Analogues of etoposide for the treatment of tumours

1. A method of treating a metastatic tumor in a subject, wherein the tumor has a multidrug-resistant phenotype that is mediated by MDR-1, and wherein said method comprises administering to the subject a compound of formula (I)

wherein X is selected from the group consisting of O, NH and S,

n is 0, 1 or 2, and

R 1 and R 2 are independently selected from the group consisting of H, methyl, and ethyl, or together form a group CR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H, methyl and ethyl.

2. The method of claim 1 , wherein said method comprises administering to a subject in need of such treatment a compound selected from the group consisting of

3. The method of claim 1 , wherein the subject is a human.

4. The method of claim 1 , wherein the tumor is resistant to treatment with a therapeutic protein or a chemotherapeutic drug exclusive of the compound of formula (I)

wherein X is selected from the group consisting of O, NH and S,

n is 0, 1 or 2, and

R 1 and R 2 are independently selected from the group consisting of H, methyl, and ethyl, or together form a group CR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H, methyl and ethyl.

5. The method of claim 1 , wherein the tumor is a solid tumor.

6. The method of claim 5 , wherein the tumor is selected from the group consisting of adenocarcinoma, hypopharynx cancer, lung cancer, diffuse large cell lymphoma, Burkitt's lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, histiocytic lymphoma, lymphatic lymphoma, acute T-cell leukemia, pre-B-acute lymphoblastic leukemia, gall bladder cancer, bile duct carcinoma, thymus carcinoma, urothelium carcinoma, testicular cancer, prostate cancer, bladder cancer, brain tumor, AIDS-related Kaposi's sarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, ovarian cancer, breast cancer, and unknown primary origin (CUP) syndrome.

7. The method of claim 1 , wherein the treatment leads to a stagnation of tumor growth or a remission of the tumor.

8. The method of claim 1 , wherein the tumor expresses at least one of CES1 and CES2.

9. The method of claim 8 , wherein a fraction of CES1 and/or CES2 expressing cells of the tumor is 50% or higher.

10. The method of claim 1 , further comprising administering to the subject a second therapeutic drug compound.

11. The method of claim 1 , wherein the metastatic tumor is resistant to etoposide treatment.

12. A method for treating a patient having a metastatic tumor, wherein the method comprises:

administering to the patient suffering from the metastatic tumor a compound of the formula:

wherein X is selected from the group consisting of O, NH and S, wherein

n is 0, 1 or 2, and wherein

R 1 and R 2 are independently selected from the group consisting of H, methyl, and ethyl, or together form a group CR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H, methyl and ethyl,

wherein the compound is administered at a daily dose of up to 350 mg/m 2 .

13. The method of claim 12 , wherein the metastatic tumor is resistant to etoposide treatment.

14. A method for treating a patient having a metastatic tumor, wherein the method comprises:

during a first period which is on consecutive days, administering to the patient suffering from the metastatic tumor a compound of the formula:

wherein X is selected from the group consisting of O, NH and S,

wherein n is 0, 1 or 2, and

wherein R 1 and R 2 are independently selected from the group consisting of H, methyl, and ethyl, or together form a group CR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H, methyl and ethyl,

not administering the compound during an intermittent period, and

administering the compound during a second period on consecutive days.

15. The method of claim 14 , wherein the metastatic tumor is resistant to etoposide treatment.

16. An in vitro method of selecting a patient having a metastatic tumor for treatment of the patient with the compound of formula (I)

wherein X is selected from the group consisting of O, NH and S,

n is 0, 1 or 2, and

R 1 and R 2 are independently selected from the group consisting of H, methyl, and ethyl, or together form a group CR 3 R 4 wherein R 3 and R 4 are independently selected from the group consisting of H, methyl and ethyl,

wherein the method comprises the steps of:

testing a sample from the tumor for expression of CES1 and/or CES2; and

selecting the patient when the testing indicates the expression of CES1 and/or CES2.

17. The method of claim 16 , wherein the patient is selected when a fraction of CES1 and/or CES2 expressing cells of the tumor is 50% or higher.

18. The method of claim 16 , wherein the metastatic tumor is resistant to etoposide treatment.