WO2000001392A1 - 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (et180ch3) for the treatment of human carcinoma of the breast - Google Patents

Abstract

The invention relates to 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET180CH3) for the treatment of human carcinomas of the breast and to the preparation of a medicament for the treatment of human carcinomas of the breast. The active ingredient used is ET180CH3, which has been transferred into a form suitable for oral administration in a liquid excipient.

Description

1-Octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET180CH3) for the treatment of human breast cancer

description

The invention relates to ET1 8OCH3 (1-octadecyl-2-methyl-sn-glycero-3-phosphocholine, also known as edelfosin, INN) for the treatment of human breast cancer.

The annual incidence of new cancer is now around 10 million worldwide. According to the World Health Report 1 997, an increase in cancer can be expected, with breast and lung cancer in particular showing a worrying trend. In the European Union, 58,000 women already die from breast cancer each year, while 25,000 new cases are added. Breast cancer is the most commonly diagnosed cancer in the United States. In the past decades there has been a fairly steady and strong increase in the incidence of breast cancer, which remains constant, while in other indications (lungs, intestines, prostate) there are already signs of decline. The risk of breast cancer today is one in eight women. Although the mortality rates in younger women are falling, they are also increasing in the age group of over 55 years of age, so that the overall mortality rate for breast cancer is unchanged worldwide (Bailar 1 997).

The treatment of breast cancer is a serious and still unsolved problem in an aging population and especially in countries where the population has unhindered access to medicines and clinics. The therapeutic approaches for breast cancer include surgery, radiation and systemic drug treatment (chemotherapy), which is the preferred treatment for this type of cancer in order to eliminate the risk of recurrence and metastasis as far as possible. In breast cancer, occult metastases are already present in every second case when the diagnosis is made. Even in relatively favorable cases, postoperative radiation is often not sufficient and systemic therapy must follow, because depending on the location of the irradiated area and the amount of the radiation dose used, there is an increased risk of developing carcinoma of the esophagus years later (Ahsan 1 998 ). Approximately 1/3 of all deaths from breast cancer are due to recurrences and metastases that occur 5 years after the initial diagnosis. Cancer cells can last for years in a so-called "dormanf state. The reason for this is presumably that the neovascularization (= new formation of vessels), which is important for tumor growth, is impeded by an inhibitory factor , the occult cancer cells grow into relapses and / or metastases (Fidler 1 997), which are generally no longer accessible for healing, which is why therapy regimens that are geared towards long-term to long-term medication are inevitable to minimize the risk of relapse or, ideally, to eliminate it entirely.

Chemotherapy, which has an undisputed place in the treatment of breast cancer, has the major disadvantage that it can only be used for a limited time. The undesirable drug effects (UAW) caused by the effective therapeutic regimens are known and feared (Petru et al. 1 987). The newest group of cytostatics, the so-called taxanes, have particularly severe ADRs, which even include the exitus letalis as drug-induced (specialist information from Taxol and Taxotere). But even adjuvant chemotherapy, which can be used for a limited time, cannot effectively prevent metastatic involvement of the lungs, liver, pleura or bone compared to placebo therapy for breast cancer with lymph node involvement (Goldhirsch et al. 1 994).

Breast cancer is recognized to be a hormone-dependent tumor. Therefore, hormone preparations in particular are used in the treatment, with the aim of influencing tumor growth by administering or withdrawing hormones. In general, hormone treatments have less severe ADR than the classic cytostatics, so that long-term use of hormone preparations is even possible. But hormone treatment also has serious disadvantages. On the one hand, the application is limited to tumors with a positive hormone receptor status, and resistance formation often occurs during therapy due to a change in the hormone receptor status. On the other hand, hormone preparations also have UAW. A well-known example is tamoxifen, of which no less than 40 side effects are known (Bulbrook 1 996). In addition, many hormone preparations themselves have a carcinogenic effect. The most commonly used tamoxifen blocks e.g. the estrogen receptors on the breast, but has estrogen-like effects in other organs. Women treated in this way are more likely to develop endometrial cancer, but also gastrointestinal tumors and thromboembolism. If hormones are administered as part of a normal, i.e. non-therapeutic, substitution over a period of 10 years, the risk of developing breast cancer increases by 30% (Bulbrook 1 996). Regardless of the purpose of the cancer treatment, it should not be overlooked the fact that the increased intake of hormones can also cause other side effects, such as infertility in humans and animals.

Even psychological stress due to the diagnosis and fear of the side effects of chemotherapy promotes tumor growth and -distribution. A study by Ohio State University in Columbus found that the stress of the upcoming treatment was reflected in an up to 20% reduction in the activity of the immune cells in the blood. For this reason, the side effects of therapy are of considerable importance.

It is therefore an object of the present invention to provide a medicament for the treatment of breast cancer which has the following advantages.

1 . Effect regardless of a specific receptor status

2. Selective effect only on cancer cells

3. Lack of organ toxicity

4. Long-term use possible without problems. 5. Antimetastatic and anti-angiogenic effect

6. Pharmacodynamic effects

7. Therapeutic effectiveness

8. Missing or at least acceptable adverse drug reactions (UAW)

This object is achieved according to the invention by using ET1 8OCH3 as an active ingredient for a medicament for the treatment of breast cancer.

ET1 8OCH3 is a phospholipid analogue and because of its similarity to the phospholipids of the cell membranes has a high affinity for the membranes themselves. The uptake in the cells is therefore independent of the receptor (Snyder 1 991). In contrast to hormone preparations, the receptor status is irrelevant. Another great advantage of ET1 8OCH3 compared to other substances used for systemic chemotherapy is that the molecule only acts selectively on tumor cells and not on normal, healthy body cells or organs (Hickmann 1,992). In healthy, non-tumorous cells, ET1 80CH3 is broken down (Magistrelli et al. 1 994). A compelling and logical consequence of this selectivity is that ET180CH3 is neither mutagenic (King et al. 1 981) nor carcinogenic (Berdel et al. 1 983) or teratogenic / embryotoxic or chromosomalic (Bauchinger et al. 1 983). The UAW caused by ET1 80CH3 are very different in severity, degree and duration from those of the known therapies used in breast cancer (see specialist information on Taxol / Taxotere; Petru et al. 1 987; Table 2). No organ toxicity occurs even under long-term therapy with ET1 80CH3.

As already explained above, in the case of tumors that tend to relapse and form metastases, the continuous administration of a drug is an indispensable prerequisite. In order for malignant cells to become metastases, they must survive a multitude of potentially fatal interactions with healthy tissue. As a result, the growth behavior and degree of resistance of the primary tumor are changed so that the multiple, exponentially proliferating tumor cell populations become less and less accessible to effective therapy. This can be delayed or even prevented by constant drug treatment. The toxicity of the medicines available today allows their use only for a limited time. However, tumor cells have lost the information for genetically programmed cell death (apoptosis) and are therefore de facto immortal. A drug that is given over a longer period of time should therefore also induce re-induction of apoptosis in the tumor cells. This is made possible by using ET1 80CH3. Mollinedo et al. , 1 993, have shown that ET1 80CH3 causes re-induction of apoptosis in treated cells. Tumor cells become mortal cells again. The drug can be administered over a practically unlimited period of time, so that the tumor cells are permanently influenced in their division behavior. The longest duration of therapy for a patient with breast cancer was 281 1 days. The patient did not suffer from any significant adverse drug effects. There were no recurrences or metastases (see Table 1).

The drugs used today can delay the recurrence or metastasis-free period, but are not able to prevent it (Goldhirsch et al., 1 994). As already mentioned above, angiogenesis (new formation of vessels) is an essential prerequisite for tumor growth. ET1 80CH3 has been shown to inhibit the formation of new vessels in tumor tissue (Candal et al., 1 994). ET1 80CH3 is also antimetastatic, as demonstrated by Berdel et al., 1 982, and Storme et al., 1 985, on a highly invasive carcinoma model.

The pharmacodynamic effects of ET1 80CH3, especially on the breast cancer model, have been tested on animals both in vitro and in vivo. Using the human MDA-MB 231 breast carcinoma cell line, it was demonstrated in the nude mouse model that the administration of ET1 80CH3 leads to an inhibition of tumor growth or a significant mitotic index (= number of dividing cells) compared to controls (Hardman et al. 1 997).

Furthermore, in a model that is being discussed more and more in the practical therapy of breast cancer, namely bone marrow transplantation with previous cleaning ("purging"), it was demonstrated that ET1 80CH3 with the same dosage on the one hand almost 100% inhibited the growth of the Carcinoma cells, but on the other hand did not significantly influence the growth of the progenitor cells of the bone marrow (Dietzfelbinger et al. 1 993).

Given the known dependence of breast cancer cells on hormones, it was also examined whether ET1 80CH3 has an influence on the uptake of

Has estrogens and the level of progesterone receptors. Through the

Treating cells with ET1 80CH3 will increase the absorption of estradiol inhibited depending on dose. This effect can be measured before the growth-inhibiting effect of ET1 80CH3 occurs (Kosano et al. 1 990).

However, experiments with tumor cell lines and studies with animal models only allow very limited conclusions to be drawn about the therapeutic efficacy of ET1 80CH3 in humans, since this substance has a highly specific effect and some important factors such as e.g. UAW can only be determined on humans ..

The therapeutic efficacy of ET1 80CH3 as an agent in the treatment of breast cancer is explained in more detail by the results shown in Table 1. In summary, ET1 80CH3 has the following advantages over the substances used in the prior art:

a) Effectiveness as relapse prevention

In operable cases, the most important prognostic factor is the number of affected axillary lymph nodes (LK) when diagnosed. From stage N1 /> 3 LK + (i.e.> 3 histologically examined lymph nodes are tumorous) the risk of a subsequent metastasis increases up to 90%. The so-called "high-risk" cases, which have particularly unfavorable prognostic factors, are therefore particularly meaningful when evaluating the effectiveness of a therapy. See cases No. 2, No. 6, No. 7, No. 8, No. 1 1 of Table 1.

b) Slowing down an existing progression

In a palliative therapy situation, in which a cure is no longer possible, the only aim to be aimed at is to slow down an existing progression and to completely negatively influence the quality of life. See cases No. 3, No. 4, No. 5, No. 9, No. 10, No. 1 2, No. 1 3 of Table 1. c) Delay / prevention of metastasis in other organs Metastatic cells have a much more aggressive growth behavior than cells of the primary tumor. The prevention of metastasis or - from a palliative point of view - its delay is a direct measure of the effectiveness of a drug, especially if it only comes into play in an "ultima ratio" situation.

See cases No. 3, No. 4, No. 5, No. 9, No. 10, No. 1 1, No. 1 2, No. 1 3 of Table 1.

d) combination therapy

A drug should ideally be combinable with commonly used drugs; there should be no multi-drug resistance reactions, nor should it affect the effectiveness of chemotherapy if it is used after the "new" therapy. See cases No. 1 2, No. 14, No. 1 5, No. 1 6, No. 1 7 of Table 1.

e) Reasonable UAW Another prerequisite for a successful therapeutic is missing or at least acceptable UAW. Due to its selective effect, the ET1 80CH3 molecule is, as expected, neither organotoxic nor teratogenic / embryotoxic / carcinogenic, nor does the drug develop serious undesirable drug effects in daily use that would require hospitalization or would have a lasting negative impact on the quality of life of those affected.

The longest permanent use of ET1 80CH3 in a breast cancer patient was 281 1 days. The patient was fully productive, did not spend time in the hospital and did not suffer from any significant ADR. The average duration of intake of the patients listed in Table 1 was 837.71 days. Not a single serious drug-induced side effect has been reported.

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All patients listed in Table 2 were treated on average with 300 mg ET1 8OCH3 / day (range between 50 and 900 mg). For this purpose, the lyophilisate was dissolved in water and placed in a carrier medium which had at least 3 to 3.5% fat content and / or a comparable proportion of proteins. The carrier medium is preferably a water-based drink, in particular milk. In this way, ET1 8OCH3 can easily be administered orally. Other suitable carrier materials can include soups (in particular alloyed soups), beer, egg liqueur and other conventional beverages. Milk-based carriers such as milk substitute, yogurt, kefir and the like are also suitable. The carrier medium-active ingredient mixture is taken throughout the day, e.g. drunk. The application is therefore oral. Treatment is entirely outpatient, unless the clinical picture makes inpatient admission inevitable.

Under these conditions, the UAW listed in Table 2 occurred. The rating "yes" means that a symptom is caused by the drug. The rating "questionable" means that the cause of the complaint is unclear.

Table 2

List of adverse drug reactions (UAW) reported under edelfosin therapy

Note: "without evaluation" means that the triggering factor for the corresponding symptom has not been assigned.

The UAW caused by the therapy with ET1 80CH3 are short-lived and in each case were within a very short time (hours) reversible. UAW often occur in the first two months of therapy and then subside completely. All UAW are always without a pathological correlate.

Cumulative toxicity was not observed even after several years of uninterrupted therapy. In contrast to treatment that can only be carried out as an inpatient due to the known toxicity, therapy with ET1 8OCH3 guarantees a maximum of quality of life.

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Claims

Expectations 1. 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET180CH3) for the treatment of human breast cancer. 2. Process for the manufacture of a medicament for the treatment of human breast carcinomas, which means that ET180CH3 is used as the active ingredient. 3. The method according to claim 2, d a d u rc h g e ke n n ze i c h n et that the active ingredient is brought into a form suitable for oral administration in a liquid carrier. 4. The method according to any one of claims 2 or 3, d a d u rc h g e ke n n ze i c h n et that the carrier material contains at least 3 wt .-% fat and / or protein. 5. The method according to any one of claims 2 to 4, so that the carrier material comprises a water-based drink, in particular milk. 6. A method of treating breast cancer, such that a pharmacologically effective amount of ET180CH3 is administered to a person in need of treatment. 7. The method according to claim 6, d a d u rc h g e ke n n z e i c h n et that the active ingredient is dissolved in a liquid, drinkable carrier material. 8. The method according to claim 7, d a d u rc h g e ke n n ze i c h n et that a liquid carrier material containing at least 3 wt .-% fat and / or protein is used. 9. The method according to claim 7 or 8, d a d u rc h ge k e n n z e i c h n et that a water-based drink, in particular milk, is used as the carrier material. 10. The method according to any one of claims 6 to 9, d a d u r c h g e k e n e i c h n et that the active ingredient is administered in an amount of 50 to 900 mg / day / person.