JP2017178960A - Improved method for treating cancer by reducing renal toxicity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for inhibiting proliferation of a tumor in a cancer patient having renal failure, or treating the cancer patient.SOLUTION: A method includes a step of administering an effective dose of Lipoplatin to a patient, which inhibits proliferation of a tumor or treats cancer. Lipoplatin (trademark) is a therapeutic composition, and is described as cisplatin micelle which contains cisplatin in its aqueous solution form. Furthermore, a second chemotherapeutic agent can be administered to the patient. In the therapeutic composition, the second chemotherapeutic agent is a DNA alkylating agent, a topoisomerase enzyme inhibitor, a dihydrofolic acid reductase inhibitor, a thymidylate synthase inhibitor or the like.SELECTED DRAWING: None

Description

  The present invention relates generally to the field of solid tumors that are responsive to platinum therapy.

Cisplatin has been used for over 30 years and has proven to be an effective drug for several malignancies including lung, ovarian, head and neck, gynecological, testicular, and urothelial cancers Has been. Cisplatin is one of the most significant and effective anticancer agents, but its toxicity is often a suppressor that prevents the treatment process from continuing. The main side effect is nephrotoxicity (renal failure). Other adverse reactions include nausea and vomiting, asthenia, and neurotoxicity.

Over the past 15-20 years, there has been extensive effort to generate other drugs as replacements for cisplatin. The main alternative was the CDDP analog, carboplatin. In addition, in certain malignancies, taxanes (paclitaxel, docetaxel), and other novel agents including gemcitabine and vinorelbine are being tested. Although nephrotoxicity was avoided by using these drugs, other side effects including bone marrow toxicity were observed. However, none of these drugs were more effective when compared to cisplatin.

Thus, there is a need for effective treatments that are relatively non-toxic. The present invention fulfills this need and provides related advantages as well.

The present invention is a method for inhibiting tumor growth or treating a cancer patient in a cancer patient, wherein the cancer patient has renal failure and an effective amount of Lipoplatin is applied to the patient. A method comprising, or consisting essentially of, or even further comprising the step of inhibiting or treating the growth of said tumor. In one embodiment, the method further comprises, consists essentially of, or even further comprises administering an effective amount of a second chemotherapeutic agent. The second chemotherapy is L
It can be administered before or after ipoplatin therapy or simultaneously. Alone,
Or Li in combination with a second or other chemotherapeutic agent, or anti-cancer agent (described above)
Applicants also provide kits with poplatin and, optionally, instructions for performing the methods of the present disclosure.

Throughout this application, the text refers to various embodiments of the present compositions and methods. The various embodiments described are meant to provide various illustrative examples and should not be construed as alternative species descriptions. Rather, it should be noted that the descriptions of various embodiments provided herein may be in overlapping ranges. The embodiments discussed herein are merely exemplary and are not meant to limit the scope of the invention.

Also, throughout this disclosure, various publications, patents, and published patent specifications are referenced by identification. The disclosures of these publications, patents, and published patent specifications are hereby incorporated herein by reference in their entirety to more fully describe the state of the art to which this invention pertains.

Definitions As used herein and in the claims, the singular forms “a”, “an”, and “t”
“he” includes plural references unless the context clearly dictates otherwise. For example,
The term “a cell” includes a plurality of cells, including mixtures thereof.

As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not the others. “Consisting essentially of”, when used to define compositions and methods, shall mean excluding any other elements of essential importance to the combination. Thus, a composition consisting essentially of the elements defined herein comprises a trace amount of contaminants from the isolation and purification methods, and a pharmaceutically acceptable carrier,
For example, phosphate buffered saline, preservatives, etc. are not excluded. “Consisting of” shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this invention.

As will be appreciated by those skilled in the art, for any and all purposes, and in particular from the perspective of providing a written description, all ranges disclosed herein are optional and all possible sub-ranges, and Combinations of these subranges are also included. Any enumerated range is
It can be easily recognized as fully describing and enabling the same range to be broken down into at least equal half, one third, one quarter, one fifth, one tenth, etc. By way of non-limiting example, each range discussed herein can be easily decomposed into the lower third, middle third, upper third, etc. As the person skilled in the art will also understand, all wordings such as "
“Maximum to”, “at least”, “greater than”, “less than”, etc. refer to ranges that include the numerical values listed and that can be resolved following the sub-ranges discussed above.

All numerical designations, including ranges, eg, pH, temperature, time, concentration, and molecular weight are approximations that vary to (+) or (−) by 0.1 or 1.0 increments, where appropriate. It is. Although not always explicitly stated, it is understood that all numerical designations are preceded by the term “about” containing a standard deviation of about 15%, alternatively about 10%, alternatively about 5%. Should. It should also be understood that although not always explicitly stated, the reagents described herein are merely exemplary and equivalents of such are known in the art.

An “effective amount” is an amount sufficient to effect beneficial or desired results. The effective amount is
One or more administrations, applications, or dosages can be administered. Such delivery depends on a number of variables including the time that individual dosage units are to be used, the bioavailability of the therapeutic agent, the route of administration, and the like. However, the specific dosage level of the therapeutic agent of the present invention for any particular subject will depend on the activity of the specific compound used, the bioavailability of the compound, the route of administration, the age of the animal and its weight, overall Health, gender, animal diet, time of administration, excretion rate,
It will be understood that this will depend on a variety of factors including the combination of the drug and the severity of the particular disorder being treated, as well as the mode of administration. Treatment doses can generally be titrated to optimize safety and efficacy. In general, in vitro and / or in vivo
The dose-effect relationship from the study can initially provide useful guidance on the appropriate dose of administration to the patient. Studies in animal models can generally be used for guidance on effective dosages for treatment of disease. In general, it will be desirable to administer an amount of the compound that is effective to achieve serum levels commensurate with concentrations found to be effective in vitro. Thus, if a compound is found to demonstrate in vitro activity, eg, as noted in the table discussed below, in v
Effective doses for ivo administration can be estimated. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks. Consistent with this definition and used herein, the term “therapeutically effective amount” refers to a pharmacological response to treat a specified disorder or disease or to treat glioblastoma. The amount is sufficient to obtain.

As used herein, “treating” or “treatment” of a disease in a patient (1) prevents the occurrence of the symptom or disease in an animal that is prone to the disease or has not yet shown symptoms of the disease, (2) refers to inhibiting a disease or stopping its occurrence, or (3) ameliorating or regressing a disease or symptom of a disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of the present invention, beneficial or desired results include one or more, but not limited to, one or more symptom relief or detection Remission, reduced degree of abnormality (including disease), stabilization of abnormal (including disease) condition (ie, does not worsen), delay or slowing of progression of abnormality (including disease), abnormality (including disease), Mention may be made of remission or alleviation of the condition and remission (partially or totally). Compounds that are potent and can be administered locally at very low doses and thus minimize systemic adverse effects are preferred.

As used herein, “surgery” or “surgical excision” refers to the surgical removal of the tumor of interest.

“Tumor recurrence” is a cancer that has recurred (returned) after a period of time during which no normal cancer could be detected, as defined herein and by the National Cancer Institute. Cancer can return to the same location as the original (primary) tumor or to another location in the body. This is also called recurrent cancer.

“Time to tumor recurrence” (TTR) is from the date of cancer diagnosis to the first recurrence, death,
Or if the patient does not have any tumor recurrence at the time of last contact, defined as the time to last contact. If the patient did not relapse, the TTR was censored at the time of death or at the last follow-up.

“Disease-free survival” refers to the length of time a patient survives without any signs of cancer or tumor after treatment of the cancer or tumor, such as surgery.

“Overall Survival” (OS) is intended to extend life expectancy when compared to naïve or untreated individuals or patients.

“Progressive disease” (PD) intends a disease that is ongoing or worsening. For example, for lung cancer, the progressive disease can be a growth of 20% of the size of the tumor from the start of treatment or the spread of the tumor.

“Relative risk” (PR) in statistical and mathematical epidemiology refers to the risk of an event (or causing disease) to exposure. Relative risk is the ratio of the probability of an event occurring in an exposed group versus an unexposed group.

  “Monotherapy” refers herein to a therapy administered by itself.

The term “determining” or “determining” is the close association or association of a patient with a group or population of patients likely to experience the same or similar clinical response.

As used herein, the terms “Stage I cancer”, “Stage II cancer”, “Stage III cancer”, and “Stage IV” refer to the TNM staging of cancer. Stage I cancer generally identifies that the primary tumor is confined to the organ of origin. Stage II intends that the primary tumor has spread into the immediate surrounding tissues that drained from the tumor area and into the lymph nodes. Stage II
I intends that the primary tumor is large with fixation to deeper structures. Stage IV is
It is intended that the primary tumor is large with fixation to a deeper structure. 20 and 21 pages, CANCER BIOLOGY, 2nd edition, Oxford University Pre
See ss (1987).

“Triple negative breast cancer” refers to a tumor that has been tested for expression of the markers: estrogen receptor (ER), progesterone receptor (PR), and herceptin (HER2 / neu) and is negative for all three markers. Intended.

Lipoplatin ™ is a therapeutic composition and its method of preparation is described in US Pat. Nos. 7,393,478, and 6,700, each incorporated herein by reference.
No. 511,676. This composition is described as cisplatin micelles containing cisplatin in its aqueous form, a) a suitable buffer, cisplatin, is combined with an effective amount of at least 30% ethanol solution to form a cisplatin / ethanol solution. B) combining this solution with a negatively charged phosphatidylglycerol lipid derivative, thereby producing a cisplatin mixture in its aqueous form in micelles, wherein the molar ratio between cisplatin and lipid derivative is , 1: 1 to 1: 2
Comprising, or consisting essentially of, or even obtained by a method comprising these. In one aspect, the cisplatin micelle comprises: a) combining a suitable buffer, cisplatin, with an effective amount of at least 30% ethanol solution to form a cisplatin / ethanol solution; and b) making the cisplatin / ethanol solution negative. Combining with a charged phosphatidylglycerol lipid derivative, thereby producing a cisplatin mixture in its aqueous form in micelles, the molar ratio between cisplatin and lipid derivative being 1: 1 to 1: 2. , Steps, or consist essentially of, or even obtained by a method consisting of these. In one aspect, the phosphatidylglycerol lipid derivative comprises dipalmitoylphosphatidylglycerol (DPPG), dimyristoylphosphatidylglycerol (DMPG), dicaproylphosphatidylglycerol (DCPG), distearoylphosphatidylglycerol (DSPG), and dioleylphosphatidylglycerol (DOPG). ). In another aspect, the molar ratio is 1: 1. In a still further aspect, L
A method of generating ipoplatin is the step of combining an effective amount of free fusion peptide, fusion peptide-lipid conjugate, or fusion peptide-PEG-HSPC conjugate with a mixture of step a), wherein the fusion peptide is N Further comprising, or derived from, a stretch of 1 to 6 negatively charged amino acids at the terminus or C-terminus, and thus can electrostatically bind to the cisplatin mixture in its aqueous solution form. Consist essentially of, or even consist of. In one aspect, the free fusion peptide, or fusion peptide lipid conjugate is DOPE or DOPE /
Contains, consists essentially of, or even further consists of a cationic lipid.

As used herein, the term “pharmaceutically acceptable carrier” refers to standard pharmaceutical carriers such as phosphate buffered saline, water, and emulsions such as oil / water or water / oil emulsions, as well as various Any type of wetting agent is included. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin (1975) R.
emington's Pharm. Sci. 15th edition (Mack Publ. Co.,
See Easton).

“Subject”, “individual” or “patient” are used interchangeably herein and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, rats, rabbits, monkeys, cows, sheep, pigs, dogs, cats, farm animals, sport animals, pets, horses, and primates, especially humans. In addition to being useful for human treatment,
The invention is also useful for veterinary treatment of companion mammals, including rare mammals, rodents, and the like, rare animals, and livestock.

The term administration includes, but is not limited to intraocular, oral, intraarterial, parenteral (eg, intramuscular, intraperitoneal, inhalation, transdermal intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant ) By inhalation spray, nasal, vaginal, rectal, sublingual, urethral (eg, urethral suppository), or local route of administration (eg, gel, ointment, cream, aerosol, intraocular, etc.) Formulated alone or together in a suitable dosage unit formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients, and vehicles appropriate for each route of administration be able to. The present invention is not limited by route of administration, formulation or dosing schedule.

A “pathological cell” is one associated with or resulting from a disease. The pathological cell can be hyperproliferative. By “hyperproliferating cell” is meant a cell or tissue that is dividing and proliferating at a rate greater than the rate at which the cell or tissue is in a normal or healthy state. Examples of such include, but are not limited to, cancer cells. For hyperproliferating cells,
Also included are dedifferentiated, immortalized, neoplastic, malignant, metastatic, and cancerous cells, such as sarcoma cells, leukemia cells, cancer cells, or adenocarcinoma cells. Designated cancers include, but are not limited to, lung cancer cells, glioblastoma cells, and esophageal cancer cells.

A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be “positive” or “negative”. For example, if the purpose of the experiment is to determine the correlation of the efficacy of the composition of the invention for the treatment of a particular type of disease or cancer, a positive control (a compound known to exhibit the desired therapeutic effect) Or composition), and negative control (
It is generally preferred to use a subject or sample that does not receive therapy or receives a placebo.

The terms “cancer”, “neoplasm”, and “tumor” are used interchangeably and in the singular or plural form to refer to a cell that has undergone malignant transformation that renders the cell pathological to the host organism. Primary cancer cells (ie, cells obtained near the site of malignant transformation) can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell as used herein includes not only a primary cancer cell but also any cell derived from a cancer cell ancestor. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that usually manifests as a solid tumor, a “clinically detectable” tumor can be, for example, a CAT scan, magnetic resonance imaging (MRI), x-ray,
It can be detected based on the tumor mass by procedures such as ultrasound or palpation.
A single biochemical or immunological finding may be insufficient to meet this definition.

A neoplasm is an abnormal mass or colony of cells produced by a relatively autonomous new growth of tissue. Most neoplasms arise from clonal expansion of single cells via neoplastic transformation. Transformation of normal cells into neoplastic cells can be caused by chemical, physical, or biological agents (or events) that alter the cell genome directly and irreversibly. Neoplastic cells have some specialized loss of function and new biological properties,
First, it is characterized by the acquisition of relatively autonomous (uncontrolled) growth properties.
Neoplastic cells convey these inherited biological properties to progeny cells.

The neoplastic past, present, and future predicted biological behavior or clinical course is further classified as benign or malignant, a very important distinction in diagnosis, treatment, and prognosis. Malignant neoplasms manifest a greater degree of autonomy, can infiltrate and spread metastases, may be resistant to treatment, and can cause death. A benign neoplasm has a lesser degree of autonomy, is usually not invasive, does not metastasize, and generally does not cause much harm if treated well.

Cancer is a general term for malignant neoplasms. Anaplasia is a characteristic property of cancer cells and represents a lack of normal structural and functional properties (undifferentiated).

Tumors are literally any type of swelling, such as inflammatory or other swelling, but modern usage generally represents a neoplasm. The suffix "--tumor" means a tumor, usually representing a benign neoplasm such as in fibroma, lipoma, etc., but occasionally, as with so-called melanoma, hepatocellular carcinoma, and seminoma, malignant Neoplasms or non-neoplastic lesions such as hematomas, granulomas,
Or even suggest hamartoma. The suffix "-blastoma" refers to a germ cell neoplasm, such as an adrenal neuroblastoma or an ocular retinoblastoma.

Tissue formation is the origin of tissue and is a method of classifying neoplasms based on tissue cells of origin. An adenoma is a benign neoplasm of the glandular epithelium. A carcinoma is a malignant tumor of the epithelium. Sarcomas are malignant tumors of mesenchymal tissue. One system for classifying neoplasia, whether benign or malignant, is the biological (clinical) behavior and the tissue of the neoplasm as determined by histogenesis, histological and cytological examination Or use cells. Neoplasms can come from almost any tissue that contains cells capable of mitosis. The neoplastic histogenesis classification is based on the tissue (or cell) of origin as determined by histological and cytological examinations.

“Inhibiting” tumor growth refers to a growth state that is limited compared to growth without any therapy. Tumor cell growth includes, but is not limited to, measurement of tumor size, ³ H-
Thymidine incorporation assays can be used to assess by any means known in the art, including determining whether tumor cells are proliferating or counting tumor cells.

“Inhibiting” tumor cell growth means the following conditions: slowing, delayed or all, and “inhibiting” tumor growth is a proliferative condition that is restricted when tumor growth stops , And shows tumor shrinkage.

The term “culturing” refers to the in-vivo of cells or organisms on or in various types of media.
Refers to in vitro growth. It is understood that the progeny of a cell grown in culture may not be completely identical (morphologically, genetically, or phenotypically) to the parental cell. “Expanded” means any growth or division of cells.

As used herein, the term “renal insufficiency” (also referred to in some embodiments as renal failure) is intended when there is insufficient renal function to maintain normal health. To do.

Illustrative Embodiments The present invention is a method for inhibiting tumor growth or treating a cancer patient with renal failure, wherein the patient is administered an effective amount of Lipoplatin, Thereby, a method is provided that comprises, consists essentially of, or even further comprises a step of inhibiting tumor growth or treating cancer. In one aspect, the method further comprises, consists essentially of, or even further comprises administration of an effective amount of a second chemotherapeutic agent. The second chemotherapy can be administered before or after Lipoplatin therapy, or simultaneously. As used herein, the term “chemotherapeutic agent” intends small and macromolecule (biomolecule-based, eg, antibody-based) therapeutic agents.

The effective amount is administered at a dose determined by the treating physician in order to provide the patient with the highest therapeutic benefit and will vary with the duration of the patient, cancer and previous treatment, and therapy.

This method inhibits the growth of solid tumors or metastatic or non-metastatic lung cancer, gastrointestinal cancer, bladder cancer, non-small cell lung cancer (NSCLC), breast cancer, triple negative breast cancer, stomach cancer, head and neck Cancer, colon cancer, colorectal cancer, rectal cancer, mesothelioma, pancreatic cancer, brain tumor,
Useful for treating (glioblastoma polymorphism or metastasis), or cancer from the group of ovarian cancer.

In a further aspect, the method further comprises, or consists essentially of, or even further comprises administering an effective amount of a second chemotherapeutic agent. Non-limiting examples described herein include, for example, oxaliplatin, paclitaxel, taxol, taxane, 5
-One or more of fluoropyrimidine (5-FU), vinorelbine, or gemcitabine, and their equivalents.

The method can be used as a first line, second line, or third line therapy for a patient. In one aspect, the patient has previously undergone surgical resection and / or radiation therapy. In a further aspect, the patient has been previously treated with first-line oxaliplatin therapy.

In one aspect, Lipoplatin is administered with paclitaxel or its equivalent. In another aspect, Lipoplatin is administered with 5-FU or an equivalent thereof. In another aspect, Lipoplatin is administered with gemcitabine or an equivalent thereof. In one aspect, treatment is administered as a first or second line therapy. In another aspect, treatment is administered as a second or third line therapy.

Any suitable route of administration is acceptable and can be determined by the treating physician. Non-limiting examples include intravenous or inhalation therapy.

In one embodiment of the present invention, the second chemotherapeutic agent is a DNA alkylating agent that attaches an alkyl group to DNA. Such agents are well known in the art and are used to treat various tumors. Non-limiting examples of DNA alkylating agents include nitrogen mustards such as mechlorethamine, cyclophosphamide (ifosfamide, trophosphamide), chlorambucil (melphalan, prednisotin), bendamustine, uramustine, and estramustine; nitrosoureas such as , Carmustine (BCNU), lomustine (semstine), hotemstin, nimustine, ranimustine, and streptozocin; alkyl sulfonates such as busulfan (mannosulfan, treosulphan); aziridines such as carbocon, ThioTEPA, triadicon, tri Ethylene melamine, etc .; Hydrazine (procarbazine); Triazenes, such as dacarbazine and temozolomide; Altretamine and Mitob Is Nitoru.

In another aspect of the present invention, the second anticancer drug is a platinum-based compound that is a subclass of a DNA alkylating agent. Such agents are well known in the art and are various cancers such as
It is used to treat lung cancer, head and neck cancer, ovarian cancer, colorectal cancer, and prostate cancer. Non-limiting examples of such agents include carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatin tetranitrate, satraplatin, alloplatin,
There are donkey platin and JM-216. (McKeage et al. (1997) J. Cli.
n. Oncol. 201: 1232-1237, and in general, Series Ba
sic and Clinical Oncology, edited by Angioli et al., 2004
CHEMOTHERAPY FOR GYNECOLOGICAL NEOPL
ASM, CURRENT THERAPY AND NOVEL APPROACHES
See).

“Oxaliplatin” (Eloxatin®) is a platinum-based chemotherapeutic agent within the same family as cisplatin and carboplatin. It is generally administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX to treat colorectal cancer. Compared to cisplatin, two amine groups are replaced by cyclohexyldiamine for improved antitumor activity. Chlorine ligands have been replaced by oxalate bidentate ligands derived from oxalic acid to improve water solubility. Oxaliplatin equivalents are known in the art and include, without limitation, cisplatin, carboplatin, alloplatin, lobaplatin, nedaplatin, and JM-216 (McKeage et al. (1997) J. Clin. Oncol., 2
01: 1232-1237, and in general, Series Basic and Cl
CHEMOT in inical Oncology, Angioli et al., 2004
HERAPY FOR GYNECOLOGICAL NEOPLASM, CURREN
T THERAPY AND NOVEL APPROACHES).

In one aspect of the invention, the second chemotherapeutic agent is a topoisomerase inhibitor that is an agent that interferes with the action of topoisomerase enzymes (topoisomerase I and II). Topoisomerase catalyzes the destruction and rejoining of the phosphodiester backbone of DNA by catalyzing D
It is an enzyme that controls changes in the NA structure. Such agents are well known in the art. Non-limiting examples of topoisomerase I inhibitors include Pommier (2006) Nat. Re
v. Cancer 6 (10): 789-802 and US Patent Application No. 2005/02.
CPT-11 / Irinotecan, SN-38, APC, NP described in No. 50854
C, camptothecin, topotecan, exatecan mesylate, 9-nitrocamptothecin,
9-aminocamptothecin, luruthecan, rubitecan, silatecan, gimatecan, difurotecan, exatecan, BN-80927, DX-8951f, and MAG-CP
Camptothecin derivatives including T; Li et al. (2000) Biochemistry, 39
(24): 7107-7116 and Gatto et al. (1996) Cancer Res.
. 15 (12): protoberberine alkaloids and their derivatives, including berberbin and coralin, described on pages 2795-2800; Makhey et al. (2003) B
ioorg. Med. Chem. 11 (8): Phenanthroline derivatives including benzo [i] phenanthridine, nitidine, and fagaronine described on pages 1809-1820; Xu (1998) Biochemistry, 37 (10): 3558-356.
Terbenzimidazole and its derivatives described on page 6; and Fogles
ong et al. (1992) Cancer Chemother. Pharmacol. 30 (
2): 123-125, Crow et al. (1994) J. MoI. Med. Chem. 37 (19)
3191-3194, and Crespi et al. (1986) Biochem. Biop
hys. Res. Commun. 136 (2): There are anthracycline derivatives including doxorubicin, daunorubicin, and mitoxantrone described on pages 521-8.

In one aspect of the invention, the topoisomerase I inhibitor is, but is not limited to, Pomm.
ier (2006) Nat. Rev. Cancer 6 (10): 789-802 and CPT-11 / irinotecan, SN-38, APC, NPC, camptothecin, topotecan, exatecan mesylate, 9-nitrocamptothecin described in US Patent Application No. 2005/0250854 9-aminocamptothecin, luruthecan, rubitecan, cilatecan, gimatecan, difurotecan, exatecan, BN-80927, DX-
8951f and camptothecin derivatives including MAG-CPT; Li et al. (2000)
Biochemistry 39 (24): 7107-7116 and Gatto et al. (
1996) Cancer Res. 15 (12): protoberberine alkaloids and their derivatives, including berberbin and coralin, as described on pages 2795-2800; Makhey et al. (2003) Bioorg. Med. Chem. 11 (8): 1809
Phenanthroline derivatives including benzo [i] phenanthridine, nitidine, and fagaronine described on pages -1820; Xu (1998) Biochemistry
37 (10): 3558-3666, terbenzimidazole and its derivatives; and Foglesong et al. (1992) Cancer Chemote.
r. Pharmacol. 30 (2): 123-125, Crow et al. (1994) J. MoI.
Med. Chem. 37 (19): 3191-3194, and Crespi et al. (1
986) Biochem. Biophys. Res. Commun. 136 (2): 52
To treat patients identified with appropriate genetic markers, which can be selected from the anthracycline-induced group, including doxorubicin, daunorubicin, and mitoxantrone, described on pages 1-8. It will be used in combination therapy with systemic chemotherapy.

Irinotecan (CPT-11) is sold under the trade name Camptosar®. It is activated by hydrolysis to SN-38 and is a semisynthetic analog of the alkaloid camptothecin that targets topoisomerase I. The chemical equivalent is
Inhibiting the interaction of topoisomerase I and DNA to produce catalytically active topoisomerase I-DN
A complex is formed. Chemical equivalents inhibit cell cycle progression in the G2-M phase, resulting in disruption of cell proliferation.

In another aspect, several second types such as, but not limited to, anthracyclines (aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin), and anthracenedione (mitoxantrone and pixantrone) The chemotherapeutic agent inhibits topoisomerase II and has DNA intercalation activity.

In one aspect of the invention, topoisomerase II inhibitors include, but are not limited to,
There are etoposide and teniposide.

In another aspect of the invention, the second chemotherapeutic agent is, but is not limited to, sintopine and other naphthacenediones, DACA and other acridine-4-carboxamides, intopricin and other benzopyridoindoles, TAS- 103 and other 7H-indeno [2,1-c] quinolin-7-ones, pyrazoloacridine, XR11576 and other benzophenazines, XR5944 and other dimeric compounds, and Denny and B
aguley (2003) Curr. Top. Med. Chem. 3 (3): 339-3
A dual topoisomerase I and II inhibitor selected from the group of anthracenyl-amino acid conjugates described on page 53. In one aspect, they can be used in combination therapy with the antibody-based chemotherapy described above to treat patients identified with appropriate genetic markers.

“Lapatinib” (Tykerb®) is an oncolytic dual EGFR and erbB-2 inhibitor. Lapatinib has been investigated in several clinical trials as an anticancer monotherapy and in combination with trastuzumab, capecitabine, letrozole, paclitaxel, and FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin). It is currently in Phase III trials for oral treatment of metastatic breast, head and neck, lung, stomach, kidney, and bladder cancer.

The chemical equivalent of lapatinib is a small molecule or compound that is a tyrosine kinase inhibitor, or a HER-1 or HER-2 inhibitor. Some TKIs have been found to have effective anti-tumor activity and have been approved or are in clinical trials. Examples of this include, but are not limited to, Zakutima (ZD6474),
Iressa (gefitinib), Tarceva (erlotinib), Imatinib mesylate (
STI571; Gleevec), erlotinib (OSI-1774; Tarceva), caneltinib (CI 1033), cemaxinib (SU5416), batalanib (PTK787 /
ZK222584), Sorafenib (BAY 43-9006), Sutent (SU11)
248), and leflunomide (SU101).

The biological equivalent of lapatinib is a peptide, antibody, or antibody derivative thereof that is a HER-1 inhibitor and / or HER-2 inhibitor. Examples of such include, but are not limited to, the humanized antibodies trastuzumab and herceptin.

In another aspect of the invention, the second chemotherapeutic agent is an antimetabolite that inhibits the use of a metabolite, ie, another chemical that is part of normal metabolism. In cancer treatment, antimetabolites are
It interferes with DNA production and thus cell division and tumor growth. Non-limiting examples of these agents include folic acid, ie dihydrofolate reductase inhibitors, such as aminopterin, methotrexate, and pemetrexed; thymidylate synthase inhibitors, such as raltitrexed, pemetrexed, etc .; purines, ie Adenosine deaminase inhibitors such as pentostatin, halogenated / ribonucleotide reductase inhibitors such as thiopurines such as thioguanine and mercaptopurine such as cladribine, clofarabine,
Fludarabine, or guanine / guanosine, etc .: thiopurine, such as thioguanine; or pyrimidines, ie cytosine / cytidine: hypomethylating agents, eg, DNA polymerase inhibitors, such as cytarabine, such as azacitidine and decitabine, For example, gemcitabine or thymine / thymidine etc .: thymidylate synthase inhibitors such as fluorouracil (5-FU).

Fluorouracil (5-FU) belongs to a family of therapeutic agents called pyrimidine antimetabolites. 5-FU is converted into various cytotoxic metabolites, which in turn are DNA
And is incorporated into RNA, thereby inducing cell cycle arrest and apoptosis. This is a pyrimidine analog that is converted into various cytotoxic metabolites that are then incorporated into DNA and RNA, thereby inducing cell cycle arrest and apoptosis. A chemical equivalent is a pyrimidine analog that results in the disruption of DNA replication. Chemical equivalents inhibit cell cycle progression in the S phase, leading to cell cycle disruption and thus apoptosis. Equivalents to 5-FU include its prodrugs, analogs, and derivatives, such as Papamicheal (1999) The Oncologist.
4: 478-487, for example, as described in 5'-deoxy-5-fluorouridine (doxyfluridine), 1-tetrahydrofuranyl-5-fluorouracil (ftoflur), capecitabine (Xeloda), S-1 (tegafur, and There are two modulators, MBMS-247616 consisting of 5-chloro-2,4-dihydroxypyridine and potassium oxonate), raltitrexed (Tomdex), noratrexed (Timitac, AG337), LY231514, and ZD9331.

Capecitabine and tegafur are examples of chemical equivalents of 5-FU. This is a pathway of three enzymatic steps, as well as two intermediate metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFU).
After R), it is converted to its active form by the tumor-specific enzyme PynPase (5FU)
Is a prodrug. Capecitabine is a Rache under the trade name Xeloda®.
Sold by.

Leukovorin (folinic acid) is an adjuvant used in cancer therapy. This is used in a synergistic combination with 5-FU to improve the efficacy of chemotherapeutic agents. Without being bound by theory, adding leucovorin is thought to enhance the efficacy of 5-FU by inhibiting thymidylate synthase. It has been used as an antidote to protect normal cells from high doses of the anticancer drug methotrexate and to increase the antitumor effects of fluorouracil (5-FU) and tegafur-uracil. This is also known as citrobolum factor and welcovorin. This compound is composed of L-glutamic acid N- [
4-[[(2-Amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl) methyl] amino] benzoyl], calcium salt (1: 1) Has a chemical name.

Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vinflunine, vindesine, and vinorelbine.

Examples of taxanes include, but are not limited to, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel. An example of epothilone is ixabepilone.

Examples of enzyme inhibitors include, but are not limited to, farnesyl transferase inhibitors (tipifarnib); CDK inhibitors (arbocidib, celiccrib); proteasome inhibitors (bortezomib); phosphodiesterase inhibitors (anagrelide); IMP dehydrogenase inhibitors (Thiazofurin); and a lipoxygenase inhibitor (masoprocol).

Examples of tyrosine kinase inhibitors include, but are not limited to, ErbB: HER1 /
EGFR (erlotinib, gefitinib, lapatinib, vandetanib, sunitinib, neratinib); HER2 / neu (lapatinib, neratinib); RTK class III: C-k
it (Axitinib, Sunitinib, Sorafenib); FLT3 (Restaurtinib); P
DGFR (axitinib, sunitinib, sorafenib); and VEGFR (vandetanib, cemaxanib, cediranib, axitinib, sorafenib); bcr-abl (imatinib, nilotinib, dasatinib); Src (bostinib kinase) and 2
(Restaurtinib).

PTK / ZK is a VEGF receptor (VEGFR), a platelet derived growth factor (PD)
GF) “Small” molecule tyrosine kinase inhibitors with broad specificity targeting the receptors, c-KIT, and c-Fms. Drevs (2003) Idrugs 6 (8): 7
87-794. PTK / ZK is expressed as VEGFR-1 (Flt-1), VEGFR-2 (K
DR / Flk-1), and targeted drugs that block angiogenesis and lymphangiogenesis by inhibiting the activity of all known receptors that bind to VEGF, including VEGFR-3 (Flt-4) is there. The chemical name of PTK / ZK is 1- [4-chloroanilino] -4- [
4-pyridylmethyl] phthalazine succinate, or 1-phthalazineamine, N- (4
-Chlorophenyl) -4- (4-pyridinylmethyl)-, butanedioate (1: 1). Synonyms and analogs for PTK / ZK are Batalanib, CGP79787D, PTK
787 / ZK222584, CGP-79787, DE-00268, PTK-787,
PTK-787A, VEGFR-TK inhibitor, ZK222584, and ZK.

Additional examples of second chemotherapeutic agents and combination therapies include, but are not limited to, amsacrine, trabectadine, retinoids (aritretinoin, tretinoin), arsenic trioxide, asparagine depleter (asparaginase / pegaspargase) ), Celecoxib, demecorsin, elescromol, elsamitrucin, etoglucid, lonidamine, lucantone, mitoguazone, mitotane, oblimersen, temsirolimus, and vorinostat.

“FOLFOX” is a type of abbreviation that is used to treat colorectal cancer. This includes 5-FU, oxaliplatin, and leucovorin. Information on this procedure can be found at the National Cancer Institute website, cancer., Last accessed on January 16, 2008. It is available at gov.

“FOLFOX / BV” is a type of abbreviation that is used to treat colorectal cancer. This therapy includes 5-FU, oxaliplatin, leucovorin, and bevacizumab. In addition, “XELOX / BV” is another combination therapy used to treat colorectal cancer, which is a combination of 5-FU known as capecitabine (Xeloda) in combination with oxaliplatin and bevacizumab. Includes prodrugs. Information on these treatments can be found at the National Cancer Institute website, cancer. Gov, or the website of the National Comprehensive Cancer Information Network last accessed on May 27, 2008, nccn. org.

Examples of second chemotherapeutic or anti-cancer drugs including therapeutic antibodies include, but are not limited to, anti-HER1 / EGFR (cetuximab, panitumumab); anti-HER2 / neu (er
bB2) Receptor (Trastuzumab); Anti-EpCAM (Katsumaxomab, Edrecolomab)
Anti-VEGF-A (bevacizumab); anti-CD20 (rituximab, tositumomab, ibritumomab); anti-CD52 (alemtuzumab); and anti-CD33 (gemtuzumab), and their biological equivalents.

Bevacizumab is sold by Genentech under the trade name Avastin. This is a humanized monoclonal antibody that binds to human vascular endothelial growth factor (VEGF) and inhibits its biological activity. A biologically equivalent antibody binds to the same epitope of the modified antibody and antigen and prevents the interaction of VEGF with its receptor (Flt01, KDR aka VEGFR2) and provides a substantially equivalent response, eg, Identified herein as resulting in a block of endothelial cell proliferation and angiogenesis.

In one aspect, a “chemical equivalent” is a target protein, DNA, RNA, or as measured by inactivation of a target protein, incorporation of a chemical into DNA or RNA, or other suitable method It means the ability of a chemical to selectively interact with these fragments. A chemical equivalent includes, but is not limited to, an agent having the same or similar biological activity, and without limitation, interacts with the same target protein, DNA, or RNA as the reference chemical, and / or A pharmaceutically acceptable salt or mixture thereof that inactivates them is included.

In one aspect, “biological equivalent” means the ability of an antibody to selectively bind to its epitope protein or fragment thereof as measured by ELISA or other suitable method. Biologically equivalent antibodies include, but are not limited to, antibodies, peptides, antibody fragments, antibody variants, antibody derivatives, and antibody mimetics that bind to the same epitope as the reference antibody. An example of an equivalent bevacizumab antibody is one that binds to human vascular endothelial growth factor (VEGF) and inhibits its biological activity.

A kit comprising Lipoplatin alone or in combination with a second or other chemotherapeutic agent, or anticancer agent (described above), and, optionally, instructions for performing the method of the present disclosure is also applicable to Applicants. Provided by.

Experimental Materials and Methods Lipoplatin ™
Lipoplatin ™ is a therapeutic composition and its method of preparation is described in US Pat. No. 7,393,478, incorporated herein by reference. Briefly, for completeness, Lipoplatin is (step A) cisplatin (
(In powder or other form) DPPG (dipalmitoylphosphatidylglycerol), or other negatively charged lipid molecule, and at least 30% ethanol, 0.1 M Tris
It can be prepared by mixing in a solution of HCl, pH 7.5, in a molar ratio of 1: 1 to 1: 2. Changing the molar ratio between cisplatin and DPPG is also of therapeutic value targeting different tissues. In step (B), the composition is heated to 50 ° C. During steps A and B, the initial powder suspension that tends to give a precipitate of yellow cisplatin powder is converted to a gel (colloid) form; during steps A and B, the positive charge of cisplatin And is converted to its aqueous form, which is the active form of cisplatin conferred with antineoplastic activity (by hydrolysis of chlorine atoms and their exchange by water molecules bound to platin); aquacisplatin At the same time complexed with negatively charged lipids into micelles in 30% ethanol. This cisplatin-DPPG electrostatic complex is
Has already improved properties for free cisplatin in tumor eradication (step C
). The properties of the complex (and below in the final formulation after Step D) in passing through the tumor cell membrane after reaching its target is improved by the addition of peptides and other molecules that give this property to the complex. (Step D). The cisplatin-DPPG micelle complex is prepared by adding preformed liposomes directly, followed by dialysis against saline and extruding through a membrane to miniaturize them to a diameter of 100-160 nm.
PPG—on liposomes encapsulating monolayers (see above FIG. 1 of US Pat. No. 7,393,478) or to other types of complexes (FIG. 7 of US Pat. No. 7,393,478) Under 1)
Converted. This is the lipid composition of the added liposomes that determines the composition of the outer surface of our final cisplatin formulation. The modification of step (A) enables the encapsulation of doxorubicin and other positively charged antineoplastic compounds. Adding positively charged groups to neutral or negatively charged compounds makes it possible to encapsulate them in liposomes as well.

Sixteen patients with lung cancer, 10 patients with gastrointestinal cancer, and 16 patients with bladder cancer were mobilized for the study. All 16 bladder cancer patients had renal failure (creatinine level 1.6-4.0 mg / dl). For patients with lung cancer, Lipopl
Patients given atin and paclitaxel (as second or third line treatment) and patients with gastrointestinal cancer are given Lipoplatin and 5-FU (as second or third line treatment), while all 16 bladder cancers Patients were given Lipoplatin and gemcitabine as first or second line treatment.

Chemotherapeutic regimens containing cisplatin are known to increase serum creatinine due to nephrotoxicity. In contrast, Lipoplatin did not cause any increase in creatinine levels in any of the patients treated in this study. More importantly, in 10/16 bladder cancer patients with renal failure, blood urea and serum creatinine levels decrease towards normal levels, which decreases with urination
observed in these patients who had ion obstruction), and the disorder returned to normal after treatment.

The lack of increased creatinine in response to the Lipoplatin containing regimen occurred without dialysis for all 42 patients. Thus, the results of this study are consistent with the very low nephrotoxicity profile of Lipoplatin recorded in previous clinical trials. Furthermore, this result spans the favorable nephrotoxicity profile of Lipoplatin in patients with renal failure and suggests that Lipoplatin can be the optimal cisplatin in this patient population.

As expected, some toxicity, grade 1 & 2, myelotoxicity was observed in this study, which was mild and did not require the use of growth factors. Regarding efficacy, complete response was observed in 5 patients with bladder cancer and partial response was observed in 15 patients (8 with bladder cancer, 2 with NSCLC, and gastrointestinal cancer) 5)
Stable disease was observed in 14 patients (3 with bladder cancer, 6 with NSCLC, and 5 with gastrointestinal cancer). Only 8 of 42 patients had progressive disease.

Thus, although the present disclosure has been specifically disclosed by means of preferred embodiments and optional features, modifications, improvements, and changes to the disclosures embodied therein are disclosed herein.
It should be understood that such alterations, improvements, and changes can be considered by those skilled in the art to be within the scope of this disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

The present disclosure has been described broadly and generically herein. Each of the narrower species and subclass classifications that fall within the general disclosure also form part of this disclosure. This includes the general description of the present disclosure, with conditions or negative limitations removing any subject matter from the class, whether or not the deleted material is specifically listed herein. .

Further, where a feature or embodiment of the present disclosure is described in terms of a Markush group, one of ordinary skill in the art will be able to describe the present disclosure accordingly in terms of any individual member or subgroup of members. You will recognize that.

All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. Yes. In case of conflict, the present specification, including definitions, will control.

Claims (6)

A method for inhibiting the growth of a tumor in a cancer patient having renal failure or treating the cancer patient, wherein an effective amount of Lipoplatin is administered to the patient, thereby reducing the growth of the tumor. Inhibiting or treating the cancer.   2. The method of claim 1, further comprising administering an effective amount of a second chemotherapeutic agent. The second chemotherapy may be before or after the Lipoplatin therapy, or Lip
The method of claim 2, wherein the method is administered concurrently with oplatin therapy. The tumor or cancer is metastatic or non-metastatic lung cancer, digestive cancer, bladder cancer, non-small cell lung cancer (NSCLC), breast cancer, triple negative breast cancer, stomach cancer, head and neck cancer, colon cancer Of colorectal cancer, rectal cancer, mesothelioma, pancreatic cancer, brain tumor, (glioblastoma polymorphism or metastasis), or ovarian cancer The method according to any one. Kit comprising Lipoplatin and instructions for the method according to any one of claims 1 to 4. 6. The kit according to claim 5, further comprising a second chemotherapeutic agent.