Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.
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PMID:Phase I clinical trial of drug-monoclonal antibody conjugates in patients with advanced colorectal carcinoma: a preliminary report. 278 31

The clinical pharmacology and toxicity of a novel anthracycline derivative, 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), was investigated in patients with advanced malignant diseases. The starting dose was 30 mg/m2 which was escalated by increments of 10 mg/m2. Twelve patients with a median age of 42 (range, 19-69) years and a median Eastern Cooperative Oncology Group performance score of 2 (range, 1-2) were entered into the study. The diagnoses included four testicular cancers, two breast cancers, two small cell lung cancers, two acute myeloid leukemias, one colon cancer, and one hemangiosarcoma. THP-adriamycin was given as an i.v. bolus injection every 3 weeks. Evaluable were 18 courses for general toxicity, 16 courses for hematological toxicity, and 16 courses for pharmacokinetics. THP-adriamycin had a short initial half-life of 1.4 +/- 0.3 min (mean +/- SD) due to rapid cellular uptake. Peak concentrations in unseparated blood cells were reached 5 min after drug injection and remained higher than in plasma throughout the observation period of 72 h. The half-lives of THP-adriamycin in plasma were 19 +/- 2.8 min in an intermediate and 13 +/- 1.6 h in the terminal phase. A linear correlation was observed between the dose and the areas under the concentration curves for THP-adriamycin in plasma (r2 = 0.97) and blood cells (r2 = 0.99). The volume of distribution was 2124 +/- 221 liters/m2 and the total clearance rate 115 +/- 11 liters/m2h. THP-adriamycin was metabolized to Adriamycin, THP-adriamycinol, and adriamycinol. The major metabolite was Adriamycin with a terminal half-life in plasma of 33 +/- 10 h. The area under the curve of Adriamycin was also correlated to the administered dose (r2 = 0.96). Since excessive peak concentrations of Adriamycin were avoided, the treatment with THP-adriamycin might be an alternative to continuous infusions or weekly administrations. The maximum tolerated dose was 70 mg/m2, and the dose-limiting toxicities were leukopenia and thrombocytopenia. Anemia, nausea, and vomiting were mild to moderate, and no other toxicity was observed. All side effects were dose dependent and reversible. In a patient with breast cancer, a disease stabilization was achieved lasting for 9 weeks. No objective remission was observed. We suggest 60 mg/m2 in pretreated or poor risk and 70 mg/m2 in untreated or good risk patients every 3 weeks for further clinical trials.
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PMID:Clinical pharmacology and toxicity of 4'-O-tetrahydropyranyladriamycin. 381 48