Combination of opioids and anticancer drugs for cancer treatment

Abstract

The invention relates to novel strategies for the treatment of cancer patients based on a combination of an opioid receptor agonist and an anticancer compound.

1 - 20 . (canceled) 
     
     
         21 . A combination of an opioid receptor agonist and at least one anticancer agent for use in the treatment of cancer, wherein
 (a) said opioid receptor agonist is administered to a patient in one or more doses to establish a therapeutically effective plasma level for a period of at least one week, and   (b) at least one anticancer agent that is selected from the group consisting of chemotherapeutical agents, cytotoxic agents, cytostatic agents, immunotoxic agents and radiotherapy, and is administered to establish a period with a therapeutically effective plasma level, and   (c) said periods of a) and b) overlap.   
     
     
         22 . The combination according  claim 21 , wherein said anticancer agent and said opioid receptor agonist are administered simultaneously or successively. 
     
     
         23 . The combination according  claim 21 , wherein said opioid receptor agonist is capable of inhibiting cell proliferation and/or inducing cell death. 
     
     
         24 . The combination according to  claim 21 , wherein the patient has received a pre-treatment comprising an anticancer agent. 
     
     
         25 . The combination according to  claim 21 , wherein the administration period for the opioid receptor agonist providing a therapeutically relevant dose is at least two weeks. 
     
     
         26 . The combination according to  claim 21  wherein the opioid receptor agonist is selected from the group consisting of:
 i. compounds of the methadone group selected from the group consisting of D/L-methadone, D-methadone, L-methadone, and normethadone; 
 ii. fentanyl derivatives selected from the group consisting of fentanyl, sufentanyl and carfentanyl; 
 iii. morphinane compounds selected from the group consisting of morphine, codeine, heroine, dextrallorphane, dextromethorphan, dextrophanol, dimemorfan, levalorphan, levofurethylnormorphanol, levomethorphane, levophenacylmorphane, levorphanol, methorphane, morphanol, oxilorphan, phenomorphan, and xorphanol; 
 iv. benzomorphane derivatives selected from the group consisting of 5,9-DEHB, alazocine, anazocine, bremazocine, butinazocine, carbazocine, cogazocine, cyclazocine, dezocine, eptazocine, etazocine, ethylketocyclazocine, fluorophen, gemazocine, ibazocine, ketazocine, metazocine, moxazocine, pentazocine, phenazocine, quadazocine, thiazocine, tonazocine, volazocine and 8-CAC; 
 v. 4-phenylpiperidine derivatives selected from the group consisting of pethidine, ketobemidone, anileridine, piminodine, phenoperidine, furethidine, alpha-prodin, trimeperidine, 4-phenylpyrrolidine derivatives, profadol, 4-phenylazepanderivates, and meptazinol; 
 vi. cyclohexane derivatives selected from the group consisting of tilidine, U-50488, tramadol and tapentadol; and 
 vii. endogenous opioids selected from the group consisting of endorphins, enkephalins, dynorphins, nociceptin, dermorphins, morphiceptin, endomorphines and fragments derived from the protein proopiomelanocortin (POMC). 
 
     
     
         27 . The combination according to  claim 21  wherein the opioid receptor agonist belongs to the methadone group. 
     
     
         28 . The combination according to  claim 27 , wherein the opioid receptor agonist is D/L methadone and the hydrochloride form thereof. 
     
     
         29 . The combination according to  claim 21  wherein the anticancer agent is selected from the group consisting of:
 i. intercalating substances selected from the group consisting of anthracycline, doxorubicin, idarubicin, epirubicin, and daunorubicin; 
 ii. topoisomerase inhibitors selected from the group consisting of irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticines and aurintricarboxylic acid; 
 iii. nitrosourea compounds selected from the group consisting of carmustine (BCNU), lomustine (CCNU), streptozocin; 
 iv. nitrogen mustards selected from the group consisting of cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid and ifosfamide; 
 v. alkyl sulfonates selected from the group consisting of busulfan and treosulfan; 
 vi. alkylating agents selected from the group consisting of procarbazin, dacarbazin, temozolomid and thiotepa; 
 vii. platinum analogues selected from the group consisting of cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate; 
 viii. Microtubule disruptive drugs selected from the group consisting of vinblastine, colcemid and nocodazole; 
 ix. antifolates selected from the group consisting of methotrexate, aminopterin, dichloromethotrexat, pemetrexed, raltitrexed and pralatrexate; 
 x. purine analogues selected from the group consisting of azathioprine, mercaptopurine, thioguanine, fludarabine, fludarabine phosphate, pentostatin and cladribine; 
 xi. pyrimidine analogues selected from the group consisting of 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine; 
 xii. steroid hormones selected from the group consisting of gestagene, androgene, glucocorticoids, dexamethasone, prednisolone, and prednisone; 
 xiii. anti-cancer antibodies selected from the group consisting of monoclonal antibodies, radioactively labeled antibodies and antibody-drug conjugates; 
 xiv. anti-cancer peptides selected from the group consisting of radioactively labeled peptides and peptide-drug conjugates; 
 xv. alpha, beta or gamma irradiation, electron particles, or radioactively labeled chemical compounds; and 
 xvi. Taxane and Taxane analogues selected from the group consisting of paclitaxel and docetaxel. 
 
     
     
         30 . The combination according to  claim 21  wherein the anticancer agent is methotrexate, cytarabine, cisplatin, temozolomide, etoposide, vincristine, thioguanine, gemcitabine, beta irradiation or gamma irradiation, and especially doxorubicin, cisplatin, oxaliplatin, rituximab or trastuzumab. 
     
     
         31 . The combination according to  claim 21  wherein patients suffer from a neoplasm as classified according the International statistical classification of Diseases and related health problems 10 th  Revision (ICD-10), and wherein the neoplasm is selected from the group consisting of malignant neoplasms of classes COO to C97, in situ neoplasms of classes D00 to D09, benign neoplasms of classes D10 to D36, and neoplasms of uncertain or unknown behaviour of classes D37 to D48. 
     
     
         32 . The combination according to  claim 31  wherein patients suffer from a neoplasm selected from the group consisting of pancreatic carcinoma, hepatoblastoma, colon carcinoma, (small cell lung cancer, melanoma, mamma carcinoma, ovarian carcinoma, prostate carcinoma, glioblastoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, pro-forms of leukemia, hairy cell leukemia, Hodgkin's disease, Non-Hodgkin lymphoma, glioblastoma-initiating stem cells, tumour stem cells and multiple myeloma. 
     
     
         33 . The combination according to  claim 21 , wherein the patient exhibits either an intrinsic or an acquired resistance. 
     
     
         34 . The combination according to  claim 33 , wherein the patient exhibits one or more of the subsequent resistances:
 i. apoptosis resistance;   ii. multi-drug resistance;   iii. anticancer drug resistance;   iv. cytotoxic drug resistance;   v. resistance to reactive oxygen species;   vi. resistance to DNA damaging agents;   vii. resistance to toxic antibodies;   viii. doxorubicin or rituximab resistance;   ix. cisplatin resistance;   x. temozolomide resistance;   xi. resistance to HER2 targeting therapy, selected from the group consisting of trastuzumab treatment   xii. single or cross resistance to one or more of the following drug substances: methotrexate, cytarabine, cisplatine, etoposide, vincristine, paclitaxel, carboplatin, cisplatin, oxaliplatin, gemcitabine, temozolomide, thioguanine, teniposide, dexamethasone, prednisolone, cyclophosphamide, diphosphamide, doxorubicin, epirubicin, idarubicin, daunorubicin, mercaptopurine and fludarabine; and   xiii. Irradiation resistance.   
     
     
         35 . The combination according to  claim 21 , wherein the anticancer agent is given at a dose equal to or lower than the recommended dose for the treatment of cancer using the anticancer agent only. 
     
     
         36 . The combination according to  claim 35 , wherein dose is 3 times lower than the recommended dose for the treatment of cancer using the anticancer agent only. 
     
     
         37 . The combination according to  claim 21 , wherein at least one additional opioid receptor agonist is administered to the patient. 
     
     
         38 . The combination according  claim 37 , wherein the opioid morphine is administered with the further opioid fentanyl to the patient. 
     
     
         39 . A method for selection of the combination according to  claim 21  and/or the doses of the drugs used within said combination comprising the following steps:
 (a) providing an vitro culture of cancer cells, cell lines or primary cells; 
 (b) optionally testing the cells from step (a) for expression of opioid receptors; 
 (c) treating the cells from step (a) with an opioid agonist, or at least one anticancer drug or a combination thereof; 
 (d) analysing the cells for cell death/viability and/or expression of opioid receptors 
 (e) selecting the opioid receptor/anticancer drug combination and preferably a dose for said combination based on the desired extent of cell death/viability or inhibition of proliferation; and/or 
 (f) selecting the anticancer agent and preferably a dose for said anticancer agent which shows the desired extent of induction of opioid receptors. 
 
     
     
         40 . A method for selection of an opioid receptor agonist for the treatment of cancer and a treatment dose for said opioid receptor agonist comprising the following steps
 (a) providing an vitro culture of cancer cells, cell lines or primary cells;   (b) optionally testing the cells from step (a) for expression of opioid receptors;   (c) treating the cells from step (a) with an opioid receptor agonist;   (d) analysing the cells for cell death/viability;   (e) selecting the opioid receptor/anticancer drug combination and preferably a dose for said combination based on the desired extent of cell death/viability or inhibition of proliferation; and/or   (f) selecting the opioid receptor agonist and preferably a dose for said opioid receptor agonist which shows the desired extent of induction of cell death.   
     
     
         41 . The combination according to  claim 21 , wherein the administration period for the opioid receptor agonist providing the therapeutically relevant dose is at least four weeks. 
     
     
         42 . The combination according to  claim 21 , wherein the administration period for the opioid receptor agonist providing the therapeutically relevant dose represents a chronic treatment. 
     
     
         43 . The combination according to  claim 35 , wherein the anticancer agent is given at a dose 30 times lower than the recommended dose for the treatment of cancer using the anticancer agent only. 
     
     
         44 . The combination according to  claim 35 , wherein the anticancer agent is given at a dose 100 times lower than the recommended dose for the treatment of cancer using the anticancer agent only. 
     
     
         45 . The method of  claim 39 , wherein said in vitro culture is isolated from a cancer biopsy or from a liquid sample selected from the group consisting of blood, amniotic fluid, pleural fluid, cerebrospinal fluid and peritoneal fluid. 
     
     
         46 . The method of  claim 40 , wherein said in vitro culture is isolated from a cancer biopsy or from a liquid sample selected from the group consisting of blood, amniotic fluid, pleural fluid, cerebrospinal fluid and peritoneal fluid.