TRANSIENT PROTECTION OF NORMAL CELLS DURING CHEMOTHERAPY
This invention is in the area of improved compounds, compositions and methods of transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, improved protection of healthy cells is disclosed using disclosed compounds that act as highly selective and short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.
1 . A method of treating a human with triple negative breast cancer (TNBC) in need thereof comprising: administering to the human an effective amount of a selective CDK4/6 inhibitor of structure:
or a pharmaceutically acceptable salt thereof; and, administering to the human an effective amount of a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, gemcitabine, paclitaxel, doxorubicin, cyclophosphamide, and a combination thereof,
wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
2 . The method of claim 1 , wherein the chemotherapeutic agent is carboplatin.
3 . The method of claim 1 , wherein the chemotherapeutic agent is cisplatin.
4 . The method of claim 1 , wherein the chemotherapeutic agent is paclitaxel.
5 . The method of claim 1 , wherein the chemotherapeutic agent is doxorubicin.
6 . The method of claim 1 , wherein the chemotherapeutic agent is cyclophosphamide.
7 . The method of claim 1 , wherein the chemotherapeutic agent is gemcitabine.
8 . A method of reducing chemotherapy-induced myelosuppression in a human receiving chemotherapy for the treatment of bladder cancer comprising administering to the human an effective amount of at least one DNA damaging chemotherapeutic agent and an effective amount of a CDK4/6 inhibitor of structure:
or a pharmaceutically acceptable salt thereof; wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the DNA damaging chemotherapeutic agent.
9 . The method of claim 8 , wherein the CDK4/6 inhibitor is administered 1/2 hour or less prior to administration of the DNA damaging chemotherapeutic agent.
10 . The method of claim 8 , wherein the chemotherapeutic agent is administered to the human on day 1 every 21 days.
11 . The method of claim 8 , wherein the DNA damaging chemotherapeutic agent is administered to the human on days 1 and 8 every 21 days.
12 . The method of claim 8 , wherein the DNA damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, campothecin, doxorubicin, gemcitabine, and etoposide.
13 . The method of claim 12 , wherein the DNA damaging chemotherapeutic agent is cisplatin.
14 . The method of claim 12 , wherein the DNA damaging chemotherapeutic agent is carboplatin.
15 . The method of claim 12 , wherein the DNA damaging chemotherapeutic agent is campothecin.
16 . The method of claim 12 , wherein the chemotherapeutic agent is doxorubicin.
17 . The method of claim 12 , wherein the chemotherapeutic agent is gemcitabine.
18 . The method of claim 12 , wherein the chemotherapeutic agent is etoposide.