Combination chemotherapy

Abstract

This invention relates to combination chemotherapy, particularly involving vitamin D or a derivative thereof hi 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 last 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.