1. 0/+ 7. 0

â€” 0.5/+ s.s

â€” 1. s/i- 7. 0

â€” 1.0/-F 4.5

â€”4. o/+ 3. 5

â€” 2.5/+ 3.00/is

0/10

1/ 5

0/10

0/10

0/ 5

2/15

1/10

0/100.92/

1.55

0.04/ 9.6t

1.58/ 1.91

i. 03/ 2. 14

0.04/li.Ot

0/10.8t

0.88/ 1.75

0. 24/ 1. 49

0.36/ 1.640.59

0.04

0.83

0. 48

0.04

0

0.50

0. 16

0.22Â±

+++

â€”

+

+++

+++

+

1*

44â€”

â€”

-

â€”

+

Â±

Effect of 1 ,3-Bis(2-chloroethyl)-1-nitrosourea (NSC-4O996@) and Two Related Compounds on Tumors

TABLE 6

Effect of Oral Administration of BCNU on 7-Day-Old Tumors

MARCH 1967 (Part 2) 187




AT END OF 2ND WEEK1@ESULTS

AT3W@EKSAv.


(gm)No.

ofdeathsAv.



oftreatment

Kanematsu SugiuraTABLE 7

(Concluded)

0.66/ 1.22

0. 77/ 2. 591. 51/ 2. 70

i.oi/ 1.311.50/ 1.41

0. 71/ 2. 02

0. 96/ 0. 81

1.02/ 1.21

0.56/ 1.54

0.21/ 9.50t0. 08/il. 3

1. 32/ 3. 46$

Â±

1-

Â±

+

+

+4+

+44

1-

14+

Â±

+

Â±

+4

Â±

Â±

+1-

1-

Â±

Mouse

BC

WOS

ROS

MLS

MM

G26

TLT

TLTa

FVL

Rat

FRC

W2 56

JRS

YRS

F4

F6

F7

MRLS

FOT

AT

BRK

20

2010

2010

20

20

20

20

2010

20

20

20

20

20

20

20

20

20

20

20

20

â€” 2.0/+ 0.5

â€” 3.5/1- 3.0

+ i.o/+ 4.0

â€” 2.0/+ 3.0

+ 3.0/1- 3.5

- 3.0/+ 4.5

â€” 3. o/+ 2. 5

â€” 2.0/+ l.s

â€” 2.5/+ 4.5

â€” 3. 5/+ 5. 5

+ i.o/+ 5.5

â€” 3.0/1-10.0

â€” 2.0/+38.0

1- 6.0/+41.0

+21.o/+57.0

1- 9.0/1-35.0

+17.o/+64.0

+14. 0/Ã·42. 0

1- 6. 0/+49. 0

â€” 2.0/+38.0

â€”37.0/â€” 8.0

â€”26.0/+4l.0

+20.0/+36.0

i/i 0

0/i 00/ 5

i/i 00/ 5

0/10

0/10

0/ 5

1/10

i/is0/ 5

2/10

0/i 0

i/is

0/10

0/is

0/ 5

0/i0

0/i 0

2/10

i/ 5

0/ 5

0/ 5

0. 04/

2. 15/

3. 50/

1. 19/

0. 91/

0. 19/

1. 22/

2. 35/

0. 25/

1. 12/

0. 92/

1. 88

3. 81

3. 19

3. 52

1. 22

1. 79

2. 08

3. 34

2. 63@

2. 2311

1. 62

0. 54

0. 300. 56

0. 771. 06

0. 35

1. 19

0. 84

0. 36

0. 020. 01

0. 38

0. 02

0. 56

1. 26

0. 34

0. 74

0. 11

0. 59

0. 70

0. 10

0.â€¢50

0. 57

Â±

Â±

Â±

Â±

14+

:1:

+

* Treatment (i. p. ) was started 24 hr after tumor Inoculation and continued for 7 days.

t Volume in ml at 10-il days.4: Spleen weight In gm at 3rd week.Â§4th week results.II8th week results.




TUMORDOSE*mg/kg/day)RESULTS


AT3WEEKSAv.


(gm)No.

ofdeathsAv.



oftreatment

Effect of 1 ,3-Bis(f2-chloroethyl)-1 -nitrosourea (NSC-409962) and Two Related Compounds on Tumors

TABLE 8

Effect of Hydroxyurea on a Spectrum of Tumors

100

500250100

500

500100

250

500100

500100

500

500100

500100

500250

500100

100

200

200

200

200

200

â€”3. 0/â€” 3. 5

+ o.s/+ 8.5

+ i.s/+ 7.0

1- 4.0/1- 5.0

1- 2.0/1- 8.0

1- 4.5/+lO.5

o/+ 4. 5

+ 4.0/+10.5

+ 3.0/1- 9.0

+ 3.0/+ 5.0

â€” o.s/+ i.s

0/1- 3.0

â€”2.0/1- 6.0

1- 6. 5/1- 6.0

1- 2.5/1- 4.0

0/-i- 2.0

1- l.s/+ i_s

1- 0.5/+ 3.5

1- 2.0/+ 3.5

1- 5.5/+ 8.0

1- 6.5/+ 8.5

+28.o/+so.0

+31.0/@41.0

+42.0/+51.0

+45.0/1-48.0

+12. 0/1-43. 0

+32.0/+47.0

0/ 5

1/ 51/ 51/ 5

0/ 5

0/i00/i0

0/ 5

0/ 50/ 5

2/1s0/ 5

1/1s

0/i 01/ s

0/ 50/ s

0/i 00/i 0

0/ 51/ 5

0/ 5

0/ 5

0/ 5

0/ 5

1/ s

0/ 5

1. 85/ l. 86

4. 4 / 9. 8t5. 6 /13. Ot6. 9 / 7. it

1.62/ 1.91

0.76/ 2.270. 73/ 2. 08

6. 1 /10. 7t

1.21/ 1.391.36/ 1.01

0.58/ 1.651. 25/ 1. 67

1.00/ 2.65

0. 35/ 0. 860. 30/ 0. 48

0. 88/ 1. 181.53/ 1.83

3. 90/ 9. 05t5. 25/ 9. 05t

2. 74/ 3. 13$2. 15/ 3. 07$

0. 99

0. 450. 430. 97

0. 85

0. 330. 35

0. 57

0. 871. 35

0. 350. 75

0. 38

0. 410. 63

0. 750. 84

0. 430. 58

0. 880. 70

1. 23

0. 61

0. 66

0. 68

0. 53

0. 67

+

+

1-

+

Â±

+

Â±

1-

+

Â±

Â±

1-

Â±

Â±

Â±

Â±

Â±

Â±

Â±

Mouse

S 180

S 180a

S37

EC

KCa

C63

BC

WOS

MM

G26

TLTa

FVL

Rat

FRC

Fl

P6

P7

MRLS

BRI(

Â±

Â±

1. 87/

1. 47/

1. 08/

0. 81/

2. 04/

1. 52

2. 41

1. 64

1. 19

3. 85

1. 10/ 1. 64

* Treatment U. p. ) was started 24 hr after tumor inoculation and continued for 7 days.

1@Volume in ml at i0-@i1 days.4: Spleen weight In gm at 3rd week.

MARCH 1967 (Part 2) 189



1967;27:179-189. Cancer Res Kanematsu Sugiura Two Related Compounds on a Spectrum of TumorsEffect of 1,3-Bis(2-Chloroethyl)-1-Nitrosourea (NSC-409962) and

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