This invention pertains to a method of treating cancer and genetic diseases, particularly for the suppression or eradication of bone marrow, and to compositions having as their active ingredient a radionuclide complexed with a macrocyclic aminophosphonic acid.
The use of agents which cause partial or total suppression or eradication of the bone marrow has become an accepted part of some procedures used to treat patients with cancers such as leukemias, lymphomas, myelomas and Hodgkin's disease as well as in the treatment of patients suffering from genetic disorders such as sickle cell anemia and thalassemia.
For example, in the treatment of patients having acute lymphoblastic leukemia and acute nonlymphoblastic leukemia, it is sometimes beneficial to employ a therapy regimen which combines chemotherapy using drugs, such as cyclophosphamide, bischloroethyl nitrosourea, cytosine arabinoside, 6-thioguanine and the like, and total body irradiation, followed by bone marrow transplantation.
In situations where the patient is suffering from a genetic disability such as thalassemia or sickle cell anemia, bone marrow transplantation may offer the possibility of a cure. In thalassemia, the afflicted individual has a genetic disorder causing the production of an abnormal hemoglobin and is only able to survive by repeated blood transfusions. Nonetheless, children afflicted with thalassemia major rarely survive to adulthood. In sickle cell anemia, the individual produces an abnormal hemoglobin (i.e., hemoglobin S). The individual homozygous for hemoglobin S has red blood cells that assume a sickle shape at ordinary oxygen tensions. These sickled red blood cells encounter mechanical difficulties in moving through small blood vessels which can lead to thromboses and tissue anoxia.
The use of radionuclides for bone marrow suppression with a phosphonic acid ligand is discussed in published European patent application 291,605 where the use of Sm-153, Gd-159, or Ho-166 complexed with a ligand selected from ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylenetriaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), or tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP) is disclosed.
Bone marrow transplantation offers the possibility of eradicating the afflicted individual's defective bone marrow and replacing it with a normal, nonpathogenic, bone marrow. If the abnormal bone marrow of an individual suffering from sickle cell anemia or thalassemia can be eradicated and then replaced with a bone marrow which takes and is reproduced and capable of producing normal hemoglobin, the individual may be cured.
For those situations where bone marrow transplantation can aid in therapy or cure, it would be desirable to have a means of selectively suppressing the bone marrow independent of or with limited total body irradiation.
The present invention is directed to a method for the suppression of bone marrow and to a composition for use in the method. The method comprises administering to a mammal in need of such treatment a bone marrow suppressing amount of at least one composition comprised of a radionuclide complexed with a macrocyclic aminophosphonic acid containing 1,4,7,10-tetraazacyclododecane as the macrocyclic moiety. The method of bone marrow suppression described herein may be used in combination with chemotherapeutic drugs and/or external radiation.
The present invention has significant benefits in that it permits selective bone marrow suppression, that is, the bone marrow can be suppressed with only minimal damage to non-target soft tissues, for example, liver and kidney. Selective bone marrow suppression offers the opportunity to pursue particular treatment regimens which would otherwise be unavailable due to the concerns of excessive non-target soft tissue damage, for example, when total body irradiation is the sole or primary means of obtaining bone marrow suppression. Using the present invention for obtaining bone marrow suppression reduces the risk to the patient since the damage to non-target soft tissue is significantly reduced thereby promoting the general health of the patient and enhancing the prospect of the patient's recovery.