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`BLL01011742826
`Cancer chemotherapy reports. Part 1.
`Bethesda, Md : National Cancer Institute,
`1968-1975.
`0069-0112
`1972
`3
`413-419
` A J Weiss, J E Stambaugh, M J Mastrang
` Phase I study of 5-azacytidine (NSC- Full
`PubMed citation/PMID: 19051503
`
`Volume:
`
`56
`
`Your shipping address:
`Carpmaels & Ransford Services Limited
`- Judicial P
`Knowledge & Information
`One Southampton Row
`LONDON
`WC1B 5HA
`United Kingdom
`
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`Carpmaels & Ransford Services Limited -
`Judicial P
`Knowledge & Information
`One Southampton Row
`LONDON
`WC1B 5HA
`United Kingdom
`
`2
`JUDICIAL P
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`

`

`r
`
`Phase I Study of 5-Azacytidine (NSC-102816) 1
`
`·'·'·~
`
`A. J. Weiss, J. E. Stambaugh, M. J. Mastrangelo,
`J. F. Lauclus,° and R. E. Bellet 0
`
`SUMMARY
`
`Thirty patients with various solid tumors were treated with
`5-azacytidine. Total doses ranged from 1.0 to 24.0 mg/kg and were
`given over a minimal period of 8 days. The major toxic effect
`was hematologic with significant l_eukopenia and thrombocytopenia
`usually occurring 20-30 days after the start of therapy, especially at
`higher dose levels. The marrow depression lasted 1-5 weeks and
`was fully reversible. Nausea and mild diarrhea were common
`following injection of the drug. Serum glutamic oxaloacetic
`transaminas~ levels rose in several patients. No other evidence
`of hepatic toxicity was seen. Objective remissions were noted in
`seven of 11 patients with cancer of the breast, two of five with
`melanoma, and two of six with~cancer of the colon.
`I
`[Cancer Chemother Rep 66 :413-419, 1972]
`
`\ ..
`
`!
`(
`
`1
`
`l
`
`5-Azacytidirie is an analog of cytidine in
`which nitrogen is substituted for the carbon
`in the 6 position of the pyrimidine ring. It was
`first synthesized by Piskala and Sorm in 1964.
`It is produced microbiologically by a species of
`Streptoverticillium, S. Ladakanus. It is a white
`crystalline material which is quite soluble in
`water and various organic solvents. Its formula
`is CsH12N~Oe (1,2).
`Studies with the compound reveal it to be
`active against several animal neoplasms, in(cid:173)
`clud~ng the L1210 tumor (3,4). It was _relative-
`
`,
`ly inactive, however, against the Walker 256
`tumor. The compound was incorporated into
`plant and bacterial RNA and DNA and inhib(cid:173)
`ited nucleic acid and protein synthesis ( 5,6).
`It is effective in causing chromosomal abnor(cid:173)
`malities in plants (7). Apparently, several pa(cid:173)
`tients have been treated in Europe; however, no
`published data on the results of the Czechoslo(cid:173)
`vakian clinical studies have been available to
`date.
`In animal experiments the efficacy of the drug
`as an antitumor agent was highly schedule(cid:173)
`dependent, the most effective schedule being a
`daily dose given over 10 days. 1 The maximum
`tolerated dose in the most sensitive animal, the
`beagle, was 0.55 mg/kg/day given over a 5-day
`period. 1 Since data from animal studies seemed
`to indicate that a 10-day schedule would be
`proper for initial clinical use, patients in our
`study received beginning total daily doses of
`0.03 mg/kg for 10 days.
`
`MATERIALS AND METHODS
`The ·drug was supplied in 50-mg vials. When
`the d~ug is to be administered, it is dissolved
`
`(NSC-102816),
`'Clinical brochure: 5-azacytidine
`Oct 1970, 25 pp. Prepared by the NCI, Bethesda, Md.
`
`'Received Nov 17, 1971; revised Mar 17, 1972; ac(cid:173)
`cepted May 3, 1972.
`' Supported by grant CA-06071 and contract NIH-
`70-2136 from Chemotherapy, Notional Cancer Institute
`(NCI), National Institutes of Health, Public Health
`Service.
`'5-Azacytidine: e-triazin-2 ( lH) -one,· 4-amino-1-/3-D(cid:173)
`ribofuranosyl-. Supplied by the Cancer Therapy Evalu(cid:173)
`ation Branch, Chemotherapy, NCI.
`• Performed ns a phase I study for the Central On(cid:173)
`cology Group (Dr. Robert 0. Johnson, University of
`Wisconsin, Chairman) .
`'Supported by Public Health Service Research
`Fellowship No. 1F03-CA-52030-01 from the Depart(cid:173)
`ment of Health, Education, and Welfare.
`• Department of Medicine, Jefferso.n Medical College,
`Thomas Jefferson University, Philadelphia, Pa.
`
`◄ I
`
`Cancer Chemotherapy Reports Part 1 Vol. 56, No. 3, June 1972
`
`413
`
`I
`
`Supplied by the British Library 24 Mar 2021, 10:42 (GMT)
`
`I
`
`

`

`,...
`
`I
`in an appropriate volume of distil1ed water and
`theh given'immediately. In this study, when the
`diug was given intravenously (iv), it was given
`as rapidly as possible. Two patients were
`lreated at ~ch dose level. A modified Fibonacci
`, scheme was used to determine dose increments.
`I After toxicity occurred, dose increments were
`I
`limited to lOo/o of the previous dose. To be eli-
`,' ',
`gible for the study, patients were required· to
`' \ have a white blood cell count (wbc) of 5000
`'cells/mm3 or greater and a platelet count of
`140,000 cells/mm3 or greater. The blood urea
`nitrogen (BUN) value had to be Jess than 12
`mg/100 ml and the bilirubin value less than
`1.2 mg/100 ml. Further contraindications for
`therapy included radiation to the pelvis, chem(cid:173)
`otherapy in the 4-week interval prior to ther(cid:173)
`apy, prior adrena1ectomy or hypophysectomy,
`or life expectancy of less than 3 months. Com(cid:173)
`plete b~ood cell counts and platelet counts were
`done at least twice weekly and blood chemistry
`tests were done once weekly.
`The criteria for objective remissions were
`those of the Central Oncology Group, that is,
`a 50o/o or greater reduction in the area of the
`tumors being measured as approximated by a
`50o/o reduction in the product of the major
`
`diameter of the tumor and its perpendicular.
`The regression must have lasted for-a-minimal
`period of 4 weeks with no new·lesions appear(cid:173)
`ing during this time .. Alf lesions were meas(cid:173)
`ured weekly.
`
`RESULTS
`
`Tables 1 and 2 present a summary of the drug
`toxicity observed in the 30 patients treated. As
`can be seen, mild hematologic depression was
`noted at total doses of 12-16 mg/kg, and, rather
`severe hematologic depression was noted in
`most patients receiving total doses of more than
`16 mg/kg. The diarrhea noted was transient,
`occurring 2-3 hours after each injection; it was
`not disabling. In this series, we did not see
`stomatitis and dermatitis was rare. Hepatic
`function changes are found in animals treated
`with 6-azacytidine. Several of our patients had
`reversible rises in serum glutamic oxaloacetic
`transaminase (SGOT) levels, but no other he(cid:173)
`patic abnormalties were noted. Although the
`hematologic depression was at times quite se(cid:173)
`vere, serious infection-· occurred in only one
`patient and no patients died from this compli(cid:173)
`cation. Nausea almost invariably occurred after
`drug administration.
`·
`
`TABLE 1.-Hematologic toxicity
`
`\
`
`PAtlent
`No,
`1 .
`
`Sex
`F
`
`2 - F
`
`3
`
`4
`
`F
`
`6 . M
`
`D"""°
`0.55 mg/kg,
`OD x 10
`0.5 mg/kg,
`OD x 15
`M 0.75 mg/kg,
`OD X 11
`1.1 mg/kg,
`OD x 10
`1.2 mg/kg,
`OD X 10
`· 1.4 mg/kg,
`OD x 10
`l.0mg/kg,
`OD x 16
`l.0mg/kg,
`OD x 15
`1.0 mg/kg,
`oo·x 15
`
`F
`
`F
`
`F
`
`F
`
`6
`
`7
`
`8
`
`9
`
`414
`
`Nadir count
`( X 10' cclla/mm1 )
`3.8
`
`Dll7 nadir
`occurn,d
`12
`
`3.8
`
`36
`
`None
`
`None
`
`3.56
`
`3.9
`
`3.6
`
`. 0.86
`
`3.1
`
`22
`
`27
`
`18
`
`28
`
`29
`
`Dair count
`normal
`
`Th n,mbocytopee1la
`Da,. nadir
`Nadir count
`( X 10' ccll■/mm') occurred
`
`Da,. count
`normal
`
`18
`
`40
`
`33
`
`30
`
`28
`
`66
`
`46
`
`116
`
`118
`
`118
`
`112
`
`116
`
`None
`
`112
`
`98
`
`42
`
`14
`
`26
`
`14
`
`23
`
`19
`
`10
`
`31
`
`32
`
`18
`
`29
`
`17
`
`30
`
`22
`
`56
`
`48
`
`62
`
`Cancer Chemotherapy Reports Part 1
`
`(
`
`.L.
`
`Supplied by the British Library 24 Mar 2021, 10:42 (GMT)
`
`

`

`TABLE 1,-Hematologic toxicity-Continued
`
`p 4 tlmt
`No.
`10
`
`Se:ll
`F
`
`11
`
`12
`
`13
`
`14
`
`16
`
`16
`
`17
`
`18
`
`F
`
`M
`
`F
`
`F
`
`F
`
`M
`
`M
`
`M
`
`1.0 mg/kg,
`OD x 16
`1.6mg/kg,
`OD x 10
`1.6mg/kg,
`OD x 10
`1.6mg/kg,
`OD X 10
`1.8 mg/kg,
`OD x 10
`1.8mg/kg,
`OD x 10
`1.8mg/kg,
`OD x 10
`2.0 mg/kg,
`OD x 10
`2.0mg/kg,
`OD x 10
`
`Nadir COl.lftt
`( X 10' eella/mm')
`
`1.9
`
`2.6
`
`2.2
`
`2.4
`
`1.8
`
`1.1
`
`3.5
`
`4.3
`
`0.6
`
`Leukopcnl.a,
`
`t>o.,, nadir
`oeeum,d
`29
`
`11
`
`20
`
`22
`
`27
`
`31
`
`17
`
`18
`
`18
`
`Tbramboeytope,,IA
`
`Nadir eount
`(X 10' ttila/mm1 l
`84
`
`Da7 nadir
`oceul'ftd
`26
`
`-0.7 COllDt
`11ermlll
`48
`
`32
`
`70
`
`26
`
`43
`
`26
`
`31
`
`Died Day 20
`
`Died Day 48
`
`0.7 count
`normal
`
`51
`
`60
`
`65
`
`28
`
`40
`
`46
`
`21
`
`20
`
`66
`
`74
`
`104
`
`98
`
`106
`
`96
`
`73
`
`22
`
`20
`
`18
`
`30
`
`5
`
`24
`
`20
`
`Abnormal
`until Day
`48
`
`None
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`26
`
`26
`
`27
`
`F
`
`F
`
`F
`
`F
`
`F
`
`M
`
`M
`
`F
`
`F
`
`2.0mg/kg,
`OD x 10
`2.0mg/kg,
`OD X 10
`2.0mg/kg,
`OD x 10
`2.0mg/kg,
`OD x 10
`2.0mg/kg,
`OD x 10
`2.0mg/kg,
`OD x 10
`2.2 mg/kg,
`OD x 10
`2.2 mg/kg,
`OD x 10
`2.4 mg/kg,
`OD X 10
`
`None
`
`1.2
`
`0.96
`
`2.9
`
`3.3
`
`1.0
`
`0.9
`
`0.25
`
`1.0
`
`22
`
`23
`
`32
`
`23
`
`28
`
`29
`
`23
`
`26
`
`42
`
`72
`
`37
`
`68
`
`60
`
`39
`
`67
`
`50
`
`88
`
`48
`
`46
`
`90
`
`96
`
`62
`
`82
`
`88
`
`116
`
`49
`
`28
`
`20
`
`11
`
`64
`
`31
`
`17
`
`23
`
`26
`
`66
`
`42
`
`66
`
`77
`
`86
`
`63
`
`27
`
`54
`
`28
`
`•OD .,. daily dose.
`Table 3 presents the initial rermss1ons seen
`in this series and the relationship of dose to
`rem1ss1on. Because parallel pharmacologic
`studies were being conducted (8), the patients
`selected for this study fell into relatively lim(cid:173)
`ited patterns of disease. Almost all patients
`treated who had either breast cancer or mela(cid:173)
`noma had soft tissue disease as their primary
`
`manifestation of cancer. In the group of pa(cid:173)
`tients with breast cancer, most had either chest
`wall recurrences or unresectable tumors involv(cid:173)
`ing the breast, while most of the patients with
`melanoma had multiple, subcutaneous, meta(cid:173)
`static disease. In either group, lesions were
`measurable. All objective remissions were par(cid:173)
`tial; no complete remissions were seen.
`
`Vol. 56, No. 3. June 1972
`
`41S
`
`Supplied by the British Library 24 Mar 2021, 10:42 (GMT)
`
`

`

`Su
`DoNt
`Na-
`StomatJtla Dennal.ltla
`F
`0.55 mg/kg, OD x 10
`0
`0
`0
`F-
`1
`0.56 mg/kg, OD x 10
`8
`1
`0
`F
`0.6 mg/kg, OD x 16
`2
`2
`1
`0
`M
`8
`0.75 mg/kg, OD x 11
`0
`0
`0
`4
`F
`1.1 mg/kg, _OD x 10
`2
`0
`0
`M
`1.2 mg/kg, OD x 10
`5
`1
`0
`0
`29
`F
`1.2 mg/kg, OD x 10
`0
`0
`0
`F
`1.2 mg/kg, OD x 11
`80
`0
`0
`0
`u mg/kg, OD X 10
`F
`6
`0
`0
`0
`F
`1.0 mg/kg, OD x 16
`7
`2
`0
`0
`F
`8
`1.0 mg/kg, OD x 16
`3
`0
`0
`9
`F
`1.0 mg/kg, OD x 16
`2
`0
`0
`F.
`10
`1.0 mg/kg, OD x 16
`2
`1
`1
`F
`1,6 mg/kg, OD x 10
`11
`2
`0
`0
`12
`M
`1.6 mg/kg, OD x 10
`1
`0
`0
`F
`13
`1.6 mg/kg, OD x 10
`1
`0
`0
`F
`1.8 mg/kg, OD x 10
`14
`2
`0
`0
`F
`16
`1.8 mg/kg, OD x 10
`1
`0
`0
`M
`16
`1.8 mg/kg, OD x 10
`1
`0
`0
`.17
`M
`2.0 mg/kg, OD X 10
`2
`0
`0
`18
`M
`2.0 mg/kg, OD x 10
`3
`1
`0
`19
`F
`2.0 mg/kg, OD x 10
`1
`0
`0
`F
`20
`2.0 mg/kg, OD X 10
`2
`1
`1
`21
`F
`2.0 mg/kg, OD x 10
`2
`0
`0
`22
`F
`2.0 mg/kg, OD x 10
`3
`1
`0
`F
`23
`2.0 mg/kg, OD x 10
`2
`0
`0
`24
`M
`2.0 mg/kg, OD X 10 .
`2
`0
`0
`26
`M
`2.2 mg/kg, OD x 10
`2
`0
`0
`F
`26
`. 2.2 mg/kg, OD x 10
`2
`0
`0
`27
`2.4 mg/kg, OD x 10
`F
`2
`0
`0
`•o ... No toxicity; 1 - mild toxicity; 2 • modernte toxicity; 3 • incapacitating toxicity.
`tOD .. dnily dose.
`The data suggest that 5-azacytidine may be
`u~~ful in the treatment of the soft tissue ~eta-
`static disease of breast cancer and malignant
`~~lar:ioma. One significant remission and one
`borclerline remission were seen in patients with
`cancer of. the colon .
`. ~veral of the patients with breast cancer
`who had obj~ctive remissions had received prior
`therapy with 5-fluorouracil (5-FU) or cytosine
`
`Rbe lu SCOT value·
`.• ~--- • (unlla)
`From
`
`To
`
`73.6
`
`14.0
`
`16
`40
`26.5
`
`20
`
`47.5
`
`75
`26.6
`
`12.6
`
`174
`
`80.0
`
`40.0
`168
`86.6
`
`95.0 .
`
`142
`
`144
`96.0
`
`29.6 :
`
`\
`
`}
`
`I
`
`I l
`I
`
`'
`
`l
`
`•
`
`t
`I
`
`I
`I
`
`I
`
`TABLE 2.-Non-hematologic toxicity•
`
`/4atJr:nt
`No.
`
`I 28
`
`!
`I
`I
`' "-
`
`\
`
`I)qreeof-
`Dlanbea
`0
`2
`1
`0
`l
`1
`0
`0
`0
`0
`1
`1
`2
`0
`1
`2
`l
`0
`1
`0
`2
`1
`1
`1
`1
`1
`1
`2
`2
`
`l
`
`arabinoside or both and were resistant to both.•
`Thus, there did not appear to ·be any cros~ _re-
`sistance to 5-azacytidine in patients treated un-
`succes_sfully with ~ther available antipyrim~-
`dines.
`The length of the remission obtained is not
`• 5-Fluorouracil: NSC-19893.
`Cytosine arabinoside: NSC-63878; cytosin~, 1-/M>·
`·,
`arobinofuranosyl-, monohydrochloride.
`
`416
`
`cancer Chemothera·py Reports Pert 1
`
`Supplied by the British Library 24 Mar 2021, 10:42 (GMT)
`
`

`

`TABLE 3.-Response to treatment with 5-o.zacytidine
`
`Disease
`Cnncer of the
`breast
`
`Cancer of the
`colon
`
`Melanoma
`
`Cancer of the
`lung
`,
`
`Soft tissue
`sarcomas
`
`Cancer of the
`ovnry
`
`Cancer of the
`pancreas
`Lymphoma
`
`Pntient
`No.
`1
`
`4
`6
`7
`9
`10
`15
`19
`
`22
`26
`27'
`
`8
`16
`20
`23
`25
`30
`
`2
`6
`·13
`'
`24
`28
`3
`17
`18
`
`12
`29
`14
`
`21
`
`11
`
`Sex
`F
`F
`F
`F
`F
`F
`F
`F
`F
`F
`F
`
`F
`M
`F
`F
`M
`F
`
`F
`M
`F
`M
`F
`M
`M
`M
`
`M
`F
`F
`
`F
`
`F
`
`. Treatment•
`0.55 mg/kg, OD x 10
`1.1 mg/kg, OD x 10
`1.4 mg/kg, OD X 10
`1.0 mg/kg, OD X 16
`1.0 mg/kg, OD x 15
`1.0 mg/kg, OD x 15
`1.8 mg/kg, OD x ~O
`2.0 mg/kg, OD x 10
`2.0 mg/kg, OD x 10
`2.2 mg/kg, OD X 10
`2.4 mg/kg, OD x 10
`1.0 mg/kg, OD x 16
`1.8 mg/kg, OD x 10
`2.0 mg/kg, OD x 10
`2.0 mg/kg, OD >< 10
`2.2 mg/kg, OD X 10
`1.2 ·mg/kg, OD X 11
`
`0.5 mg/kg, OD X 15
`1.2 mg/kg, OD X 10
`1.6 mg/kg, OD x 10
`2.0 mg/kg,OD ><'10
`0.5·5 mg/kg, OD x 10
`0.75 mg/kg, OD x 11
`2.0 mg/kg, OD x 10
`2.0 mg/kg, OD X 10
`
`1.6 mg/kg, OD X 10
`1.2 mg/kg, OD x 10
`1.8 mg/kg, OD x 10
`
`2.0 mg/kg, OD X 10
`
`Responsett
`S-0
`S-0
`0
`p
`p
`p
`S-0
`p
`
`S-0
`S-0
`S-0
`
`0
`p
`
`NC
`NC
`NC
`S-0
`
`S-0
`S-0
`NC
`NC
`p
`p
`p
`p
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`p
`p
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`S-0
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`s
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`1.6 mg/kg, OD >< 10
`
`S-0
`
`•OD "" daily dose.
`t P .. progression of disease; S .. subjective remission; 0 - objec-
`tive remission; NC • no change.
`tCriteria for objective remission: (a) decrease of 50% or more in
`the product of the two perpendicular diameters of the lesions being
`measured (two consecutive measurements); (b) no deterioration of
`the patient's general condition; ( c) no evidence of new lesions.
`
`,·.,·
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`yet known since the drug has been used for
`o'nly 10 moi:iths; however, two patients treated
`/early in the study (one with carcinoma of the
`, breast and one with melanoma) have remained
`in remission for 6 months.
`Both of the long term responses have oc(cid:173)
`curred in patients receiving maintenance ther(cid:173)
`apy, the patient with breast cancer receiving
`an average dose of 150 mg of 5-azacytidine per
`week, and the patient with· melanoma receiving
`an average dose of 225 mg per week. The initial
`remissions in patients_ not receiving mainte(cid:173)
`nance treatment were almost invariably short,
`lasting an average of 6 weeks;-we did not see
`any remissions lasting longer than ·12 ·weeks
`in these patients. It was possible, however, to
`re-induce remissions in two patients with breast
`cancer who had relapses, one 8 weeks and the
`other 10 weeks after the cessation of therapy.
`An attempt was made to establish a main(cid:173)
`tenance regimen for the patients who had had
`remissions. The minimum total weekly dose
`that produced moderate but tolerable hema(cid:173)
`tologic toxicity was usually 2.4 mg/kg given
`twice weekly. This dose usually caused leuko(cid:173)
`penia with a total wbc of 2500-4000 cells/mm3
`or thrombocytopenia with a platelet count of
`80,000-110,000 cells/mm' or both. There was
`significant variation, however, in tolerance to
`the drug of patients receiving maintenance
`therapy. The maintenance dose was commonly
`associated with moderate nausea; however, no
`patient refused to take the medication because
`of this.
`
`DISCUSSION
`5-Azacytidine, a pyrimidine analog, has been
`found to be quite active in a small group of
`patients, most of whom have breast cancer or
`melanoma. The data gathered to date present
`several interesting points.
`Remission appears to be at least partially
`independent of dose in that remissions occurred
`at dose levels that gave no significant toxicity.
`Also, remissions commonly occurred early in
`the treatment course. Three patients with
`breast cancer had obvious shrinkage of their
`
`• See footnote 7.
`
`418
`
`tumors after 3 and 4 days of drug therapy and
`long before hematologic effects were·-noted, and
`a similar finding was noted·•h; two of the pa(cid:173)
`tients with melanoma ·who had remissions.-
`It is apparent from the data obtained in ani(cid:173)
`mal studies that the total dose required to
`cause toxicity is significantly less when the drug
`is give·n intermittently over a prolonged period
`of time (ie, over 9 days) than when it is given
`as a short course of therapy. 0 It is our impres(cid:173)
`sion that this may be so for man also since the
`total dose required to cause significant toxicity
`in man was 16 mg/kg when the drug was given
`over a 10-day course and approximately 10
`mg/kg when given over a 15-day course.
`Since the primary problem with the adminis(cid:173)
`tration of drug, as far as the patient is con(cid:173)
`cerned, is nausea, and since the severity of
`the nausea and vomiting appears to be directly
`related to the amount of drug given per injec(cid:173)
`tion, it is our feeling that patient tolerance will
`be much greater when the initial loading course
`is given over a prolonged period of time. For(cid:173)
`tunately, this type o~ regimen appears to be
`the most effective in animals as far as anti(cid:173)
`tumor activity is concerned, and our data to
`date, although extremely sketchy, lead us to
`believe that this will be the case for man as
`well.
`It is also'-apparent that, compared with both
`dogs and rodents, man can tolerate high doses
`of the drug even when the doses are calculated
`on a milligram-per-kilogram basis. The reason
`for this is not clear since there are no obvious
`differences· in overall patterns of excretion
`(8,9). The relative activities of kinases, deami(cid:173)
`nases, and other pertinent enzymes in various
`species are not known, however, and drug in(cid:173)
`corporation would be related to th~se. Also, it
`seems that the mechanism of action .of the drug
`in man is not related to that of 5-FU or cytosine
`arabinoside and that resistance to one of these
`agents is not correlated with resistance to 5-
`azacytidin~. .
`Initial observations in these patients appear
`to indicate that 5-azacytidine is promising as
`an anticancer agent in the treatment of breast
`cancer and melanoma. The series is obviously
`too small to enable us to make decisions con(cid:173)
`cerning the drug's efficacy in other tumors.
`
`Cancer Chemotherapy Reports Part 1
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`REFERENCES
`
`[
`
`1. PisKALA, A., ond SoRM, F. Nucleic acid compo(cid:173)
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`1-glycosyl derivatives of 5-nzauracil and 5-azacy(cid:173)
`tosine. Coll Czech Chem Commun 29 :2060-2076,
`1964.
`2, BERGY, M. E., ond HERR, R. R. Microbiological
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`production of 5-azacytidine.
`chemical structure. Antimicrob Agents Chemother
`1966, pp 625-630.
`3. SORM, F., end VESELY, F. The activity of a new
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`4. GOLDIN, A., Wooo, H. B., JR., end ENGLE, R. R.
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`
`1
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`of 6-nzacytidine-4-["C] and of cytidine-['H] into
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`6. ZADRAZIL, s., FuciK, v., BARTL, P., ET AL, The
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`-:J
`7. FuciK, V., MICHAELIS, A., and RIEGER, R. On the
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`'l"ROETEL, W. M., WEJSS, A. J., STAMBAUGH, J. E.,
`ET AL. Absorption distribution, nnd excretion of
`5-azacytidine (NSC-102816) in man. Cancer Chem(cid:173)
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`10. RASKA, K., JR., JUROVCIK, M., SORMOVA, z., ET AL.
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`30:3001-3006, 1966.
`
`8.
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