Lomustine

Chemotherapy in human medicine 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. Pregnant patients 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 must be taken on an empty stomach of at least two hours. Lomustine is highly toxic; as such, only one dose is dispensed at a time in order to lower overdose risk. Due to the cytotoxic nature of lomustine, the drug must be dosed, administered, and disposed of with special precautions including wearing gloves to prevent dermal exposure. == Side effects ==

Lumostine causes a variety of side effects including gastrointestinal, ocular, neurologic, and other disorders. == Safety ==

Toxicities 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. Drug interactions There are 407 FDA-approved drugs which may interact with lomustine. Many of these interactions are due to severe side-effects of this chemotherapy, which are incompatible other drugs' known side effects. Lomustine is contraindicated in the administration of most live vaccines during treatment, due to infection risk. Receiving these vaccines during the course of lomustine is highly discouraged due to the immunosuppression caused by this chemotherapy. == Manufacturing ==

Lomustine is manufactured by using continuous flow manufacturing. It requires two flow reactors, with an intermediate purification to change reaction solvents. The first step in the synthesis of Lomustine is a fast reaction at room temperature. The reaction is the carbamylation of cyclohexylamine (1) by 1-chloro-2-isocyanatoethane (2) in the presence of triethylamine (TEA) to form the 1-(2- chloroethyl)-3-cyclohexylurea (3)intermediate (Diab et al.). This reaction involves the interaction between the lone pair on the nitrogen of cyclohexylamine (1) and the nitrosyl carbon center on 1-chloro-2-isocyanatoethane (2). This results in a tetrahedral intermediate, in which a proton from the nitrogen of cyclohexylamine (1) is transferred to the nitrogen of 1-chloro-2-isocyanatoethane (2). The second step in the synthesis is the nitrosation of 1-(2-chloroethyl)-3-cyclohexylurea (3) by tert-butyl nitrite (TBN) (4) in aqueous solution. The reaction involves the radical homolytic bond breaking of tert-butyl nitrates into a tert-butoxide radical and a nitrosyl radical. The tert-butoxide radical then reacts with the nitrogen-hydrogen bond on the chlorine side of the carbonyl group of 1-(2-chloroethyl)-3-cyclohexylurea (3) to form tert-butanol and a 1-(2-chloroethyl)-3-cyclohexylurea radical, which reacts with the nitrosyl in a termination step to form lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea). == Pharmacology ==

Mechanism of action Cell-cycle specific chemotherapy drugs only affect cells when they are dividing, whereas cell-cycle non-specific drugs affect cells when they are at rest. 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. == History ==

FDA approval 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. It is the standard of care for recurrent glioblastoma multiforme in Europe, and it is frequently used as a control arm in recurrent glioblastoma multiforme trials. == Society and culture ==

Pricing controversies Lomustine was manufactured in limited supply by Bristol-Myers Squibb prior to 2013. This resulted in a short supply of a key chemotherapeutic drug used in the treatment of brain cancer and Hodgkin's lymphoma. 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. == Research ==

Clinical trials 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. == References ==