JPH07501521A - 2-aminopropane 1,3-diol chemotherapeutic agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention involves contacting cells with a chemotherapeutic agent and treating tumors or cells with the following formula ( where R is C, -C2゜alkyl, alkenyl or alkynyl) in combination with a potentiating agent consisting of a compound containing and the amount of potentiating agent in an amount effective to inhibit the growth of the tumor or cell. Provided is a method for inhibiting the growth of a carcinoma disease or cell in a mammal comprising: do.

According to the invention, cells are treated with an effective amount of a potentiating agent consisting of a compound of formula I as defined above. effectiveness of a chemotherapeutic agent on cells exposed to the chemotherapeutic agent, consisting of exposing We also provide a method to increase

In another aspect of the invention, the chemotherapy is administered in an amount effective to inhibit tumor or cell growth. The chemotherapeutic agent is administered to the tumor or cells and the growth inhibition caused by the chemotherapeutic agent is administering a potentiating agent consisting of a compound of formula I as defined above in an amount effective to increase the amount of harmful Inhibition of cancerous disease or cell growth in mammals consisting of administration to tumors or cells. provide a way to harm

administering to a mammal bearing a tumor an amount of a chemotherapeutic agent effective to inhibit tumor growth; , and an amount effective to increase the amount of growth inhibition produced by the chemotherapeutic agent. comprising administering to the mammal an enhancer consisting of a compound of formula I as defined above. Also provided are methods of treating tumors in mammals.

Additionally, the present invention provides compounds of formula I (wherein R is c, C20 alkynyl).

In yet another aspect of the invention, the selected from adriamycin and cisplatin. in combination with an effective amount of a potentiating agent consisting of a compound of formula ■ as defined above. A medicament suitable for inhibiting cancerous disease or cell growth in mammals, characterized by causing provide the system. The pharmaceutical system of the present invention (in some embodiments, chemical Packaging the therapeutic agent together with but separately from the enhancer and administering the enhancer Used to administer chemotherapeutic agents prior to administration.

The present invention also provides a pharmaceutical system for inhibiting carcinoma disease or cell growth in a mammal. A chemotherapeutic agent selected from adriamycin and cisplatin and and an enhancer consisting of a compound of formula I as defined above. chemistry Packaging the therapeutic agent together with but separately from the enhancer and administering the enhancer It can be used to administer chemotherapeutic agents prior to administration.

The invention further provides adriamycin or is used in the manufacture of a drug to enhance the chemotherapeutic effect of cisplatin. The use of compounds of formula I as defined is provided.

The invention is particularly described in the appended claims and in its preferred embodiments. The details are listed below.

Brief description of the drawing Figure 1 shows that threo-2-amino-1,3-octylamine following treatment with adriamycin It is a graph showing the effect of tadecanediol hydrochloride on tumors.

Figure 2 shows threo-2-amino-1,3-octade following treatment with subbratin. It is a graph showing the effect of candiol hydrochloride on tumors.

Detailed description of the invention According to the invention, contacting the tumor or cells with a chemotherapeutic agent; Cells with the following formula: (wherein R is C5Ct. alkyl, alkenyl or alkynyl) mammals by combining contact with an enhancer consisting of a compound that Carcinoma disease or cell growth is inhibited. More preferably, R is Cl0-C2 0 alkyl or alkenyl. Most preferably R is C+4 cps alkyl It is le. As used herein, alkyl, alkenyl and alkynyl Substituents include straight chain, branched chain and cyclic molecules, preferably straight chain species.

Chemotherapeutic agents and potentiating agents are used to determine whether the combination of the amount of chemotherapeutic agent and the amount of potentiating agent or contacting the tumor or cell in an amount effective to inhibit the growth of the cell.

The amount of drug effective in inhibiting the growth of carcinoma cancerous disease and/or cancerous cells in mammals is defined as Decrease cancerous disease or cell growth rate when combining a chemotherapeutic agent with an enhancer , preventing further growth of cancerous disease or cells, already existing cancerous disease or cancerous an amount that reduces the size of a cell or eliminates cancerous disease or cells altogether means.

In the present invention, inhibition of growth is defined as tumorigenic or undesirable growth, i.e. In other words, it inhibits the growth of normal cells. Growth inhibition is associated with tumors and /or decrease in the growth rate of cancerous cells, further growth of tumors and/or cancerous cells inhibition, reduction in the size of pre-existing tumor and/or cancerous cells; Characterized by the removal of all tumor and/or cancerous cells. growth inhibition is It also includes inhibition of cell growth and division, ie, cell proliferation.

Growth inhibition is generally detected by comparing tumor size before and after treatment. I can get it out. Healthy and tumorigenic mammals before and after treatment and/or Comparing cells will also indicate the degree of inhibition of cell growth. Growth stunting 1 year old Cell cultures are tested before and after treatment to detect the extent of cell proliferation and cell death. It can also be detected by Detects inhibition of cell growth known to those skilled in the art Other methods of doing so are also encompassed by the present invention.

Chemotherapeutic agents and potentiating agents are administered to tumors or cells in combination with each other. chemistry Administration of therapeutic agents and potentiating agents in combination with each other refers to the treatment of cancer cells or tumors. treatment, before or after administration of the enhancer, or substantially simultaneously with the administration of the enhancer. In addition, the chemotherapeutic agent is administered to a mammal, typically a human patient. identification The method of administration depends on the age, health and weight of the patient, the nature and severity of symptoms, and the current The power may vary depending on the type of treatment being used, the frequency of treatment, and the desired effect. Wear. Generally, the chemotherapeutic agent and potentiating agent are administered sequentially in one administration or application. or administered simultaneously. For example, prior to or following administration of a potentiator, a chemical A therapeutic agent can be administered. It is also possible to combine chemotherapeutic agents and potentiators in a single application. They can also be administered substantially simultaneously, or for separate applications in which each other is administered within a short period of time. . In a preferred embodiment of the invention, the potentiating agent is about 90 to about 90 minutes after administration of the chemotherapeutic agent. Administer 15 minutes before administration. In a more preferred embodiment, the potentiating agent is a chemotherapeutic agent. Administer about 20 to about 70 minutes before administration. Most preferably, the enhancer is a chemotherapeutic agent. Administer about 25 to about 35 minutes before administration.

In studies using murine tumor models, approximately 9 o - approximately 15 minutes prior to administration of chemotherapeutic agents. Tumor and/or cell growth caused by chemotherapeutic agents administering potentiating agents The results suggested that long-term inhibition was significantly increased. Optimal number of doses of potentiators and chemotherapeutic agents and the order will vary depending on the cell type or mammalian species being treated. desirable the order and timing of administration of the potentiating agent and the chemotherapeutic agent at various times and orders; Compare the results obtained by selecting combinations that produce the desired effect. determined by

Another aspect of the invention is to treat cells or tumors with compounds of formula 1, where R is C, -C2° (alkyl, alkenyl, or alkynyl). The presence of chemotherapeutic agents on cells or tumors exposed to chemotherapeutic agents, including Proposes ways to increase or "potentiating" efficacy. provide More preferably R is CIOC20 alkyl or alkenyl.

Most preferably R is CI4cps alkyl. The enhancement used here is refers to the ability to cause or increase the effectiveness of chemotherapeutic agents. However, Therefore, the potentiating agent of the present invention that potentiates a chemotherapeutic agent is suitable for cancer or cancer-specific uncontrollable cancers. making such therapeutic agents effective or more effective in treating bacterial cell growth.

Chemotherapeutic agents act in many ways in the treatment of cancer or tumorigenicity.

For example, chemotherapeutic agents target intermediary metabolism or DNA function. hatondo chemistry The ultimate goal of therapeutic agents is to kill tumor cells or reduce the proliferation of cancerous cells. Is Rukoto. Therefore, the mechanism by which eradication of cancerous cells and/or tumors is achieved is Chemotherapy agents kill the growth of cancerous cells, regardless of their origin, or If the ability to decrease is increased, the effectiveness of the chemotherapeutic agent is enhanced. Presence of therapeutic agent Methods to assess efficacy are known to those skilled in the art. For example, as mentioned above, Normal and cancerous cells and/or tumors at various times after treatment of cells or tumors. by comparing tumor growth or before and after administration of chemotherapeutic and potentiating agents. Efficacy can be assessed by comparing cell and/or tumor growth in Wear. To effectively measure the increase in the amount of growth inhibition due to the contribution of enhancers, chemotherapy Inhibition of cell and/or tumor growth by agents alone and in the presence of potentiating agents of the invention By comparing the inhibition of cell and/or tumor growth of chemotherapeutic agents in This can be done.

Another aspect of the invention provides for administering to a cell a chemotherapeutic agent in an amount effective to inhibit the growth of the cell. and to increase the amount of growth inhibition produced by chemotherapeutic agents. amount of the compound of formula treatment of mammalian tumor cells by administering to the cells an enhancer consisting of Provided are methods for inhibiting cell growth. More preferably, R is C7°-CZO alkyl Kyl or alkenyl. Most preferably R is CI4Cl11 alkyl It is.

Additionally, the present invention provides for administering to a tumor a chemotherapeutic agent in an amount effective to inhibit tumor growth. administered to mammals and increases the amount of growth inhibition produced by chemotherapeutic agents. administering to a mammal an enhancer consisting of a compound of formula I as defined above in an amount effective to Also provided is a method of treating a tumor in a mammal, the method comprising administering.

Finally, the present invention provides compounds of formula I, in which R is C5C20 alkynyl, or Compositions for enhancing chemotherapeutic agents are provided.

Surprisingly, the methods and compositions of the invention are effective in potentiating chemotherapeutic agents. Something was discovered. The potentiating agents described herein inhibit tumor inhibition when administered alone. Administering the enhancer according to the method of the invention, although it has only a marginal effect on harm. Significant tumor inhibition is then observed. With a chemotherapeutic agent according to the method of the invention When administered in combination, the chemotherapeutic agent or the potentiating agent alone The resulting inhibition of tumor growth resulted in a synergistic inhibition of tumor growth. Main departure Results of synergistic effects of potentiators administered in combination with chemotherapy according to the method of As a result, lower doses of chemotherapy can be used in the treatment of cancer and neoplastic conditions. Agents can be used. Alternatively, traditional doses can be combined with potentiators for shorter The administration may be for a period of time. Therefore, using lower doses of chemotherapeutic agents This may lead to complications associated with tumor treatment, such as myocardial toxicity, myelosuppression, nephrotoxicity, and thrombosis. Many harmful side effects can be avoided. Commitment to any theory or mode of action However, the enhancement of the present invention in increasing the effectiveness of chemotherapeutic agents Applicant believes that the efficacy of the compound is due to its protein kinase C inhibitory activity. I'm guessing. Some of the enhancers that can be used in the method of the invention are protein kinases. ZeC inhibitory activity is described in U.S. Pat. No. 4, issued March 28, 1989. 816.　 It is described in No. 450.

Tumors are characterized by uncontrolled cell proliferation or tumorigenicity. mammalian tumor cells Cell growth inhibition is directed toward inhibiting uncontrolled cell proliferation associated with cancer and tumorigenesis. I'm pissed. Protein kinase C is directly involved in cell growth control; Therefore, it is believed to be involved in tumor formation. Protein kinase C is usually treated with Although activated by ruglycerols (DAC), protein kinase C is Also, as not a single phorbol ester, which is a very potent tumor promoter is also a major intracellular receptor. Phorbol myristate acetate (PM A) Phorbol esters such as It has complex effects on cells, including effects on offspring expression. Phorbol esters and Other tumor-promoting agents bind and activate protein kinase C.

Furthermore, studies on cells transformed with the oncogene ras have shown that the protein kinase We showed that activation of ZeC is accompanied by an increase in DAC. Therefore, Proteinkina -ase C leads to an intracellular increase in DAC, accompanied by an increase in protein kinase C. It may mediate the actions of certain oncogenes such as ras.

In some types of tumors, such as breast and lung carcinomas, protein kinase C is There are several studies showing increased expression. Increased expression at gene level However, activated protein kinase C was detected in human colon carcinoma. It's being served.

As used herein, chemotherapeutic agents refer to mammalian tumor cells and/or mammalian tumor cells. Compounds that can inhibit the growth of mammalian tumors, cancers or other precancerous conditions. Refers to useful treatment. Cisplatin (soonamine dichloroplatinum, cisplatin) (also known as latina), adriamycin, mechlorethamine, cyclophosph amido, chlorampcil, BCNU, 5-fluorouracil, cytoan arabino nd, 6-thioguanine, vp-16, vinca alkaloid, mydomycin C, Pleomycin, actinomycin D1 midoxantrone and mAMSA are 1 is an example of a chemotherapeutic agent that can be used in the method of the invention. The above chemotherapeutic agents are known , available from pharmaceutical suppliers. Preferred chemotherapeutic agents are adriamycin and Contains cisplatin and cisplatin. Generally, such drugs are free of the potentiating agent of the present invention. It also has some cancer-inhibiting effects.

The full picture of the oncological disease is not yet fully understood, and the treatment method of the present invention While therapeutic agents are useful for many of these diseases, the methods of the present invention are useful for treatment with chemotherapeutic agents. It is useful in the treatment of diseases to which it is known to be susceptible or treatable. example For example, adriamycin is used to treat acute lymphoblastic leukemia, acute myeloblastic leukemia, and Wilms tumor, neuroblastoma, parenchyma and osteosarcoma, breast carcinoma and ovary It has been used to bring about the control of infectious neoplastic conditions such as carcinoma. cisplati The drug is used to treat metastatic ovarian tumors and metastatic ovarian tumors. In addition, the sysp Latin is used to treat advanced bladder cancer. The above example is not limited to this. and limit the types of tumors or conditions that can be effectively treated by the methods of the invention. isn't it.

Pharmaceutically acceptable salts of the enhancers of the invention can also be used in the invention. like this Pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, fumaric acid, phosphoric acid, maleic acid, Contains salts of succinic acid, pamoic acid, sulfuric acid and phosphoric acid .

Cells to be exposed to chemotherapeutic or potentiating agents are contacted with such agents. Main departure The chemotherapeutic agents and potentiators used in the method of It may be administered by any method that brings the substance into contact with the site of action within the body; This includes, but is not limited to, oral, intravenous and intraperitoneal administration. present invention The potentiator may be used alone or in combination with other potentiators or other treatments such as radiation therapy. Can be administered together. Preferably the enhancer is compatible with the route of administration and standard pharmaceutical It is conventionally administered with a pharmaceutically acceptable carrier or diluent.

Chemotherapeutic agents useful in the methods of the invention follow established protocols known to those skilled in the art. Administered in formulation and dose. For example, Adriamy is used to treat metastatic ovarian tumors. Cisplatin 50 mg/m2 administered intravenously once every 3 weeks 50 mg/m2 is administered intravenously once every 3 weeks. Cisplatin once every 4 weeks It can also be administered intravenously at a dose of 00 mg/m2. Adriamycin is 21 It can be administered intravenously at a dose of 60-75 mg/m2 at daily intervals. one throw Administration: intravenous infusion in free-flowing sodium chloride or 5% dextrose It is to be. Cyclophosphamide 40-50mg/kg divided over 2-5 days Can be administered intravenously in divided doses, or 10-15 mg/kg to 7-10 It can be administered intravenously in two doses.

A therapeutically effective amount or concentration effective to increase the efficacy or therapeutic action of a chemotherapeutic agent. The enhancer is administered to the mammal at a specific time. The dose given in a particular case is a specific enhancer. factors such as the pharmacokinetic properties of the drug, as well as the form and route of administration, the patient's age, health and Severe; nature and severity of symptoms; dependent on concomitant treatments, frequency of treatment, and desired effect do. The dosage of the enhancer is about 5 to about 400 mg/kg body weight, preferably about 5 to about 400 mg/kg body weight. About 10 to about 200 mg/kg is administered in combination with chemotherapeutic agents.

Enhancers useful in the methods of the invention are given to Bell et al., March 28, 1989. No. 4,816,450, see the entire teachings thereof. It is included here as . Enhancers may be natural or synthetic. especially , alkyl and alkenyl substituents are described in U.S. Patent No. 4. No. 816.450, in which the methods or starting materials disclosed therein are not obvious. It can be manufactured by changing it to something suitable. Augmentation of formula ■ with alkynyl substituents The agent may be prepared by methods known in the art or as disclosed in U.S. Pat. No. 4,816,450. Alternatively, it can be produced by changing the starting materials to obvious and suitable ones. present invention Enhancers are also commercially available; for example, threo-2-amino-1,3-octa Decanediol hydrochloride was manufactured by Sigma Chemical Company, Sen. Available from Truis, Missouri. Enhancers can also be N-phenylsulfonyl protected N-protected serine, such as serine, is reacted with an appropriate saturated or unsaturated Grignard reagent. It can be easily synthesized by reacting. For example, a suitable bromo- or chloro- Reacting substituted alkyl, alkenyl or alkynyl compounds with magnesium to form a Grignard reagent, which is then reacted with N-protected serine to form N -Produce a protected 2-amino-1,3-propanediol derivative. Then N-ho The protecting group is removed from the enhancer.

Whether the enhancer will be formulated as a medicine and will be in solid preparations such as capsules, tablets, and powders. or administered orally as liquid formulations such as elixirs, tablets and suspensions. can be done. It can also be administered intraperitoneally as a sterile liquid preparation. Enhancers are medical The dosage forms can be formulated by standard methods in the art of pharmaceutical compounding. this Remington's Pharmaceut is a standard document in the field. ical 5sciences, A, 0sol, Mack Publishing Company, Easton, Pennylvania.

For example, enhancers include lactose, sucrose, mannitol, starch, and cellulose inducers. conductors, mixed with powder carriers such as magnesium stearate and stearic acid Insert into gelatin capsules or form into tablets. tablets and capsules Both can be manufactured as sustained release agents that continuously release the drug for a certain period of time.

Compressed tablets can be sugar-coated or film-coated to eliminate unpleasant tastes. shielding to protect the tablet from the atmosphere or as an enteric coating for selective partitioning in the gastrointestinal tract. It can be made to be understood.

Liquid dosage formulations for oral administration include pharmaceutically acceptable agents such as water, buffered agents, or saline. In addition to diluents, colorants and flavoring agents may be included to make them easier for patients to accept. You can stay there.

For intraperitoneal administration, enhancers can be added to water, oil, saline, dextrose (glucosuria), aqueous solutions, and related aqueous sugar solutions, as well as propylene glycol and polyester Mixed with a suitable carrier or diluent such as glycols such as tyrene glycol good. Preferably, the solution for intraperitoneal administration includes a water-soluble salt of the potentiating agent. stabilizer, Antioxidants and preservatives may also be added. A suitable antioxidant is sodium bisulfite , sodium sulfite, and ascorbic acid, citric acid and its salts, and Contains sodium EDTA.

For the pharmaceutical system of the present invention, chemotherapeutic agents may be used together with, but separately from, potentiating agents. Can be packaged separately. For example, co-administration of chemotherapeutic agents and potentiating agents When desirable, the chemotherapeutic agent and potentiator can be packaged in the same container. can. When it is desirable to administer chemotherapeutic agents and potentiating agents at different times, These are packaged together, but in separate containers. chemotherapeutic agent Do not administer chemotherapeutic agents and potentiators together, even if they are administered by different routes. However, it is preferable to package them in separate containers. The pharmaceutical system according to the present invention May also be supplied with instructions for administration of chemotherapeutic agents and potentiators. The examples below are intended to illustrate the invention and are not to be construed as limiting the scope of the invention. must not.

Example 1 - Delaying tumor regrowth - Adriamycin and threo-2-amino-1 ,3-octadecaneol hydrochloride This assay was developed by Corbett et al. Ancer Te5t Rep, 621471, 1978) This was carried out using a 16C mouse mammary carcinoma transplanted into a C3H mouse. briefly describe Then, cells were prepared from a 16C tumor that had been removed from a C3H mouse, and the tumor was The tumor was transplanted. 2 x 105 cells in 0.002 ml of phosphate buffered saline (PBS) The cells were injected intramuscularly into the hind legs to form experimental tumors and treated with chemotherapeutic agents and/or augmentation. It was monitored to determine the effectiveness of the strong drug.

To determine the size of the tumor, a plastic ring with various angles is passed through the hind leg where the tumor is located. Measurements are taken 3-5 times per week. The smallest ring that the tumored hind leg can pass through. The tumor weight is then converted to tumor weight using a calibration curve prepared in advance. of size Tumors with small variations were selected at the beginning of the experiment and divided into various treatment groups. after treatment Measurements were taken to determine the number of days the tumor reached 4-5 times its starting size as a function of treatment. Record.

Mice with experimental tumors were divided into groups of 5 mice in each group and subjected to the following treatments ( 1) Control (vehicle, i.p. (i, p, ); (2) Adriamycin only ( 10mg/kg, i, I), ); (3) Adriamycin (10mg/kg, 3 hours before administration of threo-2-amino-1,3-octadecanedio Hydrochloride (Sigma Chemical Company, St. Louis, MI) Zuri, 40mg/kg, i, p, ); (4) Adriamycin (10mg/ kg, i, p,) threo-2-amino-1,3-octadecane 1 hour before administration. Diol Hydrochloride (Sigma Chemical Company, St. Louis) (5) Adriamycin (10 30 minutes before administration of mg/kg, i, p, Tadecanediol hydrochloride (Sigma Chemical Company, Ent Lewis.

Missouri, 40 mg/kg, i, p,). threo-2-amino-1,3-octa The results of adriamycin administration in combination with decanediol hydrochloride are shown in Figure 1 . Control results are shown as open circles. Black triangles are the results of the group treated with adriamycin alone. shows. Threo-2-amino-1,3-oct 3 hours before adriamycin administration The results of the group treated with tadecanediol hydrochloride are shown in black squares. The black circle is Adriama Threo-2-amino-1,3-octadecanediol salt 1 hour before isin administration The results of the group treated with acid salts are shown. White triangles are taken 30 minutes before administration of Adriamycin. The results of the group treated with rheo-2-amino-1,3-octadecanediol hydrochloride show. Previous research has shown that threo-2-amino-1,3-octadecane Treatment with diol hydrochloride alone had no effect on tumor growth, and control (open circles) ) was found to give the same result. By day 4, control mice had tumors of 1 ．． It grew to a weight of 0 g (based on externally measured tumor size). adria Tumors treated with mycin alone showed an initial decrease in tumor growth rate, but by day 14 the tumor growth rate decreased. The tumor grew larger than 0.8 g. Threo-3 hours before adriamycin treatment Tumors treated with 2-amino-1,3-octadecanediol hydrochloride substantially The tumor size decreased to below the palpable limit (0.1 g) by the 6th day. decreased. Threo-2-amino-1,3- 1 hour before adriamycin treatment Tumors treated with octadecanediol hydrochloride showed little or no growth. By the fourth day, the size of the tumor was below the limit of palpation. of adriamycin Treatment with threo-2-amino-1,3-octadecanediol hydrochloride 30 minutes before treatment. Treated tumors show little or no growth, and by day 5 the tumor size has decreased. It decreased to below the limit of palpation. Threo-2-amino-1,3-octadecanedio Tumor weight decreased by day 6 and thereafter in all mice treated with alcohol hydrochloride. It was less than 0.1 g (palpable limit).

Threo-2-amino-1,3-octadecanediol hydrochloride/Adriamycin Table 1 shows the survival rate on day 14 of mice treated with .

Table 1 Group number of survivors\overall mortality rate (1) Control 5\50 (2) Adriamycin alone 5\50 (3) 3-hour pretreatment 0\5100 (4) 1 hour pre-treatment 3\5 40 (5) 30 minutes pre-treatment 5\50 100% survival was observed in control mice as well as with Adriamycin alone or with Adria. threo-2-amino-1,3-octadecanediol 30 minutes before administration of mycin. seen in mice treated with hydrochloride. By day 14 of adriamycin administration. 40% of mice treated 1 hour before and 3 hours before adriamycin administration. 100% of treated mice died. Threo-2-amino-1 by day 16 , all remaining mice treated with 3-octadecanediol hydrochloride were moribund. died.

Example 2: Delaying tumor regrowth - cisplatin and threo-2-amino-1,3 -Octadecanediol hydrochloride 7 subratin (5 mg/kg or 10 mg/kg) instead of adriamycin , i, I), ), and the enhancer threo-2-amino-1,3-octade Example 1 except that the dose of candiol hydrochloride was 20 tng/kg, i, p. Tumor regrowth delay assay was performed by the method of . Cisplatin (Cisplatin) (also known as num, shown in Figure 2) Figure 2 shows that cisplatin is followed by threo-2-amino-1,3-octadecanedio Figure 2 is a graph showing the effect of alcohol on tumors treated with alcohol hydrochloride. Excipient control is black Indicated by a circle. Administration results of threo-2-amino-1,3-octadecanediol hydrochloride Fruits are indicated by white circles. The results of single administration of cisplatin (5 mg/kg) are shown in white angle of view. . Cisplatin (5 mg/kg) and threo-2-amino-1,3-octade The results of administration of candiol hydrochloride (20 mg/kg) are shown in black. The white ball corner is Data are shown from a group of mice treated with Suplatin (10 mg/kg) alone.

Black triangles indicate cisplatin (10 mg/kg) and threo-2-amino-1,3- Data from a group of mice treated with octadecanediol hydrochloride (20 mg/kg) Indicates the data.

As is clear from Figure 2, the control tumor decreased in size to a weight of approximately 1.5 g after 5 days. It increased. Threo-2-amino-1,3-octadecanediol hydrochloride 20mg Mice treated with 1/kg alone showed similar results. Cisplatin 5mg/kg Threo-2-amino-1,3-octadecanediol hydrochloride 2 30 minutes before administration Mice treated with 0 mg/kg showed virtually no difference between administration of cisplatin 10 mg/kg alone and inhibited tumor growth to the same extent. The tumor size remained stable until day 5; It started to increase after that. More dramatically, cisplatin lQmg/kg administration 30 minutes ago threo-2-amino-1,3-octadecanediol hydrochloride 20 mg Tumors in mice treated with 1.0 kg/kg showed little or no tumor growth; The size decreased to below the limit of palpation by the fourth day. The tumor is palpated until the 15th day. It remained below the limit, after which the tumor size began to increase.

Therefore, threo-2-amino-1,3-octadecanediol hydrochloride has 1 6C enhances the anticancer effect of cisplatin in mouse breast carcinoma model.

reptile book (5) Iso drive ((5) Greeting drive

Claims (13)

[Claims] 1. an effective amount of a chemotherapeutic agent selected from adriamycin and cisplatin; The following expression for: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is C5-C20 alkyl, alkenyl or alkynyl) A mammalian carcinoma characterized in that it is combined with an enhancer consisting of a compound having Pharmaceutical systems suitable for tumor or cell growth inhibition. 2. Packaging the chemotherapeutic agent together with but separately from the potentiator Claims characterized in that the claim is suitable for administering a chemotherapeutic agent prior to administration of a chemotherapeutic agent. The system described in paragraph 1. 3. Claim 1 or R is Cl0-C20 alkyl or alkenyl The system described in Section 2. 4. According to any one of claims 1 to 3, R is C14-C18 alkyl. The system described. 5. The enhancer is threo-2-amino-1,3-octadecanediol hydrochloride The system according to any one of claims 1 to 4. 6. In the manufacture of pharmaceutical systems for inhibiting the growth of mammalian cancer tumors or cells, a chemotherapeutic agent selected from doriamycin and cisplatin, and an effective amount of The formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is C5-C20 alkyl, alkenyl or alkynyl) The use of potentiators consisting of compounds that 7. Packaging the chemotherapeutic agent together with but separately from the potentiator Claims characterized in that the claim is suitable for administering a chemotherapeutic agent prior to administration of a chemotherapeutic agent. Uses as described in Section 6. 8. Adriamycin or Cisplatin in the Treatment of Mammalian Cancer or Tumors In the production of medicines to enhance the effect of chemotherapeutic drugs, the following formula: ▲ Formula, There are chemical formulas, tables, etc.▼ (wherein R is C5-C20 alkyl, alkenyl or alkynyl) Use of compounds that 9. Claims 6 and 7, wherein R is Cl0-C20 alkyl or alkenyl. or the use described in Section 8. 10. Any one of claims 6 to 9, wherein R is Cl4-C18 alkyl Uses as described in. 11. The enhancer is threo-2-amino-1,3-octadecanediol hydrochloride. Use according to any one of claims 6 to 10. 12. Method of inhibiting the growth of mammalian cancer tumors or cells in vitro And, Adriamycin and Cis in an amount effective to inhibit the growth limit of the tumor or cell. administering to the tumor or cells a chemotherapeutic agent selected from platin; and An amount effective to induce the enhancement of growth inhibition produced by the therapeutic agent of the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is C5-C20 alkyl, alkenyl or alkynyl) the above method comprising administering to the tumor or cell an potentiating agent comprising a compound that . 13. Claims that expose cells or tumors to an enhancing agent prior to exposing the cells to a chemotherapeutic agent The method described in item 12.