-
効能
抗悪性腫瘍薬, トポイソメラーゼII阻害薬
-
説明
Valrubicin was launched as a new 'chemotherapeutic agent for the
treatment of bladder cancer, particularly in patients with BCG-refractory
carcinoma in situ (CIS) of the bladder for whom immediate cystectomy is
unacceptable. It belongs to the class of anthracyclines, the widest used in
human cancers, and is a N-trifluoroacetyl 14-valerate derivative of doxorubicin.Valrubicin can be obtained in 3 steps from daunomycin by N-trifluoroacetylation
of the sugar moiety then iodination of the 2-acetyl group and introduction of a
valerate residue. A proposed mechanism involved in the cytotoxicity of
Valrubicin coud be the blockade of SV40 large T antigen helicase; this cellular
enzyme is involved in the formation of a ternary complex with DNA to maintain
the topographic structure of DNA during transcription. In patients with CIS of
bladder refractory to front line and second line therapies, intravesical instillation
of Valrubicin resulted in a complete response with a significant rate and allowed
a delay in cystectomy. Systemic absorption was minimal and accordingly
produced a lower incidence of cardiotoxicity compared with doxorubicin.
-
化学的特性
Red Solid
-
使用
Chemotherapy drug used to treat cancer of the bladder.
-
一般的な説明
Valrubicin is available in 200-mg vials for intravesicular administrationin the treatment of bladder cancer (orphan drugstatus). The increased lipophilicity associated with the valericacid ester and trifluoro acetate functionalities increasestissue penetration and remains intact because, in large measure,of the lack of exposure to hydrolyzing enzymes causedby direct delivery into the bladder followed by voiding ofthe instilled solution. This local action also minimizes cardiotoxicityand other adverse effects seen with other anthracyclines.The major adverse effects that are seen are bladderirritation and reddening of the urine.
-
作用機序
Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. In cells, it inhibits the incorporation of nucleosides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in G2. Although valrubicin does not bind strongly to DNA, valrubicin metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.
-
臨床応用
Valrubicin currently has orphan drug status in the treatment of bacille Calmette-Guérin (BCG)–refractory bladder cancer (the total patient population is ~1,000 individuals) and is used with patients for whom surgical intervention would result in high morbidity or death.
-
副作用
The most commonly reported adverse reactions are abdominal pain, urinary tract infection, hematuria, and dysuria. Systemic exposure to the drug and its metabolites would, of course, be greater in patients whose bladder wall integrity has been compromised by disease, and these patients should not receive valrubicin.
-
安全性プロファイル
Poison by intraperitoneal route.Human mutation data reported. When heated todecomposition it emits toxic fumes of Fí and NOx.
-
代謝
It is administered directly into the bladder through a catheter (intravesically). The lipophilic drug is water insoluble, but it dissolves in an aqueous vehicle that includes polyoxyethylene glycol and ethanol. The patient retains the drug in the bladder for 2 hours, then voids the solution in the normal fashion. Valrubicin is active as administered, and despite the fact that hydrolysis of the ester and trifluoroacetamide can be envisioned, it is excreted essentially unchanged. Less than 1% of an administered dose is absorbed systemically, so there is essentially no exposure to metabolizing enzymes. The reduced C13-alcoholic metabolite does not form to any appreciable extent during the 2-hour treatment period. Therapy is considered to be almost exclusively local, and there is little risk for cardiac toxicity, bone marrow suppression, drug–drug interactions, or other side effects.
