CN1636598A - Methods to potentiate intravenous estramustine phosphate - Google Patents

Abstract

Estramustine phosphate is an antimitotic chemotherapeutic drug with established anticancer efficacy. The present invention describes a method of potentiating the therapeutic effect of intravenous estramustine phosphate. The present invention provides intravenous estramustine phosphate which can be administered once in a large dose exceeding 1300 mg. The pharmacokinetics of estramustine phosphate is thereby effectively improved. It is further provided that estramustine phosphate may be administered intravenously, for use in a combination regime with other chemotherapeutic agents. Therapeutic advantages achieved with intravenous estramustine phosphate formulations can be applied to the treatment of a variety of cancers, including prostate, breast, lung, colorectal, pancreatic, ovarian, melanoma, and other cancers .

Description

Methods of enhancing the action of intravenous estramustine phosphate

This application claims priority from US Provisional Application No. 60/079542, filed March 27,1998. This application is a divisional application of the Chinese invention patent application with the application number 99800823.0 with the same title.

technical field

The invention relates to the use of estramustine phosphate as a large-dose transfusion solution. The estramustine phosphate is a non-mustard carbamate derivative of estradiol-17b-phosphate. The invention further relates to methods of action of intravenously administered estramustine phosphate and methods of treating cancer by intravenous administration of estramustine phosphate.

Background technique

Cytotoxicity has been shown to be caused by the intact estramustine molecule (Hartley-Asp, 1982). Tissue culture studies have shown that estramustine (EM) is an anti-mitotic agent that can block tumor cell differentiation in metaphase, and this blocking effect depends on the dose (Hartley-Asp, 1984). Metaphase arrest is known to be caused by the disturbing effect of drugs on the microtubule structure that forms the mitotic spindle. A dose-dependent impairment of interphase microtubules was shown by means of immunohistochemical studies in cultured human prostate cells (Mareel 1988, Dahllof 1993). In vitro EM treatment inhibited the formation of microtubules composed only of tubulin, demonstrating that EM directly interferes with tubulin (Dahllof, 1993). In addition, it has been demonstrated to interfere with microtubule-associated proteins (MAPs) (Stearns, 1988). MAPs are macromolecular proteins believed to be important for stabilizing microtubules. It has been established in vivo that EM exhibits an antimitotic mechanism of action (Eklv, 1992).

Thus, estramustine phosphate is an antimitotic agent currently used in the treatment of severe prostate cancer. As a single agent, its activity against hormone-refractory prostate cancer was comparable to several other cytotoxic agents studied by the National Prostate Cancer Program in a series of multi-institutional, randomized trials (Murphy, 1983). The drug is usually administered orally at a dose of 10-15 mg/kg/day, although it is also approved for intravenous administration in several countries. However, when estramustine phosphate is administered intravenously, it follows a predetermined schedule parallel to the oral dosing, that is, the recommended dose is 300-600 mg intravenously per day, usually over consecutive days Dosing repeatedly. Then give it orally.

Details of approximately 500 patients treated with an intravenous formulation followed by oral treatment can be found in published sources. Typically in these studies, 300-600 mg daily was administered intravenously for 7-21 days, followed by daily oral administration. Administered by slow intravenous injection or bolus at a dose of 300 mg/day, thrombophlebitis and local irritation at peripheral intravenous injection sites are considered to require establishment of central intravenous administration or discontinuation of treatment in most patients The main limitation of the method of administration. At a dose level of 450 mg/day, Nagel and Kölln (1977) stated that this dose level caused such "severe gastrointestinal problems that 300 mg/day was adopted as the maximum daily intravenous dose". In a work edited by Andersson et al., of 245 patients who received 300-600 mg/day for 21 days, followed by the same dose once or twice weekly for 2 months, 20% of patients showed thrombotic venous Inflammation, 17% showed gastrointestinal problems, and 9% showed liver dysfunction. Toxic effects resulting from this repeated dosing regimen often require cessation of dosing (Lundgren, 1995). Maier (1990) reported that 11 to 18 patients (61%) who received 900 mg/day intravenously for 7-10 days and then received oral treatment developed severe liver problems and had no phlebitis. One died due to toxic liver failure.

Thus, it is typical of the prior art to utilize an intravenous formulation of estramustine phosphate as a single agent followed by chronic oral estramustine therapy. Furthermore, intravenous administration of large doses of estramustine phosphate is generally considered contraindicated due to toxicity. It was neither known nor obvious to the prior art that estramustine phosphate be administered in a feasible intravenous manner in single, bolus doses. Although oral doses as high as 1200 mg/ ^m2 have been given (Keren-Rosenberg, 1997), differences in drug metabolism and bioavailability do not allow extrapolation of higher doses of intravenous formulations because oxyestramole after oral administration The relative bioavailability of estromustine is only 44% (Gunnarsson, 1984), also because of the dephosphorylation of the phosphate moiety in oral formulations as opposed to intravenous formulations. Furthermore, it is not known in the prior art that intravenous estramustine phosphate can be used in combination chemotherapy regimens, including the use of high doses of intravenous estramustine phosphate. Furthermore, it is not known in the prior art that intravenous estramustine phosphate has clinical utility for many cancers other than prostate cancer indications.

In previous work, Dr. Beryl Hartley-Asp, co-inventor of the present invention, was the first to recognize the synergistic effect of estramustine phosphate with other cytotoxic agents (Mareel, 1988). Several experiments have demonstrated that prolonged exposure to estramustine is necessary to achieve increased efficacy. Therefore, daily dosing was deemed necessary, making use of oral formulations following previous intravenous (IV) formulation data, suggesting that consistently higher levels would not be achieved clinically with IV dosing.

Estramustine and many other cytotoxic agents have shown additive and possibly synergistic antimicrotubule effects on cells in vitro (Mareel 1988, Speicher 1992, Pienta 1993, Batra 1996). Thus, the combination of estramustine phosphate and other drugs is accomplished using estramustine phosphate oral formulations in humans. The combination of estramustine phosphate and vinblastine has been studied in phase II trials in hormone-refractory prostate cancer (Seidman 1992, Hudes 1992, Pienta 1994, Hudes 1996). In these trials, 88 patients demonstrated a 50-75% reduction in PSA. The most common toxicity also moderated to moderate nausea. Of particular note, the incidence of significant cardiovascular toxicity was 10.5% (4/37), including one case of deep vein thrombosis (DVT), one case of myocardial infarction, one case of congestive heart failure, and one case of reversible neuropathy, These patients required discontinuation of treatment, and these toxic effects were caused by estramustine phosphate. In another phase II trial by Pienta et al. (1994), estramustine phosphate (oral) was used in combination with etoposide. Fifty-two patients were evaluated: 20 patients with soft tissue disease were included, of which 3 complete responses (CR) (15%) and 6 partial responses (PR) (30%) were observed. Of the 32 patients with bone metastases, 8 improved (25%) and 12 stabilized (38%). A total of 13 men (25%) had a 75% reduction in PSA and 28 men (54%) had a 50% reduction. A phase I-II study of paclitaxel (Hudes, 1992) and estramustine phosphate was conducted on seventeen hormone-refractory prostate cancer patients. Levels of reduction were measurable in six patients, 3 of whom had PRs of 2+, 6 and 8 months. Prostate-specific antigen (PSA) reduction ≥ 50% accounted for 58.8%. The median duration of response was 7 months. Grade 3-4 neutropenia and mucositis occurred in 2 patients, grade 1-2 nausea occurred in 70.5%, and grade 3 occurred in one patient. Edema was seen in 8 patients (47%), and grade 1-3 transient elevations of liver enzymes occurred in 6 patients (35.2%).

In a recent study, Petrylak et al. (1997) demonstrated an overall PSA reactivity rate of 62% with oral administration of escalating doses of docetaxel and estramustine phosphate. Among patients with two-dimensionally measurable disease, 3 (43%) achieved a partial response of the lymph nodes and 1 achieved a minor response of the ischial group. This demonstrates that combination therapy with oral estramustine is effective. However, combining intravenous estramustine phosphate with these cytotoxic agents is unknown in the art. Differences in the metabolism of oral and intravenous formulations of estramustine phosphate, especially with regard to the phosphate moiety, make combination therapy with intravenous formulations non-obvious.

Unlike other antimitotic agents, the action of estramustine phosphate appears to be dependent on the presence of estramustine binding protein (EMBP) (Eklöv, 1996). This is only found in the prostate under normal conditions (Forsgren 1979, Flucher 1989). However, similar proteins have also been identified in many cancerous tissues, as well as in prostate tumors such as lung, breast glioma, colon, pancreas (Björk 1991, Bergh 1988, Eklöv 1996, Edgren 1996, Von Schoultz 1994, Bergenheim 1993). This protein binds estramustine and oxyestamustine (EaM and EoM) with very high affinity and is thought to be responsible for the selective retention of EoM in prostate tumors, where estramustine phosphate was administered orally, respectively. Plasma/tumor ratios of 1:6 to 1:11 were found in prostate cancer patients treated with intravenous and intravenous administration (Norlen 1988, Walz 1988). Recently, we have demonstrated the correlation between EMBP levels and EaM and EoM levels in human prostate tumors prior to radical prostatectomy after one-time intravenous administration of estramustine phosphate to patients, indicating that EMBP May be responsible for drug retention (Walz, 1996).

As a reference, the present invention also cites the following references except the U.S. provisional application 60/079542 filed on March 27, 1998 in its entirety:

1. Andersson SB, Lundgren R, Svensson L: Gas chromatographic determination of four metabolites of estramustine phosphate on plasma (Gas chromatographic determination of four metabolites of estramustine phosphate on plasma), Acta Pharm.Suec19: 1-10, 1982 ;

2. Batra S, Karlsson R, Witt L: Potentiation by estramustine of the cytotoxic effect of vinblastine and doxorubicin in prostatic tumor cells, Int J Cancer 68:1-6, 199;

3. Bergenheim AT, Gunnarsson PO, Edman K, von Schoultz E, Hariz MIHenriksson R: Uptake and retention of estramustine and the presence of estramustine-binding proteins in human malignant brain tumors presence of astramustine binding protein in malignant brain tumors in humans), Br J Cancer67: 358-361, 1993;

4. Bergh J, Bjrk P, Westlin J-E, Nilsson S: Expression of an Estramustine-binding associated protein in human lung cancer cell lines (Expression of an Estramustine-binding associated protein in human lung cancer cell lines), Cancer Res 48 : 4615-4619, 1988;

5. Bjrk P, Borg A, Fem M, Nilsson S: Expression and partial characterization of estramustine-binding protein (EMBP) in human breast cancer and malignant melanoma protein (EMBP) in human breast cancer and malignant melanoma), Anticancer Res 11(3): 1173-1182, 1991;

6.bjrk P, Jonsson U, Andrén-Sandberg : Binding sites of cytotoxic metabolites of estramustine phosphate (Estracyt⑧) in mouse and human pancreas different from pancreatic estrogen binding protein for the cytotoxic metabolites of Estramustine phosphate (Estracyt⑧) in rat and human pancreas that are distinct from pancreatic Estrogen-binding protein), Pancreas 6:1:77-89, 1991;

7. Dahllf B, Hartley-Asp B, Billstrm A, Cabral F: Estramustine depolymerizes microtubules by binding totuulin, Cancer Res 53: 4573-4581 , 1993;

8. Edgren M, Westlin JE, Letocha et al: Estramustine-binding protein (EMBP) in renal cell tumor immunohistochemistry, immunoscintigraphy, and the effective role of estramustine in vitro (Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estromustine effects), Acta Oncol 35(4): 483-488, 1996;

9. Eklv S et al., Evidence for a non-estrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo, The Prostate 20:43-50;1992;

10. Eklv S, Mahdy E, Wester K et al.: The content of estramustine-binding protein (EMBP) in four different cell lines and its correlation with estramustine-induced metaphase arrest (Estramustine -binding protein (EMBP) content in four different cell lines and its correlation to estramustine induced metaphase arrest), Anticancer Res 16 (4A): 1819-1822, 1996;

11. Flüchter S, Nelde HJ, Bjrk P et al.: Effect of treatment on the expression of estramustine-binding protein (EMBP) in prostate cancer patients: an immunohistochemical study (Effect of treatment on the expression of estramustine -binding protein (EMBP) in prostatic cancer patients: An immunohistochemical study), The Prostate 14: 27-43, 1989;

12. Forsgten B, Bjrk P, Carlstrm K, Gustafsson J, Pusette A, HogbergB: Major proteins binding to nitrogen mustard derivatives of estramustine, estradiol-17β in the rat prostate Purification and distribution of a major protein in rat prostate that bindsetramustine, a nitrogen mustard derivative of estradiol-17β), Proc.Natl.Acad.Sci USA: 76: 3149-3153, 1979;

13. Gunnarsson PO, Andersson S-B, Johansson S-A et al.: Pharmacokinetics ofestramustine phosphate (Estracyt⑧) in prostatic cancer patients, EurJ.Clin. Pharmacol, 26:113-119, 1984;

14. Gunnarsson PO, Plym Forshell G, Fritjofsson A, Norlén BJ: Plasma concentrations of estramustine phosphate and its major metabolites in prostate tumor patients treated with different doses of estramustine phosphate ((Estracyt⑧) (Plasma concentration of Estramustine phosphate and its major metabolites in patients with prostatic carcinoma treated with different doses of Estramustine phosphate (Esstracyt ⑧)), Scand J. Urol Nephrol 15: 201-206, 1981;

15.Hartley-Asp B: Estramustine induced mitotic arrest in two human prostatic carcinoma cell lines DU 145 and PC-3, The Prostate 5: 93-100, 1984;

16. Hartley-Asp B, Gunnarsson PO: Growth and cell survival following treatment with estramustine, nor-nitrogen mustard, estradiol, and testosterone from a human prostate cancer cell line (DU 145) estramustine, nor-nitrogen mustard, estradiol and testosterone of a human prostatic cancer cell line (DU145)), J Urology 127:818-822, 1982;

17.hudes G, Obasaju C, Chapman A, Gallo J, McAleer C, Greenberg R: Phase I study of Paclitaxel and Estramustine: Preliminary activity in hormone-refractory prostate cancer activity in hormone refractory prostate cancer), Sem Oncol, vol.22:3, Suppl 6:6-11, 1995;

18. Hudes GR, GreenbergR, Krigel RL, Fox S, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer (Phase II study ofestramustine and vinblastine, two microtubule inhibitors, in hormone-refractoryprostate cancer), J Clin Oncol 10:1754-1761, 1992;

19. Keren-Rosenberg, S. Muggia, FM: Response to estramustine phosphate and paclitaxelin patients with advanced breast cancer: A Phase I Study, Seminarsin Oncology 24:5 S3-26-S3-29, 1997;

20. Lindberg B: Treatment of rapidly improving prostate tumors with Estracyt (Treatment of rapidly of progressing prostatic carcinoma with Estracyt), Journal of Urol108: 303-305, 1972;

21. Maier U, Hienert G, Simak R: Estramustine phosphate in secondary hormone-resistant carcinoma of the prostate (Estramustine phosphate in secondary hormone-resistant carcinoma of the prostate), Eur Urol 17: 216-218, 1990;

22. Mareel MM, Storme GA, Dragonetti CH, De Bruyne GK, Hartley-Asp B, Segers JL, Rabaey ML,: Anti-invasive activity of estramustine on malignant MO ₄ murine cells and on DU 145 human prostate tumor cells in vitro (Antiinvasive activity of estramstine on malignant MO ₄ mouse cells and DU 145 human prostate carcinoma cells in vitro), CancerRes., 48:1842-1849, 1988;

23. Murphy GP, Slack NH, Mittleman A: Experiences with Estramustine Phosphate (Estracyt, Emcyt) in prostate cancer, Seminars in oncology 10(3) Suppl 3, 34-42, 1983;

24. Nagel R, Klln C-P: Treatment of advanced carcinoma of the prostate with estramustine phosphate, British Journal of Urol 49:73--79, 1977;

25. Norlén, B.J., Andersson S.B., Bjrk P., Gunnarsson PO., Fritjofsson □, Uptake of Estramustinephosphate (Estracyt) metabolites in prostate cancer ), Journal of Urology 140:1058-1062, 1988;

26. Petrylak DP, Shelton GB, Mac Arthur RB et al.: Phase I trial of Docetaxel-Estramustine in androgen insensitive prostate cancer (Phase I trial of DocetaXel-Estramustine in androgen insensitive prostate cancer), Cancer Investigation 16, Supp 162, 1997;

27. Pienta KJ, Lehr JE: Inhibition of prostate cancer growth by etoposide and etoposide: Evidence for interaction at the nuclear matrix , Journal of Urol 149:1622-1625, 1993;

28. Pienta KJ, Redman B, Hussain M, Cummings G et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory prostate cancer refractory adenocarcinoma of theprostate), J Clin Oncol 12:2005-2012, 1994;

29. Seidman AD, Scher HI, Petrylak D, Dershaw DD, Curley T: Estramustine and vinblastine: use of prostate specific antigen as a clinical trial endpoint in hormone-responsible prostate cancer (Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer), J Urol 147:931-934, 1992;

30.Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and Taxol in human prostatic carcinoma cell lines, Cancer Res 52 : 4433-4440, 1992;

31. Stearns M, Tew KD: Estramustine binds MAP-2 to inhibit microtubule assembly in vitro (Estramustine binds MAP-2 to inhibit microtubule assembly in vitro), J CellScience 89:331-342, 1988;

32. von Schoultz E, Carlstrm K, Henriksson R et al.: Estramustine binding proteinin primary tumors and metastases of malignant melanoma , Melanoma Res 4(6): 401-405, 1994;

33. Walz PH, Bjrk P, Edman K, Gunnarsson PO, Hartley-Asp B: Absorption and distribution of the estramustine phosphate metabolite estramustine following a single dose infusion in prostate cancer patients. the etramustine-phosphate metabolite estrsmustine after single-dose injection in patients with prostatic cancer), Akt Urol 27:92-93, 1996;

34. Lundgren.R, Estracyt intravenost for behandling avhormonrefraktarprostatacancer: Svenska Lakaresallskapets Rikstamma, 1995.

Summary of the invention

The present invention describes methods of enhancing the therapeutic use and efficacy of intravenously administered estramustine phosphate. The method provides intravenous administration of estramustine phosphate in doses exceeding 1300 mg. It also provides intravenous administration of estramustine phosphate at doses in excess of 950 mg/ ^m2 (milligrams per square meter of body surface area). It further provides for one-time, high-dose intravenous administration of estramustine phosphate, and the administration may be weekly or longer. The invention optimizes the pharmacokinetics, maximizes the therapeutic effect, and further makes it possible to use intravenous estramustine phosphate in combination with other treatments, including other chemotherapy to further improve the therapeutic effect. The present invention enables the use of intravenous estramustine phosphate as a therapy for various types of tumors, including prostate, breast, lung, ovarian, colorectal, melanoma, pancreas, and brain cancers.

Accordingly, one application of the present invention is to provide intravenous therapy of estramustine phosphate in large doses, wherein the dose exceeds 950 mg/m ² .

Another application is to provide a regimen for intravenous administration whereby the regimen can optimize the pharmacokinetics of estramustine phosphate and its metabolites with minimal toxicity and thus further facilitate combination therapy regimens efficient.

Thus, one application of the present invention is to allow intravenous estramustine phosphate to be used in combination with other therapeutic regimes, including cytotoxic chemotherapy.

Another application of the present invention is to provide a method that increases the saturation of estramustine phosphate or its metabolites combined with estramustine binding protein or estramustine binding protein-like protein (EMBP), Extended duration of binding.

Thus, the present invention provides the use of intravenous administration to treat cancers with EMBP, including but not limited to prostate, breast, lung, ovarian, colorectal, melanoma, pancreatic and brain cancers.

Another application of the present invention is to provide a method for rapid relief of secondary symptoms of cancer, including but not limited to pain and urinary tract obstruction caused by cancer.

In addition, the present invention further enables these applications to be adapted for intravenous estramustine phosphate independently of the formulation. Thus, the present invention provides estramustine phosphate infusion in the form of free drug, protein-bound drug or liposome drug.

Thus, the present invention describes a formulation of estramustine phosphate wherein estramustine phosphate is administered intravenously together with liposomes.

Therefore, the method of the present invention is extremely unexpected, and in this method, the dose of safe and effective regimen administration can reach more than 900 mg/m ² (generally more than 1300 mg per dose).

The present invention presents the advantages of intravenous estramustine in combination with other chemotherapeutic agents. The present invention further provides the advantages of using high dose intravenous estramustine in combination with other chemotherapeutic agents.

We show in the present invention that intravenous estramustine phosphate can be used to treat tumors with high levels of EMBP-like protein (abbreviated here as EMBP).

The novel and non-obvious aspects of the present invention can be appreciated from the comparison of the pharmacokinetic data following oral administration of estramustine phosphate with the pharmacokinetic data following intravenous administration of high dose estramustine phosphate application. Pharmacokinetic and toxicity data on high doses of intravenous estramustine phosphate are unknown in the art. After oral administration of estramustine phosphate, the main metabolic steps in the human body are that estramustine phosphate becomes estramustine (EM) through dephosphorylation, and then oxidizes into oxyestine (EM) at the 17th position ( EoM), which is the estrone analogue of EM. When estramustine phosphate is administered on a daily oral regimen, the major metabolite found in plasma is EoM. The relative bioavailability based on oxyestamustine is about 44% (Gunnarsson, 1984). After intravenous administration, estramustine phosphate is initially found in plasma, but it is rapidly hydrolyzed to the same metabolites found after oral administration, the major metabolite being estramustine oxyestine. Estramustine and oxyestradiol are further metabolized by carbamate cleavage to yield approximately 15% estradiol and estrone, respectively (Gunnarsson, 1981, 1984). We have demonstrated that the main metabolite, oxyestamustine, is unexpectedly available for a prolonged period of time after high-dose intravenous administration, which can lead to unexpected clinically beneficial effects. Previous data in patients treated with a single 300 mg intravenous dose demonstrated an elimination half-time of oxyestamustine of 10-20 hours. The main route of elimination is the metabolism of estramustine phosphate to estramustine, oxyestradiol, and estrone. Particularly important estramustine phosphate efficacy data are the half-life of estramustine phosphate (Figure 1) and the major cytotoxic metabolite oxyestramustine (Figure 2). By applying the method of the present invention, we have confirmed this new finding: after one-time, intravenous administration of estramustine phosphate in a large dose of 1000 mg/ ^m2 , the half-life of estramustine is about 100 hours (figure 2). This discovery further enables the therapeutic use of high-dose intravenous estramustine phosphate.

Brief description of the drawings

A better understanding of the present invention and its many advantages may be better understood by referring to the following detailed description, in conjunction with the accompanying drawings, in which:

Figure 1 illustrates the concentration of estramustine phosphate (mean ± SEM, N=4+4+3) after a one-time intravenous administration of estramustine phosphate (Estracyt), and the administration dose is 1000 mg (range 980- 1070mg), 1000mg/m ² and 1500mg/m ² ;

Figure 2 illustrates the concentrations of estramustine oxyestamustine (mean ± SEM, N=4+4+3) after a one-time intravenous administration of estramustine phosphatase, and the administration dose is 1000mg (range 980-1070mg), 1000mg /m ² and 1500 mg/m ² .

Detailed Description of the Preferred Embodiment

According to the present invention, estramustine phosphate can be administered at a dose of 950 mg/m ² or more (ie greater than 1300 mg).

The method of the present invention is implemented as follows. In a preferred method, estramustine phosphate is administered at a single infusion dose exceeding 950 mg/ ^m2 . Intravenous administration can be by either central or peripheral intravenous routes. In the process of preparing the target drug, the package content of estramustine phosphate for intravenous administration is in a dissolved form, and the package content therein may consist of, but not limited to, estramustine phosphate Freeze-dried powder of meglumine salt in a vial, or similar freeze-dried estramustine phosphate, first dissolved in sterile water, e.g. 5 mL of sterile water per 300 mg of estramustine phosphate , or dissolved in 5% glucose solution for intravenous administration. In a preferred method, 5% dextrose in water is used as diluent. In a preferred method, during the preparation of the dissolved form, the drug should not be shaken but mixed by slow inversion. The solution is then obtained for intravenous infusion, with a preferred duration of infusion ranging from 30 minutes to 3 hours, whereby infusion over 1-2 hours is a safe and convenient method. Saline solutions can lead to drug precipitation and are therefore not preferred for infusion.

When estramustine phosphate is administered by the peripheral intravenous route, it is preferable to utilize longer infusion durations and larger total infusion volumes to minimize vascular irritation. Alternatively, estramustine phosphate solution may be mixed with varying amounts, but preferably 3-5% human albumin or other plasma proteins, including synthetic plasma proteins, to achieve protein binding of estramustine phosphate, Thereby reducing any possible vascular damage.

The invention may be further practiced using other formulations or formulations of estramustine phosphate. A particularly advantageous formulation of the chemotherapeutic agent estramustine phosphate involves combining estramustine phosphate with liposomes for infusion (herein referred to as liposome-encapsulated estramustine phosphate or liposomal estramustine), enabling estramustine phosphate to be infused via peripheral or central veins in bolus doses and doses below 1300 mg. In a preferred method of preparing liposomal estramustine, a solution of estramustine phosphate is first prepared in the manner described above and then injected into vials containing empty liposomes available in the form of lyophilized powder. Following proper hydration of the liposomes, the vials are vortexed and sonicated prior to infusion into the patient.

When estramustine phosphate is administered by a central venous route, the administration can be through temporary or permanent venous access devices, including but not limited to triple lumen catheters, Hickman catheters, subclavian line, jugular vein line or medi-port. Said administration may be accompanied by anticoagulant therapy or additionally in varying amounts, but preferably 3-5% of human albumin or other plasma proteins or liposomal estramustine, but not necessary, in order to reduce any contribution to the administration. Vascular injury that may be caused by drug patients.

The dose of estramustine phosphate in the present invention is greater than 1300 mg, but preferably the patient is treated at a dose in excess of 950 mg/ ^m2 . Therefore, a preferred method is one-time intravenous administration at a dose of 1000 mg/m ² . Another preferred method is one-time intravenous administration at a dose of 1500 mg/m ² . Also, the dosage may be 2000 mg/m ² . However, the present invention includes other doses above 950 mg/m ² and the preferred doses are not meant to be limiting.

The most preferred dosage regimen of estramustine phosphate in the present invention is one-time infusion, once a week, with a maximum dose of 4000 mg or 3500 mg/m ² . Another preferred regimen is one-time infusion administration, once every two weeks. Another preferred regimen is one-time infusion administration, once every three weeks. Another preferred regimen is one-time infusion administration, once every four weeks. Considering the regimen with other concomitant therapies, one regimen may be preferred over the other. These protocols can be repeated in a continuous or iterative fashion.

The inventive methods described herein can prolong high blood and/or tissue levels of estramustine phosphate metabolites, including oxyestramustine, estramustine, estrone, and estradiol. Thus, mutual synergy with other therapies including, but not limited to, chemotherapy, radiotherapy, monoclonal antibodies, and biological therapies can be enhanced. The present invention provides maximal therapeutic effect by prolonging high blood and tissue levels of estramustine phosphate and its metabolites. Thus maximal therapeutic effect is achieved where estramustine phosphate is administered intravenously at doses in excess of 950mg/ ^m2 , it is administered in combination with other cancer therapies including but not limited to radiotherapy, chemotherapy, monoclonal Antibodies and biological therapies.

In a preferred method, estramustine phosphate is administered intravenously in a single dose in excess of 950 mg/m ² , potentiating the therapeutic effect with other cytotoxic chemotherapeutic agents. In a preferred method, the method for realizing the combination drug is to administer estramustine phosphate intravenously within 3 days of administration of other chemotherapeutic agents, preferably on the day of administration of other chemotherapeutic agents or the day before administration . A particularly preferred approach is achieved when the other chemotherapeutic agents are composed of anti-mitotic or anti-microtubule agents, including but not limited to taxanes, including taxol and taxotere, and including vinblastine, vincristine , etoposide, navelbine, doxorubicin, irinotecan (CPT-11), and liposome-encapsulated chemotherapeutic agents, including liposome-encapsulated taxanes such as Liposome-encapsulated paclitaxel. It is more beneficial if used in combination with monoclonal therapy, including radioactive nucleotides or anti-growth factor agents.

Plasma or serum levels of oxyestamustine were further maintained when estramustine phosphate was administered intravenously as a single infusion at doses exceeding 950 mg/ ^m2 . The infusion can optionally be repeated in a continuous or repetitive fashion to maintain elevated blood levels of estramustine phosphate metabolites. Sustained levels of estramustine phosphate and its metabolites thus enable a sustained therapeutic effect.

The present invention therefore provides a method for increasing the binding of estramustine or its metabolites to estramustine-binding proteins or similar by intravenous administration of estramustine phosphate in a single infusion dose exceeding 950 mg/ ^m2 . The saturation of protein binding. Likewise, prolonged binding of estramustine phosphate or its metabolites to estramustine-binding protein or estramustine-binding protein-like protein (EMBP) persists by administering intravenous doses exceeding 950 mg/ ^m2 time. Thus, all cancers with estramustine-binding proteins or estramustine-binding-like proteins can be treated with intravenous estramustine phosphate. It is especially preferred to treat prostate cancer in this way. Breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancer are also preferably treated in this way. It is especially preferred to administer estramustine phosphate intravenously, where the single dose exceeds 950 mg/m ² , in cancers with estramustine binding protein or estramustine binding protein-like proteins, including but not Restricted to a group of cancers, including prostate, breast, ovarian, pancreatic, melanoma, lung, and brain cancers.

The cancer can be further treated with liposomal estramustine, alone or in combination with other chemotherapy. The administration method is preferably repeated in a continuous or repetitive manner according to the protocol of the present invention, with or without other treatments. Thus, the regimen may include intravenous estramustine phosphate in combination with other chemotherapeutic agent regimens, administered weekly, every two weeks, every three weeks, or every four weeks, and variations thereof.

Particularly preferred is estramustine phosphate administered intravenously in combination with other chemotherapeutics when used to treat cancers of the prostate, breast, melanoma, lung, pancreas, colorectum, ovary, and brain. Co-administration of cytotoxic agents. It is further particularly preferred that intravenously administered estramustine phosphate is administered in combination with radiotherapy when used for the treatment of prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, brain cancer. It is further preferred that in the treatment of cancers with estramustine binding protein or estramustine binding protein-like proteins, including prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancer, estrogen Mustin phosphate can be administered in intravenous doses exceeding 950 mg/ ^m2 when used in combination with other cancer therapies.

The present invention can achieve objective and subjective therapeutic effects. Beneficial effects relate to reduced tumor size, improved quality of life, reduced tumor obstruction, such as urinary tract obstruction, relief of tumor-induced pain, improved survival, reduced time to tumor recurrence, or other signs of improvement. In particular, a rapid objective or subjective therapeutic effect can be achieved by intravenous administration of estramustine phosphate in doses exceeding 950 mg/m ² , alone or preferably in combination with other cancer therapies. Therefore, the present invention can rapidly relieve urinary tract obstruction caused by cancer, and rapidly relieve pain caused by cancer.

Other features of the present invention will be apparent from the description of the following exemplary embodiments, which are provided for the purpose of illustrating the invention and not for limiting the invention.

Example

The following clinical case is presented by way of example and not limitation.

Example 1: Two patients with severe metastatic prostate cancer were treated with central intravenous administration of estramustine phosphate. The patient received estramustine phosphate at a dose of 2500 mg/m ² . Estramustine phosphate was administered in a repeated fashion following a once-weekly infusion regimen. Each infusion lasted 90 minutes. The infusion was well tolerated, there were no serious toxic effects, and prostate-specific antigen (PSA) responses (reductions) were confirmed in both patients.

Example 2: Three patients with severe metastatic prostate cancer were treated with estramustine phosphate via central intravenous administration at a dose of 1000 mg/m ² . Estramustine phosphate was administered in a repeated fashion following a once-weekly infusion regimen. Each infusion lasted 30 minutes. The infusions were well tolerated, with several patients demonstrating PSA reactions.

Example 3: Three patients with severe metastatic prostate cancer were treated with estramustine phosphate via central intravenous administration at a dose of 1500 mg/m ² . Estramustine phosphate was administered in a repeated fashion following a once-weekly infusion regimen. Each infusion lasted 30 minutes or 1 hour. Infusions were well tolerated, with one patient demonstrating a massive tumor adenopathy response.

Example 4: Three patients with severe metastatic prostate cancer were treated with central intravenous administration of estramustine phosphate. The patient received estramustine phosphate at a dose of 2000 mg/m ² . Estramustine phosphate was administered in a repeated fashion following a once-weekly infusion regimen. Each infusion lasted 60 minutes. To prevent venous thrombosis, antithrombotic agents are additionally given. Estramustine phosphate infusion was well tolerated with no serious toxicity and signs of PSA reaction.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims the invention may be practiced otherwise than as specifically described herein.

Claims (43)

1. produce the method for the high blood plasma level estramustine that prolongs, to promote the mutual synergism of estramustine and second kind of chemotherapeutics, wherein:

Estramustine is with the iv formulation administration; With

Estramustine administration in described second kind of chemotherapeutics administration same day or 3 days.

2. method according to claim 1, wherein said second kind of chemotherapeutics comprises antimitotic agent or anti-microtubule agent.

3. method according to claim 2, wherein said anti-microtubule agent is a taxane.

4. method according to claim 1, wherein iv formulation comprises estramustine phosphate.

5. method according to claim 4, wherein estramustine phosphate disposable infusion dosage surpasses 1300mg.

6. method according to claim 4, wherein estramustine phosphate disposable infusion dosage surpasses 950mg/m ²

7. method according to claim 1 is to strengthen therapeutic effect.

8. produce the method for high blood plasma level estramustine metabolite Estromustine, with the mutual synergism of accelerating oxidation estramustine and second kind of chemotherapeutics, wherein:

Estramustine is with the iv formulation administration; With

Estramustine administration in described second kind of chemotherapeutics administration same day or 3 days.

9. method according to claim 8, wherein said second kind of chemotherapeutics comprises antimitotic agent or anti-microtubule agent.

10. method according to claim 9, wherein said anti-microtubule agent is a taxane.

11. method according to claim 8, wherein iv formulation comprises estramustine phosphate.

12. method according to claim 11, wherein estramustine phosphate disposable infusion dosage surpasses 1300mg.

13. method according to claim 11, wherein estramustine phosphate disposable infusion dosage surpasses 950mg/m ²

14. method according to claim 8 is to strengthen therapeutic effect.

15. keep the method for estramustine and Estromustine blood plasma level, wherein with estramustine phosphate with the disposable infusion intravenous administration, dosage surpasses 1300mg; Repeat transfusion alternatively in a continuous manner.

16. method according to claim 15, wherein therapeutic effect is continued.

17. keep the method for estramustine and Estromustine blood plasma level, wherein with estramustine phosphate with the disposable infusion intravenous administration, dosage surpasses 950mg/m ²Repeat transfusion alternatively in a continuous manner.

18. method according to claim 17, wherein therapeutic effect is continued.

19. improve the method that estramustine or analogous protein conjugated protein with estramustine combines saturation, wherein:

Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 1300mg; With

It is protein-bonded in conjunction with saturation to improve estramustine thus.

20. method according to claim 19, wherein this method is used for the treatment of and has the conjugated protein or estramustine of estramustine in conjunction with the proteinic cancer of sample.

21. method according to claim 20, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.

22. improve estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for saturation, wherein:

Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 950mg/m ²With

It is protein-bonded in conjunction with saturation to improve estramustine thus.

23. method according to claim 22, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.

24. method according to claim 23, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.

25. prolong estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for persistent period, wherein:

Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 1300mg; With

It is protein-bonded in conjunction with the persistent period to prolong estramustine thus.

26. method according to claim 25, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.

27. method according to claim 26, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer and brain cancer.

28. prolong estramustine or its metabolite is conjugated protein with estramustine or analogous protein combines the method for persistent period, wherein:

Estramustine is with estramustine phosphate iv formulation form administration, and disposable infusion dosage surpasses 950mg/m ²With

It is protein-bonded in conjunction with the persistent period to prolong estramustine thus.

29. method according to claim 28, wherein this method is used for the treatment of the cancer with the conjugated protein or analogous protein of estramustine.

30. method according to claim 29, wherein said cancer are selected from the group of being made up of carcinoma of prostate, breast carcinoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer, melanoma and brain cancer.

31. the estramustine phosphate preparation, wherein estramustine is that to be encapsulated in lipid intravital.

32. preparation according to claim 31 is used for intravenous administration.

33. chemotherapeutics is formed by being encapsulated in the intravital estramustine phosphate of lipid.

34. product comprises estramustine phosphate and one or more chemotherapeutics of being applicable to intravenous administration, as combination formulations, is used for anti-cancer therapies simultaneously, respectively or continuously.

35. product according to claim 34, wherein said one or more chemotherapeutics are selected from the group of being made up of CPT-11, amycin, etoposide, NVB and Taxane derivative.

36. product according to claim 34, the wherein said estramustine phosphate of intravenous administration that is applicable to surpasses the disposable infusion of 1300mg as dosage.

37. product according to claim 34, the wherein said estramustine phosphate of intravenous administration that is applicable to surpasses 950mg/m as dosage ²Disposable infusion.

38., be used for the treatment of carcinoma of prostate, breast carcinoma, melanoma, pulmonary carcinoma, cancer of pancreas, colorectal carcinoma, ovarian cancer or brain cancer according to any described product of claim 34 to 37.

39. the preparation that intravenous uses comprises estramustine phosphate and albuminous mixture.

40. according to the described preparation of claim 39, wherein the dosage of active component disposable infusion surpasses 1300mg.

41. according to the described preparation of claim 39, wherein the dosage of active component disposable infusion surpasses 950mg/m ²

42. according to any described preparation of claim 39-41, wherein albumin is a human albumin.

43. product comprises the estramustine phosphate of lyophilized form and contains albuminous parenteral physiological solution.

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