ZA200408114B - Pharmaceutical compositions comprising arsenite for the treatment of malignancy - Google Patents
Pharmaceutical compositions comprising arsenite for the treatment of malignancy Download PDFInfo
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- ZA200408114B ZA200408114B ZA200408114A ZA200408114A ZA200408114B ZA 200408114 B ZA200408114 B ZA 200408114B ZA 200408114 A ZA200408114 A ZA 200408114A ZA 200408114 A ZA200408114 A ZA 200408114A ZA 200408114 B ZA200408114 B ZA 200408114B
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- ZA
- South Africa
- Prior art keywords
- tumour
- salt
- composition
- arsenite
- meta
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 65
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 12
- 201000011510 cancer Diseases 0.000 title claims description 10
- 230000036210 malignancy Effects 0.000 title claims description 10
- AQLMHYSWFMLWBS-UHFFFAOYSA-N arsenite(1-) Chemical compound O[As](O)[O-] AQLMHYSWFMLWBS-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 210000001072 colon Anatomy 0.000 claims description 9
- 210000002307 prostate Anatomy 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 210000004881 tumor cell Anatomy 0.000 claims description 8
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 claims description 7
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 7
- 230000002496 gastric effect Effects 0.000 claims description 7
- 230000002611 ovarian Effects 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims description 2
- 210000003411 telomere Anatomy 0.000 claims 3
- 102000055501 telomere Human genes 0.000 claims 3
- 108091035539 telomere Proteins 0.000 claims 3
- 230000001419 dependent effect Effects 0.000 claims 2
- 230000009758 senescence Effects 0.000 claims 2
- 208000031404 Chromosome Aberrations Diseases 0.000 claims 1
- 108010017842 Telomerase Proteins 0.000 claims 1
- 230000002759 chromosomal effect Effects 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 9
- 229910052785 arsenic Inorganic materials 0.000 description 3
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical class [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- UKUVVAMSXXBMRX-UHFFFAOYSA-N 2,4,5-trithia-1,3-diarsabicyclo[1.1.1]pentane Chemical compound S1[As]2S[As]1S2 UKUVVAMSXXBMRX-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000001495 arsenic compounds Chemical class 0.000 description 1
- 229940052288 arsenic trisulfide Drugs 0.000 description 1
- OWTFKEBRIAXSMO-UHFFFAOYSA-N arsenite(3-) Chemical compound [O-][As]([O-])[O-] OWTFKEBRIAXSMO-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229940093920 gynecological arsenic compound Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940097322 potassium arsenite Drugs 0.000 description 1
- HEQWEGCSZXMIJQ-UHFFFAOYSA-M potassium;oxoarsinite Chemical compound [K+].[O-][As]=O HEQWEGCSZXMIJQ-UHFFFAOYSA-M 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
~~
PHARMACEUTICAL COMPOSITION COMPRISING ARSENITE FOR THE TREATMENT OF MALIGNANCY
The present invention relates to a pharmaceutical
N composition containing arsenic for the treatment of a malig- nancy.
Pharmaceutical compositions containing arsenic are known for cancer therapy. For example, the review by Waxman
S. et al (The Oncologist 6(suppl. 2), pp. 3-10 (2001)) de- scribes arsenic disulfide, arsenic trisulfide and arsenic trioxide the use of said composition comprising a salt of meta-arsenite (AsO; ) and a pharmaceutically acceptable auxil- i0 iary.
Due to their inherent toxicity, and the advent of good alternatives, interest in arsenic compounds has remained low.
The object of the present invention is to provide a pharmaceutical composition suitable for use in cancer ther- apy, which allows for the treatment of solid tumours. The pharmaceutical composition may be used for treatment of such solid tumours for which currently no treatment exists, or as an alternative or supplementary treatment. for such solid tu- mours.
To this end, the pharmaceutical composition accord- ing to the present invention is characterized in that it is a pharmaceutical composition for the treatment of a solid ma- lignancy chosen from the group consisting of colon tumour, gastric tumour, mammary tumour, ovarian tumour, prostate tu- mour, and renal tumour, said composition comprising a salt of meta-arsenite (AsO;”) and a pharmaceutically acceptable auxil- iary. . It has been found that the specified types of tumour are surprisingly sensitive to the meta-arsenite salt. In the . salt the counter-ion of meta-aresenite may be any pharmaceu- tically acceptable counter-ion.
In the article by Waxman, mention is made of an ar- ticle by Tarnowski G.S. et al (Cancer Research, 26(2), pp. 181-206 (1966)) where 8 tumour types were investigated with
“x 2 14 different anti-tumour chemicals. Potassium arsenite af- fected only the growth of Ehrlich ascites tumour. Regarding . this tumour type it is remarked that it is more sensitive in the ascites than in the sold form. This emphasizes the sur- . 5 prising finding of the present invention.
According to a preferred embodiment, the salt is an alkaline or earth alkaline metal salt. According to a more preferred embodiment, the alkaline metal salt is a potassium or sodium salt.
Such salts are readily soluble and are readily available for exerting their anti-tumour effect.
The invention also relates to the use of a salt of meta-arsenite (AsO;") for the manufacture of a pharmaceutical composition for the treatment of a solid malignancy chosen from the group consisting of colon tumour, gastric tumour, mammary tumour, ovarian tumour, prostate tumour, and renal tumour.
It was found that solid malignancy belonging to the group consisting of colon tumour, mammary tumour, prostate tumour, and renal tumour were particularly sensitive.
Finally, the present invention relates to a method of treating a human individual suffering from a solid malignancy chosen from the group consisting of colon tumour, gastric tu- mour, mammary tumour, ovarian tumour, prostate tumour, and renal tumour, with a pharmaceutically effective dose of a salt of meta-arsenite (As0;7).
The present invention will now be elucidated with reference to the following non-limiting example.
Various human tumor cells were grown at 37°C in a ) humidified atmosphere (95% air, 5% CO2) in monolayer cultures in RPMI 1640 medium with phenol red (Life Technologies, , Karlsruhe, Germany) supplemented with 10% fetal calf serum.
Cells were trypsinized and maintained weekly.
Cytotoxicity assay
A modified propidium iodide assay (based on W.A.
MA 3
Dengler et. al, Anti-Cancer Drugs, 6, pp. 522-532 (1995)) was used to examine the antiproliferative activity of the study ' compounds. Briefly, cells will be harvested from exponential phase cultures growing in RPMI 1640 medium supplemented with ¢ 5 10% fetal calf serum by trypsination, counted and plated in 96 well flat-bottomed microtiter plates (140 pl cell suspension, 8 x 10° cells/ml). After a 24h recovery, to allow cells to re- sume exponential growth, 10 pl culture medium (6 control wells per plate) or culture medium containing the test drug were added to the wells. Each drug concentration was plated in triplicate. After 4 days of incubation culture medium was re- placed by an aqueous propidium iodide solution (6 pg/ml). Mi- crotiter plates were kept at -18°C for 24 h, resulting in a total cell kill. After thawing of the plates, fluorescence was measured using a Millipore Cytofluor 2350-microplate reader (excitation 530 nm, emission 620 nm) in order to quantify the total cell number. The assay included untreated and positive controls (5-FU and vindesine).
Growth inhibition is expressed as Treated/Control x 100 (or T/C%). ICso and ICso values were determined by plotting compound concentration versus cell number. Mean ICso and ICs values were calculated according tc the formula: n
T log (ICsq,70)x x=1
Mean ICsg,70 = —_—— 10°
With x = specific tumor cell line and n = total num- ber of cell lines studied. If ICsp or IC; could not be deter- mined within the examined dose range, the lowest or highest concentration studied was used for the calculation.
Assays were considered valid only if the positive control (5-FU) induced a tumor growth inhibition of T/C <30% and if vehicle treated control cells had a fluorescence in- tensity >500 units.
Results 40 The results have been summarized in Table I, which
~ 4 shows that in particular tumour cell lines of the type gas- tric tumour, ovarian tumour, and in particular prostate tu- : mour, mammary tumour, renal and colon tumour were sensitive to the meta-arsenite compound. In comparison, promyelocytic t 5 leukaemia, which is known to respond to arsenic trioxide, showed an ICj¢ value of 6.82 pg/ml. Hence, the tumour cells to which the present invention relates are about 2 tec 20 times more sensitive to the meta-arsenite compound according to the present invention.
TABLE I
Claims (17)
1. Pharmaceutical composition for the treatment of a solid malignancy chosen from the group consisting of colon tumour, gastric tumour, mammary tumour, ovarian tumour, prostate tumour, and renal tumour, said composition comprising a salt of meta-arsenite (AsO,’’)and a pharmaceutically acceptable auxiliary.
2. Pharmaceutical composition according to claim 1, characterized in that the salt is an alkaline or earth alkaline metal salt.
3. Pharmaceutical composition according to claim 2, characterized in that the alkaline metal salt is a sodium salt.
4. Use of a salt of meta-arsenite (AsO,’)for the manufacture of a pharmaceutical composition for the treatment of a solid malignancy chosen from the group consisting of colon tumour, gastric tumour, mammary tumour, ovarian tumour, prostate tumour, and renal tumour.
5. Use according to claim 4 characterized in that solid malignancy is chosen from the group consisting of colon tumour, mammary tumour, prostate tumour, and renal tumour.
6. A substance or composition for use in a method of treating a human individual suffering from a solid malignancy chosen from the group consisting of colon tumour, gastric tumour, mammary tumour, ovarian tumour, prostate tumour, and renal tumour, said substance or composition comprising a salt of meta-arsenite(AsO,’’),and said method comprising administering an effective dose of said substance or composition.
7. A substance or composition for use in a method of treatment according to claim 6, in which the effective AMENDED SHEET
PCT/NL02/00231 ® 6 dose of a salt of meta-arsenite (As0,’’) is different from that of arsenic trioxide, in that it is lower than that of arsenic trioxide. (as becomes apparent from the different IC,, profiles towards human tumour cell lines).
8. A substance or composition for use in a method of treatment according to claim 6 and 7, in which the effective dose of a salt of meta-arsenite (As0,”) is 2-20 times lower than that of arsenic trioxide.
9. A substance or composition for use in a method of treatment according to claim 6, in which the effective dose of a salt of meta-arsenite (As0,’’)depends on the type of tumour to be treated.
10. A substance or composition for use in a method of treatment according to claim 6 and 9, in which the 16 effective dose of a salt of meta-arsenite (AsO,’’)depends on the telomere length of the tumour typed to be treated, in that a salt of meta-arsenite (As0,’’) is more effective on tumour cells having shorter telomere lengths.
11. A substance or composition for use in a method of treatment according to claim 6, characterized in that the tumour suppressing effect of a salt of meta-arsenite (As0,’’) is based on introducing senescence in tumour cells specifically, in a concentration dependent manner.
12. A substance or composition for use in a method of treatment according to claims 6 and 11, characterized in that a salt of meta-arsenite (As0,’’) induces senescence in tumour cells in a concentration dependent manner that results from marked telomere reduction, leading to chromosome abnormalities with chromosomal end- to-end fusions, but that a salt of meta-arsenite (AsO,’") does not inhibit telomerase activity, as is the case with arsenic trioxide.
13. A substance or composition for use in a method of treatment according to claim 12, which includes AMENDED SHEET
PCT/NL02/00231 ® 7 considering the difference in working mechanism of a salt of meta-arsenite (As0,’’) and of arsenic trioxide in clinical trial design.
14. A composition according to claim 1, substantially as herein described and illustrated.
15. A substance or composition for use in a method of treatment according to claim 1, or claim 6, substantially as herein described and illustrated.
16. Use according to claim 4, substantially as herein described and illustrated.
17. A new composition, a substance or composition for a new use in a method of treatment, or a new use of a salt of meta-arsenite, substantially as herein described. AMENDED SHEET
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200408114A ZA200408114B (en) | 2004-10-07 | 2004-10-07 | Pharmaceutical compositions comprising arsenite for the treatment of malignancy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200408114A ZA200408114B (en) | 2004-10-07 | 2004-10-07 | Pharmaceutical compositions comprising arsenite for the treatment of malignancy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200408114B true ZA200408114B (en) | 2006-06-28 |
Family
ID=38293009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200408114A ZA200408114B (en) | 2004-10-07 | 2004-10-07 | Pharmaceutical compositions comprising arsenite for the treatment of malignancy |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200408114B (en) |
-
2004
- 2004-10-07 ZA ZA200408114A patent/ZA200408114B/en unknown
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