Combination chemotherapy

Abstract

This invention relates to combination chemotherapy, particularly involving vitamin D or a derivative thereof. In one aspect, the invention provides a method of killing a cell by first administering to the cell vitamin D (or a derivative) and subsequently administering to the cell a cytotoxic agent. Where this strategy is applied to an intact tumor, the present invention provides a method of retarding the growth of the tumor by first administering vitamin D (or a derivative) to the tumor and subsequently administering the cytotoxic agent. A further aspect of the invention concerns a method of treating prostate cancer within a patient by co-administration of vitamin D (or a derivative) and a glucocorticoid to the patient. In yet a further aspect, the invention provides an improved method of treating a patient with vitamin-D involving the adjunctive administration of zoledronate.

1 . A method of killing a cell within a patient comprising the steps of (a) first administering to a cell within the patient vitamin D or a derivative thereof and (b) subsequently administering at least one cytotoxic agent to the cell, wherein the cell is susceptible to said steps (a) and (b).  
     
     
         2 . The method of  claim 1 , wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.  
     
     
         3 . The method of  claim 2 , wherein the glucocorticoid is dexamethasone.  
     
     
         4 . The method of  claim 2 , wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.  
     
     
         5 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.  
     
     
         6 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.  
     
     
         7 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.  
     
     
         8 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D 3 .  
     
     
         9 . The method of  claim 8 , wherein the analog is Ro23-7553 or Ro24-5531.  
     
     
         10 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is 1,25D 3 .  
     
     
         11 . The method of  claim 1 , wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μg and about 15 μg.  
     
     
         12 . The method of  claim 11 , wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μg and about 12 μg.  
     
     
         13 . The method of  claim 1 , wherein the cytotoxic agent selectively acts on cells in the G 0 -G 1  phase of the cell cycle.  
     
     
         14 . The method of  claim 1 , wherein the cytotoxic agent is a platinum-based cytotoxic agent.  
     
     
         15 . The method of  claim 1 , wherein the cytotoxic agent is a glucocorticoid.  
     
     
         16 . The method of  claim 1 , wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.  
     
     
         17 . The method of  claim 1 , wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.  
     
     
         18 . The method of  claim 1 , wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m 2 .  
     
     
         19 . The method of  claim 1 , wherein said cytotoxic agent is docetaxel.  
     
     
         20 . The method of  claim 1 , wherein the vitamin D or a derivative thereof is 1,25D 3  and wherein said cytotoxic agent is docetaxel.  
     
     
         21 . The method of  claim 1 , further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.  
     
     
         22 . A method of retarding the growth of a tumor within a patient comprising the steps of (a) first administering to the tumor within the patient a vitamin D or a derivative thereof and (b) subsequently administering to the tumor at least one cytotoxic agent, wherein the cell is susceptible to said steps (a) and (b).  
     
     
         23 . The method of  claim 22 , wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.  
     
     
         24 . The method of  claim 23 , wherein the glucocorticoid is dexamethasone.  
     
     
         25 . The method of  claim 23 , wherein the patient is human and the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.  
     
     
         26 . The method of  claim 22 , wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.  
     
     
         27 . The method of  claim 22 , wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.  
     
     
         28 . The method of  claim 22 , wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.  
     
     
         29 . The method of  claim 22 , wherein the vitamin D derivative is a nonhypercalcemic analog of 1,25D 3 .  
     
     
         30 . The method of  claim 29 , wherein the analog is Ro23-7553 or Ro24-5531.  
     
     
         31 . The method of  claim 22 , wherein the vitamin D derivative is 1,25D 3 .  
     
     
         32 . The method of  claim 22 , wherein the patient is human and the daily dose of the vitamin D or a derivative thereof is between about 4 μg and about 15 μg.  
     
     
         33 . The method of  claim 32 , wherein the daily dose of the vitamin D or a derivative thereof is between about 8 μg and about 12 μg.  
     
     
         34 . The method of  claim 22 , wherein the cytotoxic agent selectively acts on cells in the G 0 -G 1  phase of the cell cycle.  
     
     
         35 . The method of  claim 22 , wherein the cytotoxic agent is a platinum-based cytotoxic agent.  
     
     
         36 . The method of  claim 22 , wherein the cytotoxic agent is a glucocorticoid.  
     
     
         37 . The method of  claim 22 , wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.  
     
     
         38 . The method of  claim 22 , wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.  
     
     
         39 . The method of  claim 22 , wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m 2 .  
     
     
         40 . The method of  claim 22 , wherein said cytotoxic agent is docetaxel.  
     
     
         41 . The method of  claim 22 , wherein said vitamin D or a derivative thereof is 1,25D 3  and wherein said cytotoxic agent is docetaxel.  
     
     
         42 . The method of  claim 22 , further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.  
     
     
         43 . A method of treating a human patient with vitamin D or a derivative thereof, wherein the patient has a condition responsive to vitamin D and a cytotoxic agent, comprising the steps of (a) first administering to the patient vitamin D or a derivative thereof and (b) subsequently administering to the patient at least one cytotoxic agent, wherein the dose of the vitamin D or a derivative thereof exceeds 1 μg/day.  
     
     
         44 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 4 μg/day.  
     
     
         45 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 8 μg/day.  
     
     
         46 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 12 μg/day.  
     
     
         47 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 18 μg/day.  
     
     
         48 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 30 μg/day.  
     
     
         49 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 40 μg/day.  
     
     
         50 . The method of  claim 43 , wherein the dose of vitamin D or a derivative thereof is at last about 50 μg/day.  
     
     
         51 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is administered orally.  
     
     
         52 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is administered intravenously.  
     
     
         53 . The method of  claim 43 , wherein step (a) further comprises the administration of a glucocorticoid concurrently with the vitamin D or a derivative thereof.  
     
     
         54 . The method of  claim 53 , wherein the glucocorticoid is dexamethasone.  
     
     
         55 . The method of  claim 53 , wherein the glucocorticoid is dexamethasone and is administered at a dosing schedule of between about 1 mg and 10 mg on alternative days.  
     
     
         56 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is administered from 1 to 3 days before the cytotoxic agent.  
     
     
         57 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is administered at least once daily for at least two successive days.  
     
     
         58 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is administered at least once daily on alternate days.  
     
     
         59 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is a nonhypercalcemic analog of 1,25D 3 .  
     
     
         60 . The method of  claim 59 , wherein the analog is Ro23-7553 or Ro24-5531.  
     
     
         61 . The method of  claim 43 , wherein the vitamin D or a derivative thereof is 1,25D 3 .  
     
     
         62 . The method of  claim 43 , wherein the cytotoxic agent selectively acts on cells in the G 0 -G 1  phase of the cell cycle.  
     
     
         63 . The method of  claim 43 , wherein the cytotoxic agent is a platinum-based cytotoxic agent.  
     
     
         64 . The method of  claim 43 , wherein the cytotoxic agent is a glucocorticoid.  
     
     
         65 . The method of  claim 43 , wherein the cytotoxic agent is carboplatin, cisplatin, dexamethasone, paclitaxel, or docetaxel.  
     
     
         66 . The method of  claim 43 , wherein the cytotoxic agent is carboplatin and is administered at a dose calculated to achieve AUC of about 5.  
     
     
         67 . The method of  claim 43 , wherein the cytotoxic agent is paclitaxel and is administered at a dose of about 80 mg/m 2 .  
     
     
         68 . The method of  claim 43 , wherein said cytotoxic agent is docetaxel.  
     
     
         69 . The method of  claim 43 , wherein said vitamin D or a derivative thereof is 1,25D 3  and wherein said cytotoxic agent is docetaxel.  
     
     
         70 . The method of  claim 43 , further comprising adjunctively administering at least one bisphosphonate selected from the group of bisphosphates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.  
     
     
         71 . A method of treating prostate cancer within a patient in need of such treatment comprising adjunctively administering vitamin D or a derivative thereof and a glucocorticoid to the patient.  
     
     
         72 . The method of  claim 71 , wherein the treatment is repeated.  
     
     
         73 . The method of  claim 71 , wherein the vitamin D or a derivative thereof and glucocorticoid are administered to the patient on alternative days between 2 and 4 times a week.  
     
     
         74 . The method of  claim 71 , wherein the glucocorticoid is administered to the patient prior to the administration of the vitamin D or a derivative thereof.  
     
     
         75 . The method of  claim 71 , wherein the glucocorticoid is administered to the patient following the administration of the vitamin D or a derivative thereof.  
     
     
         76 . The method of  claim 71 , wherein the vitamin D derivative is a nonhypercalcemic analog.  
     
     
         77 . The method of  claim 71 , wherein the vitamin D derivative is 1,25D 3 .  
     
     
         78 . The method of  claim 71 , wherein the glucocorticoid is selected from the group of glucocorticoids consisting of cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.  
     
     
         79 . The method of  claim 71 , wherein the glucocorticoid is dexamethasone.  
     
     
         80 . The method of  claim 71 , further comprising administering at least one bisphosphonate to the cell selected from the group of bisphosphonates consisting of alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronate.