Lomustine

Chemical compound
Lomustine (INN; abbreviated as CCNU; original brand name CeeNU, now marketed as Gleostine''') is an alkylating nitrosourea compound used in chemotherapy. It is closely related to semustine and is in the same family as streptozotocin. It is a highly lipid soluble drug, thus it crosses the blood–brain barrier. This property makes it ideal for treating brain tumors, which is its primary use, although it is also used to treat Hodgkin lymphoma as a second line option. It has also been used in veterinary practice as a treatment for cancers in cats and dogs. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. Lomustine is cell cycle nonspecific.

Lomustine is an alkylating chemotherapy drug that is indicated by the FDA for the treatment of patients with brain tumors (primary and metastatic), following any necessary surgery and radiation, as well as for treatment of progressive Hodgkin’s lymphoma. Lomustine is approved for the treatment of brain tumors, breast cancer, lung cancer, Hodgkin’s lymphoma, and melanoma by Health Canada. Lomustine is also used as an anti cancer drug in several European countries, including the United Kingdom.

While current data is only based on animal studies, there is reason to believe that lomustine use during pregnancy can cause harm to a fetus, potentially leading to miscarriages or birth defects. Patients are advised not to take lomustine while pregnant. Clinical trials have demonstrated the drug's success in treating progressive lymphomas, mast cell tumors, and brain cancers. The chemotherapy has also been used to treat sarcomas and spinal cord tumors in these animals. One dose of the drug is administered orally every 6 weeks, generally at a dosage of 130 mg/m2 for all patients. The dose may be lowered based on the patients blood counts and immune strength, but is still administered every 6 weeks.

Lomustine use is linked to a variety of organ toxicities hepatotoxicity, nephrotoxicity, and pulmonary toxicity. Only one dose of the drug is dispensed at a time to lower overdose risk. The first step in the synthesis of Lomustine is a fast reaction at room temperature. Lomustine is a chloroethlyating compound and it causes alkylation and cross linking of RNA and DNA at the O6 position of guanine containing bases. If the DNA and RNA is not repaired, this cross linking causes breakage during replication and eventually causes cell death via apoptosis. Lomustine is also a lipid soluble, which allows it to permeate the blood brain barrier well. This quality made it a reasonable candidate for the chemotherapy of intrinsic brain tumors. Lomustine is administered orally in six to eight week intervals and with nadirs at five weeks after administration due to its delayed myelosuppressive properties.

Lomustine was approved by the FDA to treat high grade gliomas in 1976. Lomustine, alone or in combination with other chemotherapeutic drugs, was the standard of care following surgery and/or radiation up until the early twenty first century. In the United States, lomustine is currently approved for recurrent high grade gliomas. It is also approved for treatment of Hodgkin’s lymphoma in combination with other chemotherapies, following disease progression with initial chemotherapy. In 2013, Bristol Myers Squibb discontinued production of lomustine. NextSource Biotechnology took over as the sole distributor of lomustine in the United States. NextSource recognized the medical importance of lomustine, so they acquired the manufacturing rights from Bristol Myers Squibb in partnership with Corden Pharma. They relaunched the product under the name of Gleostine the next year. In December 2021, the Glioblastom Foundation announced a new partnership with Continuity Pharma to manufacture a generic form of lomustine. The agreement allowed the drug to be manufactured in the United States, which made it more accessible to patients and lowered the cost of brain cancer treatment by approximately 90%. The manufacturing agreement also resulted in lomustine once again being included in the Medicare federal drug discount program. Continuity Pharma was able to develop the generic form of lomustine due to the technology of continuous flow manufacturing. Continuity Pharma provides the active pharmaceutical ingredients (API) for lomustine to the Glioblastoma Foundation. Pending FDA approval, the foundation will oversee the manufacturing and distribution of the drug to patients across the United States.

Lomustine has been part of eighty eight clinical trials. Twenty five trials are currently active, thirty eight have been completed, eleven have been terminated, four have been withdrawn, and the status of ten trials is unknown. Of the currently active trials, nine of them are in stage three, twelve are in stage two, and four are in stage one. The conditions that the active trials are researching include Anaplastic Astrocytoma, Untreated Childhood Medulloblastoma, High Grade Glioma: Glioblastoma, Brain Neoplasm, Central Nervous System Neoplasm, High Grade Glioma: Gliosarcoma, Medulloblastomas, Oligodendroglioma, Acute T Cell Leukemia Lymphoma, Bone Cancer, Breast Neoplasms, Colorectal Neoplasms, Lung Neoplasms, Malignancies Multiple, Metastatic Cancer, Pancreatic Cancer, Refractory Cancer, Renal Cancer, Resistant Cancer, Diffuse Intrinsic Pontine Gliomas, Ependymoma, Recurrent Brain Tumors, and MGMT Methylated Glioblastoma.