Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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The present invention relates to a tumor antidote contain~
ing compour.ds of the lysolecithin type in a pharmaceutically
usual formulation.
German Offenlegungsschrift No. 2,00~,3~2 and U.S. Patent
No. 3,752,886 describe the use of synthetic lysolecithin com-
pounds for increasing the resistance and for use as immullologic
auxiliaries.
It is also known that lysolecithin analogs which may
alternatively be called lysophosphatides increase phagocytosis
of peritoneal macrophages. Moreover, after an injection of
lysophosphatides, activated cells are formed which are able
to increase the resistance of the body against damaging in-
fluences.
It has now been found surprisingly that lysolecithin ana-
logs of the formula I have a special effect on the growth of
tumors.
The present invention provides therefore tumor antidotes
consisting of or containing a compound of the formula I, in a
pharmaceutically usual formulation.
Formula I-
H2C - R1
R2 ~ C - R3
H2C - O - R4
wherein
R1 is alkylcarbonyl (ester~ or alkoxyl (ether) having a chain
length of 8 to 20 carbon atoms, preferably 16 to 18 carbon
atoms;
R2 is H or CH3;
R3 is H, OH, alkylcarbonyl or alkoxyl having a chain length of
- 2 - ~
~r
109~4~5 OE 76/S 005
1 to 8, preferahly 1 to 3, carbon atoms, or benzyl;
R1 and R3 may be interchanged in princip]e:
R1 long-chain substituted = ~ -lysolecithin analog
R2 long-chain substituted = B-lysolecithin analog
R4 is O (phosphorylcholine deri-
~P ~ ~ C~2 ~ CH2 -N (R5)3 vatives; R5 being H or
( ) lower alkyl having 1
to 3 carbon atoms,
preferably CH3);
or O
- P - O - CH2 - CH2 N 2 (phosphoryl-ethanol-
O (-~ - amine)
The compound cited as example and hereinafter called ET-
18-OCH3 in a thorou~hly abhreviated manner has the following
formula
Formula II:
H2C - o - (CH2)17 3
HC - OCH30
2 , 2 2 N (CH3)3
O (--)
The compounds of the formula I may be prepared according
to one of the methods described in the literature, for example
according to
Arnold, D., Weltzien, H.U. and 0. Westphal;
~ber die Synthese von Lysolecithinen und ihren ~theranaloga;
Liebigs Ann. Chem. 709, 234-239 (1967)
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10944~5 HOE 76/S 005
-.
Weltzien, H.U. and O. Westphal;
O-Methylierte und O-acetylierte Lysolecithine;
Liebigs Ann. Chem. 709, 240-243 (1967)
Eibl, H. and O. Westphal;
;. 5 Palmitoyl-propandiol-(1,3)-phosphorylcholin (2-Desoxy-lysoleci-
thin~ und ~,~-Alkandiol-Analoga
Liebigs Ann. Chem. 709, 244-247 (1967)
The activity of compounds of the formula I against the
A
growth of tumors is advantageously demonstrated on tumors of
test animals. for this purpose, various experimental tumors
are used, for example Ehrlich ascites tumor, a methylcholanthr
ne-induced tumor and a myeloma tumor in mice, furthermore a
chemically induced rat tumor.
The anti-tumor substances are administered parenterally to
the tumor-carrying test animals, preferably by intravenous,
intra- or subcutaneous injection. Oral administration is possible
when the tumor antidote is used in a physiologically tolerable
formulation, for example capsules.
t An advantageous dosage rate for parenteral administration
is from about 0.05 to 5 mg/kg of body welght.
Especially efficient are the compounds of the formula II
and those which contain OH or H instead of the methoxyl group
of formula II. At low concentration, they cause a reduction
of the growth rate of tumors and at mean concentration, a re-
gression of the tumors is often observed. After regression of
; the t~mors, the test animals display a specific resistance
against attempts to implant again a tumor of the same kind:
the t~mor does not grow any more. In order to let persist the
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HOE 76/S 005
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tumor an-tidotes in the circulatory system for a prolonged period,
it is often useful to administer the medicaments daily or in in-
tervals of 2 or 3 days.
The following test examples illustrate the activity of the
tumor medicaments of the invention.
TEST EXAMPI,E 1:
Mice carrying Ehrlich ascites carcinoma cells (see Table 1)
were treated the 7th day after the tumor inoculation with the
anti-tumor compound ET-18-OCH3 by means of intravenous injection.
The survival rate was evaluated of the mice which had been
inoculated intraperitoneally with a varying number of tumor cells.
Table 1 shows the test resul~s and the dependence of the efficien
cy of the tumor antidote ET-18-OCH3 on the daily dose intravenous-
ly administered, expressed as ratio of surviving animals to total
number of mice.
T A_B L E 1:
Daily doses of Number of tumor cells applied per mouse fox
ET-18-OCH3 tumor inoculation
per 20 g mouse
.. . ..
1 x 10 1 x 104 5 x 104 1 x 105 5 x 105
1 ~g 0/5 3/5 3/5 3/5 1/5
10 ~g 0/5 1/5 1/5 1/5 1/5
100 ~g 0/5 3/5 2/5 3/5 1/5
` Control
(without ET-18-OCH3) 0/5 0/5 0/5 0/5 0/5
)Surviving/total number of test animals
: '
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HO~ 76/S 005
TEST EXAMPI.E 2:
By intravenous injection of ET-18-OH (see formula II, OCH3
being replaced by OH~, the growth of methylcholanthrene-induced
tumor cells in (Ba1b/c x C57hl/6)F1 mlce can be controlled.
The following Table 2 s~.ows the possibility to vary the start
of treatment within several daysafter inoculation of the tumor.
At a corresponding dosage rate of the tumor antidote, in each
case the ratio of surviving test animals to their total number
is more favorable than that obtained with untreated control
animals, of which no mouse survives.
Table 2 shows the survival rate of the animals at graduated
start of treatment. The tumor antidote was intravenously admini-
stered each day for a fortnight.
T A B L E 2:
Start of treat- dose ET-18-OH/20 g mouse
mentlday 1 ~g 10 ~g 100 ~g
+ ~ 2/5 3/5 4/5
+ 3 3/5 3/5 2/5
+ 5 3/5 4/5 3/5
+ 7 2/5 1/5 3/5
+ 9 3/5 2/5 4/5
Control 0/5
) Surviving/total number of test animals
A comparable test result was obtained when the tumor anti-
dote was administered by intracutaneous instead of intravenous
injection. Comparable survival rates of the animals are obtain-
ed when from 10 to 50 llg per mouse and day of the compound
HOE 7~/S ~05
10944S5
ET-18-OH, dissolved in isotonic saline so]ution in a concen--
tration of from 10 to 100 ~g per m] are orally administered.
TEST EXAMPLE 3:
5 x 104 myeloma tumor cells (Potter x 5563) were subcutane-
ously inoculated in C3H mice. The mice were then treated with
the tumor antidote ET-18-OCH3 by administering 10~g/20 g mouse
intracutaneously for 14 days at a place remote from the tumor.
The following Table 3 shows the survival rate of the test
animals, depending on the start of treatment with the tumor
antidote.
T A B L E 3:
Start of treat- Surviving/total number
mentlday of test animals
+ 1 4/5
+ 7 3/5
+ 11 3/5
+ 15 1/5
Control (without ET-18-OCH3) 0/5
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