CA1120399A - Pharmaceutical compositions for treatment of tumor cells - Google Patents
Pharmaceutical compositions for treatment of tumor cellsInfo
- Publication number
- CA1120399A CA1120399A CA000336631A CA336631A CA1120399A CA 1120399 A CA1120399 A CA 1120399A CA 000336631 A CA000336631 A CA 000336631A CA 336631 A CA336631 A CA 336631A CA 1120399 A CA1120399 A CA 1120399A
- Authority
- CA
- Canada
- Prior art keywords
- tumor
- fatty acid
- mono
- disaccharide
- tumor cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The present invention relates to a pharmaceutic-al composition effective for enhancing the capacity of a host to reject a large number of tumor cells, retarding growth in tumor size or in inducing hemorrhagic necrosis, which comprises a fatty acid ester of a mono or di-saccharide, in admixture with a pharmaceutically accept-able carrier, the fatty acid having 12 to 18 carbon atoms and the mono or disaccharide being selected from maltose, galactose, glucose, mannose, arabinose and cellobiose.
The present invention relates to a pharmaceutic-al composition effective for enhancing the capacity of a host to reject a large number of tumor cells, retarding growth in tumor size or in inducing hemorrhagic necrosis, which comprises a fatty acid ester of a mono or di-saccharide, in admixture with a pharmaceutically accept-able carrier, the fatty acid having 12 to 18 carbon atoms and the mono or disaccharide being selected from maltose, galactose, glucose, mannose, arabinose and cellobiose.
Description
lV?~9 The present invention relates to a novel compo-sition which is particularly effective for use in cancer therapy.
BACKGROUND OF THE INVENTION
Surgical removal of certain operable cancers is a routine clinical procedure in the treatment of most non-lymphoreticular human cancers. Remissions induced by this procedure alone are, generally, of a limited duration and a majority of patients return with recurring cancers. The inability to prevent tumor recurrence in patients who have undergone surgery poses a major problem in the reduction of cancer mortality rates. The problem is more acute in developing countries where high cost and/or non-availa-bility of anti-cancer drugs permit surgery and radio-therapy as the only means of cancer treatment.
Considering that the effectiveness of surgery lies in adequate tumor removal and the subsequent develop-ment of host defenses (cell-mediated immunity against tumor cells) to arrest cancer development, tumor reappear-ance can be regarded as being due to insufficient surgeryor a weakness in the host to mount an effective immune response against its remaining cancer cells. If the latter proposition is true, it would appear that immuno-potentiating agents should reduce tumor recurrence after adequate surgical tumor excision in a larger number of cancer cases.
SUMMARY OF THE INVENTION
In accordance with the present invention it has now been found the administration of certain fatty acid esters of mono- or disaccharides will surprisingly elicit an antitumor response as shown in an enhancement of the host's capacity to reject a large number of tumor cells, ~lZ~
to retard growth in tumor size and to induce hemorrhagic necrosis. It has also been surprisingly found that these compounds are devoid of endotoxic activity.
More particularly, it has been found that the fatty acid esters of maltose, galactose, glucose, mannose, arabinose and cellobiose are particularly useful for the purposes of the present invention. As suitable fatty acids for preparing the desired fatty acid esters there may be mentioned those having 12 to 18 carbon atoms, for example, lauric acid, palmitic acid, stearic acid and oleic acid.
DETAILED DESC IPTION OF THE INVENTION
Some of compounds useful for the purposes of the present invention have been described in the chemical literature as useful in the detergent field. Other of these compounds have also been described as suitable agents for enhancing the absorption of orally administered medicaments such as antibiotics and vitamin B12 as dis-closed in U.S.P. 3,160,565, Dec. 8, 1964. Some of these compounds are also useful as food and cosmetic additives.
In view of the known uses of these compounds, it is most surprising that they would be useful in inducing an immune rejection of tumors and thus act as non-toxic immunopotentiators with antitumor activity.
The compounds which are particularly useful for the purposes of the present invention are the various palmitate esters of maltose, and particularly the maltose tetrapalmitate, the palmitate esters of galactose, glucose, mannose, arabinose and cellobiose.
The compounds useful in the present invention may be prepared by any of the well-~nown methods for preparing acid esters such as by reacting the fatty acid, its chloride or anhydride with the selected mono- or di-saccharide in pyridine which acts as a solvent-catalyst.
Depending upon the manner of reacting the acids and the saccharide there may be obtained the mono, di, tri, tetra or hexaacid ester of the saccharide or mixture thereof and the desired ester may then be isolated from the mixture.
M DE OF AD~I[NISTRATION
Generally speaking the fatty acid esters of mono- or disaccharides useful for the purposes of the present invention are combined with the usual pharmaceuti-cal excipients for oral or subcutaneous administration.
It has been found that the useful fatty acid of mono- or disacsharides are particularly useful when administered in dosages of from 0.05 to 0.5 mg/kg at a frequency of 3 to 4 times a week.
IMMUNOLOGIC ACTION
The full mechanism of the action of the compo-sitions of the present invention is not fully understood.
It is believed that when a tumor starts to develop in a host there is a natural reaction which produces an immune-reaction against the tumor, but in most tumor-bearing host, this i~munereaction is very weak so that eventually the growth of the tumor continues.
It is believedthat the compositions of the present invention enhance the natural immunereaction thus potentiating the ability of the host to either prevent the growth of the tumor or at least to substantially retard its growth. One feasible postulation as to the mode of operation of the compositions of the present invention is that they appear to modify the normal vascularity of tumors by substantially blocking the supply of materials responsible for the development of the tumor thus inducing ~ZV399 a form of hemorrhagic nicrosis.
It would thus appear that the compositions of the present invention are particularly useful in arresting the growth of the tumor in the ezrly stages of its development, or in substantially preventing or retarding the development of tumor where 'che host has been subjected to cytoreductive therapy such surgery, chemotherapy or radiotherapy.
The compositions of the present invention have been found particularly effective against solid tumors, for example melanoma, prostatic carcinoma, lung cancer, mammary cancer, subcutaneous sarcoma and colon tumor.
The following examples are given to illustrate the invention.
Treatment_after surgery Hamsters and rats were injected with tumor cells under the skin. After 2-3 weeks palpable tumors de-veloped. These tumors were surgically excised. Half of the animals were treated with saline and the other half with 10 ~g of maltose tetrapalmitate 3 times weekly.
Animals were observed for tumor recurrence and tumor sizes were determined. The administration of the said compo-sition generally reduced recurrence and often retarded tumor size development. Results are reported in Table I.
llZV399 TABLE I
Tumor type Treatment % recurrence Average 2 tumor size tcm ) Mammary None 100 6.74 carcinoma MTP 75 3.65 Hamster None 35 1.78 sarcoma MTP o Treatment of animals after tumor innoculation Tumor injected: (1) Mammary adenocarcinoma,
BACKGROUND OF THE INVENTION
Surgical removal of certain operable cancers is a routine clinical procedure in the treatment of most non-lymphoreticular human cancers. Remissions induced by this procedure alone are, generally, of a limited duration and a majority of patients return with recurring cancers. The inability to prevent tumor recurrence in patients who have undergone surgery poses a major problem in the reduction of cancer mortality rates. The problem is more acute in developing countries where high cost and/or non-availa-bility of anti-cancer drugs permit surgery and radio-therapy as the only means of cancer treatment.
Considering that the effectiveness of surgery lies in adequate tumor removal and the subsequent develop-ment of host defenses (cell-mediated immunity against tumor cells) to arrest cancer development, tumor reappear-ance can be regarded as being due to insufficient surgeryor a weakness in the host to mount an effective immune response against its remaining cancer cells. If the latter proposition is true, it would appear that immuno-potentiating agents should reduce tumor recurrence after adequate surgical tumor excision in a larger number of cancer cases.
SUMMARY OF THE INVENTION
In accordance with the present invention it has now been found the administration of certain fatty acid esters of mono- or disaccharides will surprisingly elicit an antitumor response as shown in an enhancement of the host's capacity to reject a large number of tumor cells, ~lZ~
to retard growth in tumor size and to induce hemorrhagic necrosis. It has also been surprisingly found that these compounds are devoid of endotoxic activity.
More particularly, it has been found that the fatty acid esters of maltose, galactose, glucose, mannose, arabinose and cellobiose are particularly useful for the purposes of the present invention. As suitable fatty acids for preparing the desired fatty acid esters there may be mentioned those having 12 to 18 carbon atoms, for example, lauric acid, palmitic acid, stearic acid and oleic acid.
DETAILED DESC IPTION OF THE INVENTION
Some of compounds useful for the purposes of the present invention have been described in the chemical literature as useful in the detergent field. Other of these compounds have also been described as suitable agents for enhancing the absorption of orally administered medicaments such as antibiotics and vitamin B12 as dis-closed in U.S.P. 3,160,565, Dec. 8, 1964. Some of these compounds are also useful as food and cosmetic additives.
In view of the known uses of these compounds, it is most surprising that they would be useful in inducing an immune rejection of tumors and thus act as non-toxic immunopotentiators with antitumor activity.
The compounds which are particularly useful for the purposes of the present invention are the various palmitate esters of maltose, and particularly the maltose tetrapalmitate, the palmitate esters of galactose, glucose, mannose, arabinose and cellobiose.
The compounds useful in the present invention may be prepared by any of the well-~nown methods for preparing acid esters such as by reacting the fatty acid, its chloride or anhydride with the selected mono- or di-saccharide in pyridine which acts as a solvent-catalyst.
Depending upon the manner of reacting the acids and the saccharide there may be obtained the mono, di, tri, tetra or hexaacid ester of the saccharide or mixture thereof and the desired ester may then be isolated from the mixture.
M DE OF AD~I[NISTRATION
Generally speaking the fatty acid esters of mono- or disaccharides useful for the purposes of the present invention are combined with the usual pharmaceuti-cal excipients for oral or subcutaneous administration.
It has been found that the useful fatty acid of mono- or disacsharides are particularly useful when administered in dosages of from 0.05 to 0.5 mg/kg at a frequency of 3 to 4 times a week.
IMMUNOLOGIC ACTION
The full mechanism of the action of the compo-sitions of the present invention is not fully understood.
It is believed that when a tumor starts to develop in a host there is a natural reaction which produces an immune-reaction against the tumor, but in most tumor-bearing host, this i~munereaction is very weak so that eventually the growth of the tumor continues.
It is believedthat the compositions of the present invention enhance the natural immunereaction thus potentiating the ability of the host to either prevent the growth of the tumor or at least to substantially retard its growth. One feasible postulation as to the mode of operation of the compositions of the present invention is that they appear to modify the normal vascularity of tumors by substantially blocking the supply of materials responsible for the development of the tumor thus inducing ~ZV399 a form of hemorrhagic nicrosis.
It would thus appear that the compositions of the present invention are particularly useful in arresting the growth of the tumor in the ezrly stages of its development, or in substantially preventing or retarding the development of tumor where 'che host has been subjected to cytoreductive therapy such surgery, chemotherapy or radiotherapy.
The compositions of the present invention have been found particularly effective against solid tumors, for example melanoma, prostatic carcinoma, lung cancer, mammary cancer, subcutaneous sarcoma and colon tumor.
The following examples are given to illustrate the invention.
Treatment_after surgery Hamsters and rats were injected with tumor cells under the skin. After 2-3 weeks palpable tumors de-veloped. These tumors were surgically excised. Half of the animals were treated with saline and the other half with 10 ~g of maltose tetrapalmitate 3 times weekly.
Animals were observed for tumor recurrence and tumor sizes were determined. The administration of the said compo-sition generally reduced recurrence and often retarded tumor size development. Results are reported in Table I.
llZV399 TABLE I
Tumor type Treatment % recurrence Average 2 tumor size tcm ) Mammary None 100 6.74 carcinoma MTP 75 3.65 Hamster None 35 1.78 sarcoma MTP o Treatment of animals after tumor innoculation Tumor injected: (1) Mammary adenocarcinoma,
(2) Novikoff hepatoma, (3) Hamster sarcoma, (4) Mouse colon tumor, and (5) Melanoma.
When these tumor cells are injected at an appropriate dose into the appropriate animals, tumors develop and grow to large sizes and eventually kill the animals. However if, after tumor innoculation, the animals are administered with 10 ~g of tetrapalmitate
When these tumor cells are injected at an appropriate dose into the appropriate animals, tumors develop and grow to large sizes and eventually kill the animals. However if, after tumor innoculation, the animals are administered with 10 ~g of tetrapalmitate
3 times weekly, the % of animals bearing tumor is lower and the tumor size is smaller than the controls. Results are reported in Table II.
112~)399 TABLE_II
Tumor Type Treatment % of animals Average tumor with develop- size (cm ed tumor (1) Mammary None (control)100 3.2 carclnoma MTP 80 1.9 (2) Novikoff None (control)89 3.9 hepatoma MTP 58 1.8 (3) Hamster None (control)55 4.0 sarcoma MTP 11 2.6
112~)399 TABLE_II
Tumor Type Treatment % of animals Average tumor with develop- size (cm ed tumor (1) Mammary None (control)100 3.2 carclnoma MTP 80 1.9 (2) Novikoff None (control)89 3.9 hepatoma MTP 58 1.8 (3) Hamster None (control)55 4.0 sarcoma MTP 11 2.6
(4) Colon None (control)75 2.0 tumor MTP 8 l.S
(5) Melanoma None (control)100 2.9 MTP 80 1.8 Treatment of a large size tumor after chemotherapy Animals were innoculated with mammary carcinoma When the tumors had grown, the animals were treated with either of the three chemotherapeutic anticancer drugs at recommended doses which were bleomycin and vinblastine.
After three doses of these drugs, half of the animals were left untreated and the other half were treated with lO~g of maltose tetrapalmitate 3 times weekly. It was observed that animals treated with our composition had smaller size after 3 weeks than those left untreated when the chemotherapeutic drugs used were bleomycin and vinblastine. No differences were observed in case of animals treated with cytosine arabinoside and then either left untreated or treated with our composition.
Results are reported in Table III.
ll~V~9 TABLE III
Tumor type Treatment Tumor size 50% death centimeter square (days) Mammary untreated 17.72 28 carcinoma Mammary bleomycin 17.72 28 carcinoma Mammary bleomycin 12.25 30 carcinoma + MTP
Mammary vinblastine 25.0 28 carcinoma vinblastine 22 33 ~ MTP
l~Z~)3~9 A simple property for judging the effectiveness of a particular compound in this series (fatty acyI
esters of mono and disaccharides)for antitumor activity, is its ability to augment synthesis of DNA in lymphocytes as detected by an increase in the incorporation of radio-active thymidine into cellular DNA. Table IV shows results obtained with some of the compounds falling within the scope of the present invention.
TABLE IV
Addition to rat spleen Tritiated thymidine lymphocytes in culture incorporation Count pers. min.
None 295 Arabinose monopalmitate 1596 (2 ~g) Galactose monopalmitate 1976 (2 ~g) Maltose tetrapalmitate 1575 (2 ~g) Maltose hexapalmitate 2158 (2 ~g)
After three doses of these drugs, half of the animals were left untreated and the other half were treated with lO~g of maltose tetrapalmitate 3 times weekly. It was observed that animals treated with our composition had smaller size after 3 weeks than those left untreated when the chemotherapeutic drugs used were bleomycin and vinblastine. No differences were observed in case of animals treated with cytosine arabinoside and then either left untreated or treated with our composition.
Results are reported in Table III.
ll~V~9 TABLE III
Tumor type Treatment Tumor size 50% death centimeter square (days) Mammary untreated 17.72 28 carcinoma Mammary bleomycin 17.72 28 carcinoma Mammary bleomycin 12.25 30 carcinoma + MTP
Mammary vinblastine 25.0 28 carcinoma vinblastine 22 33 ~ MTP
l~Z~)3~9 A simple property for judging the effectiveness of a particular compound in this series (fatty acyI
esters of mono and disaccharides)for antitumor activity, is its ability to augment synthesis of DNA in lymphocytes as detected by an increase in the incorporation of radio-active thymidine into cellular DNA. Table IV shows results obtained with some of the compounds falling within the scope of the present invention.
TABLE IV
Addition to rat spleen Tritiated thymidine lymphocytes in culture incorporation Count pers. min.
None 295 Arabinose monopalmitate 1596 (2 ~g) Galactose monopalmitate 1976 (2 ~g) Maltose tetrapalmitate 1575 (2 ~g) Maltose hexapalmitate 2158 (2 ~g)
Claims (3)
1. A pharmaceutical composition effective for enhancing the capacity of a host to reject a large number of tumor cells, retarding growth in tumor size or in inducing hemorrhagic necrosis, which comprises a fatty acid ester of a mono or disaccharide, in admixture with a pharmaceutically acceptable carrier, the fatty acid having 12 to 18 carbon atoms and the mono or disaccharide being selected from maltose, galactose, glucose, mannose, arabinose and cellobiose.
2. The pharmaceutical composition of Claim 1, which comprises a dosage unit containing from 0.05 to 0.5 mg/kg of fatty acid ester of the mono or disaccharide.
3. The pharmaceutical composition of Claims 1 or 2, wherein the fatty acid ester of the disaccharide is maltose tetrapalmitate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000336631A CA1120399A (en) | 1979-09-28 | 1979-09-28 | Pharmaceutical compositions for treatment of tumor cells |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000336631A CA1120399A (en) | 1979-09-28 | 1979-09-28 | Pharmaceutical compositions for treatment of tumor cells |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120399A true CA1120399A (en) | 1982-03-23 |
Family
ID=4115240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000336631A Expired CA1120399A (en) | 1979-09-28 | 1979-09-28 | Pharmaceutical compositions for treatment of tumor cells |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1120399A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100382A1 (en) * | 1982-08-02 | 1984-02-15 | Unitika Ltd. | An intravenous nutrient |
| EP0249008A2 (en) * | 1986-05-09 | 1987-12-16 | Pulverer, Gerhard, Prof. Dr.Dr.h.c. | Use of specific monosaccharides for the preparation of a medicament for the prevention of metastases of malignic tumours |
| WO1996018632A1 (en) * | 1994-12-16 | 1996-06-20 | Universite De Sherbrooke | Methods for the preparation of pure homologous series of mono to tetra fatty acyl esters of sugars; characterization of one antitumor component as maltose 1, 6, 6' tripalmitate: and pharmaceutical formulations useful in the treatment of cancer. |
| WO2011110190A1 (en) * | 2010-03-08 | 2011-09-15 | Romina Znoj | A cellobiose compound from herbal extracts having apoptotic activity |
| EP2889035A4 (en) * | 2012-08-24 | 2016-07-13 | Kakui Co Ltd | Anti-tumor agent |
-
1979
- 1979-09-28 CA CA000336631A patent/CA1120399A/en not_active Expired
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100382A1 (en) * | 1982-08-02 | 1984-02-15 | Unitika Ltd. | An intravenous nutrient |
| EP0249008A2 (en) * | 1986-05-09 | 1987-12-16 | Pulverer, Gerhard, Prof. Dr.Dr.h.c. | Use of specific monosaccharides for the preparation of a medicament for the prevention of metastases of malignic tumours |
| EP0249008A3 (en) * | 1986-05-09 | 1989-09-27 | Gerhard Prof. Dr. Med. Pulverer | Agent and process for the prevention of metastases of malignic tumours |
| WO1996018632A1 (en) * | 1994-12-16 | 1996-06-20 | Universite De Sherbrooke | Methods for the preparation of pure homologous series of mono to tetra fatty acyl esters of sugars; characterization of one antitumor component as maltose 1, 6, 6' tripalmitate: and pharmaceutical formulations useful in the treatment of cancer. |
| US5625044A (en) * | 1994-12-16 | 1997-04-29 | Goudreau Gage Dubec & Martineau | Methods for the preparation of pure homologous series of mono to tetra fatty acyl esters of sugars and pharmaceutical formulations useful in the treatment of cancer |
| WO2011110190A1 (en) * | 2010-03-08 | 2011-09-15 | Romina Znoj | A cellobiose compound from herbal extracts having apoptotic activity |
| EP2889035A4 (en) * | 2012-08-24 | 2016-07-13 | Kakui Co Ltd | Anti-tumor agent |
| CN106361757A (en) * | 2012-08-24 | 2017-02-01 | 可克意株式会社 | Antitumor agent |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5225404A (en) | Methods of treating colon tumors with tumor-inhibiting camptothecin compounds | |
| CA2065285C (en) | Antimalarial compositions | |
| Moertel et al. | Mitomycin C therapy in advanced gastrointestinal cancer | |
| JP2824917B2 (en) | Antitumor agent | |
| CA1093971A (en) | Carcinostatic composition and method of treating a malignant condition | |
| RU95122792A (en) | PHARMACEUTICAL COMPOSITION WITH ANTI-TUMOR ACTIVITY AND METHOD FOR PRODUCING IT, AND ALSO METHOD FOR TREATING HUMAN CANCER CELLS | |
| CA1120399A (en) | Pharmaceutical compositions for treatment of tumor cells | |
| Marshall et al. | Treatment of hormone‐refractory stage D carcinoma of prostate with coumarin (1, 2‐benzopyrone) and cimetidine: A pilot study | |
| CA1038291A (en) | Methods and pharmaceutical preparations for the treatment of hypercholesterolaemia | |
| JPS6328045B2 (en) | ||
| DE3263832D1 (en) | Gallium chloride, an anti-cancer drug | |
| Pronzato et al. | Phase II study of lonidamine in metastatic breast cancer | |
| US3326761A (en) | 6-demethyl-6-deoxytetracycline, anti-tumor antibiotic | |
| Yron et al. | Effects of methanol extraction residue and therapeutic irradiation against established isografts and simulated local recurrence of mammary carcinomas | |
| Venditti et al. | Chemotherapy of advanced mouse leukemia L1210: comparison of methotrexate alone and in sequential therapy | |
| Ohkoshi et al. | Clinical experience with a protease inhibitor [N, N-dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)-phenylacetate] methanesulfate for prevention of recurrence of carcinoma of the mouth and in treatment of terminal carcinoma | |
| JPS57106618A (en) | Anticancer agent consisting of polyprenyl compound | |
| CN111558045A (en) | Medicine composition for treating lung cancer | |
| US4444791A (en) | Pharmaceutical composition and method for treating cachexia in humans due to cancer | |
| EP1392266A2 (en) | Cancer treatment method and compositions comprising compounds of the ginger family | |
| US4725625A (en) | Pharmaceutical composition and method for treating cachexia in humans due to cancer | |
| Damia et al. | Flavone acetic acid antitumour activity against a mouse pancreatic adenocarcinoma is mediated by natural killer cells | |
| US3988447A (en) | Pharmaceutical preparations | |
| Sawada et al. | Establishment of a new ovarian tumor line in nude mice and its application to treatment of the donor patient | |
| Ortonne et al. | Oral photochemotherapy in lichen planus (LP) and mycosis fungoides (MF): Ultrastructural modifications of the infiltrating cells |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |