D Melnychuk

McGill University, Montréal, Quebec, Canada

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Publications (7)155.45 Total impact

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    ABSTRACT: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose. Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability). Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% +/- 37%. The terminal phase half-life was similar after intravenous (58.4 +/- 23.5 minutes) or oral (64.0 +/- 34.8 minutes) administration. The total plasma clearance was 20.4 +/- 8.8 L/h/m2, and the apparent volume of distribution was 29.9 +/- 17.6 L/m2. The area under the plasma concentration-time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses. SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.
    Journal of Clinical Oncology 02/2003; 21(2):232-40. DOI:10.1200/JCO.2003.03.047 · 18.43 Impact Factor
  • L C Panasci · V Sandor · D Melnychuk ·

    New England Journal of Medicine 01/1999; 339(26):1940-1; author reply 1941. · 55.87 Impact Factor
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    L C Panasci · D Melnychuk ·

    JNCI Journal of the National Cancer Institute 12/1997; 89(21):1631-2. DOI:10.1093/jnci/89.21.1631-a · 12.58 Impact Factor
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    ABSTRACT: Glutathione S-transferase (GST) represents a multifunctional enzyme family consisting of four known cytosolic isoforms (alpha, mu, pi, and Phi) that detoxify a variety of xenobiotic chemicals and may confer resistance to both chemotherapeutic drugs and carcinogens in various experimental models. GST-pi has already been extensively studied in clinical specimens, including breast cancer. We studied the immuno-histochemical distribution and relative immunopositivity of GST-alpha and GST-mu, based on a grading system for immunointensity, in samples of 51 neoplastic and 46 normal breast samples and 12 lymph node metastases from patients treated with intensive chemotherapy and bone marrow transplant. In normal breast tissue, GST-alpha localized predominantly to the cytoplasm of scattered cells lining the luminal aspects of the ducts. Occasional cells showed both cytoplasmic and nuclear GST-alpha immunoreactivity. GST-mu was stained in myoepithelial cells preferentially as well as in occasional ductal cells (including apocrine epithelium), vascular smooth muscle, and plasma cells. GST-alpha and GST-mu were detected in 22 of 51 (43%) and 24 of 48 (50%) invasive cancers, respectively. In paired samples of normal and malignant tissue from the same patient, GST-alpha immunostaining in cancers was significantly less intense compared to that of normal breast tissue in 13 of 41 (32%) cases. No such trend was found for GST-mu in paired samples. Neither GST-alpha nor GST-mu immunopositivity in tumor or nonneoplastic breast was found to correlate with relapse-free or overall survival in this clinical context; however, the apparent decreased expression of GST-alpha in malignant versus normal breast epithelial cells could have important implications in breast carcinogenesis.
    Clinical Cancer Research 06/1997; 3(5):661-7. · 8.72 Impact Factor
  • T Wang · X Chen · R L Schecter · S Baruchel · M Alaoui-Jamali · D Melnychuk · G Batist ·
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    ABSTRACT: Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine. The fact that some drug-resistant cell lines have increased GSH levels, and that enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. We previously showed a selective enhancement by the cysteine "pro-drug," L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of tumor-bearing rats, whereas there is a paradoxic GSH depletion in tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model. We have examined the OTZ "activating" enzyme, 5-oxoprolinase, in these tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in tumor in response to OTZ. A limited number of human breast cancer samples show similar activity.
    Journal of Pharmacology and Experimental Therapeutics 04/1996; 276(3):1169-73. · 3.97 Impact Factor
  • D Melnychuk · L C Panasci ·

    New England Journal of Medicine 10/1994; 331(11):741-2; author reply 744-5. · 55.87 Impact Factor
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    ABSTRACT: . One may conclude that the total dose is the underlying basis for the observed differences, whereas the authors prefer to postulate a nonlinear dose-response or intensity-response effect . If the survival benefit of adjuvant chemotherapy mostly accrues to patients who are incurable sbecause of a drug- resistant minority clone, then both theory' and laboratory models' suggest that total dose is indeed the important de- terminant up to the point at which the sensitive cell popula- tion is eliminated in the majority of patients . If so, the con- clusion that doses "should not be reduced" is unsound and may lead to inappropriate risk taking in the face of excessive toxicity . Although it is good clinical practice to give the maximal well-tolerated dose, it may be possible to compen- sate for dose reductions or delays with additional therapy to achieve the target total dose .