Metabolism and reactions of alkylating agents

Farmer, Peter B.

doi:10.1016/0163-7258(87)90099-4

Cited by 57 publications

(27 citation statements)

References 330 publications

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“…Melphalan represents one of nitrogen mustard derivates, the group of earliest and effective antitumor drugs used in cancer therapy [12]. It acts through formation of interstrand cross-links in major groove of DNA [13].…”

Section: Introductionmentioning

confidence: 99%

Combined therapy with disintegrin and melphalan as a new strategy in inhibition of endometrial cancer cell line (Ishikawa) growth.

Miltyk

Surażyński²,

Wołczyński³

et al. 2010

Folia Histochem Cytobiol.

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Abstract:Endometrial cancer is one of the most frequently diagnosed cancer in females with prevalence of 22 in 100,000 women. The etiology of the cancer remains unclear. Despite significant progress towards understanding the patho-mechanism of the disease, effective treatment is still lacking. The results of the study suggest that combined treatment of Ishikawa cells for 24 h with disintegrin and then for 24 h with melphalan severely inhibits important biological functions of the cells. We showed that such strategy have a potent cytotoxic effect. The mechanism of process undergoes probably through inhibition of integrin -dependent signaling. In this study we shown down regulation of Shc and FAK proteins in cells treated with echistatin and melphalan. It suggests that signaling pathways that involve Shc and FAK participation may represent target for antineoplastic strategy. The functional significance of the combined treatment of Ishikwa cells with echistatin and melphalan was found at the level of collagen biosynthesis. Decreased biosynthesis of collagen in extracellular matrix may suppress cell growth and induce apoptosis. The treatment with echistatin and melphalan also showed decreased expression of IGF receptor in comparison to the cells treated with both compounds separately. The data presented suggest that combined therapy with disintegrin -echistatin and alkyalting drug -mephalan may represent a new approach to more effective and safe cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Combined therapy with disintegrin and melphalan as a new strategy in inhibition of endometrial cancer cell line (Ishikawa) growth.

Miltyk

Surażyński²,

Wołczyński³

et al. 2010

Folia Histochem Cytobiol.

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“…Alkylating agents represent a class of anticancer drugs which demonstrate considerable cytotoxic activity against a variety of tumour types (Farmer, 1987).…”

Section: Discussionmentioning

confidence: 99%

In vivo therapeutic potential of combination thiol depletion and alkylating chemotherapy

Siemann

Beyers²

1993

Br J Cancer

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Summary The effect of administering the thiol modulating agent buthionine sulfoximine (BSO) in conjunction with alkylating chemotherapy was investigated in vivo in the mouse KHT sarcomas and bone marrow stem cells. Tumour response to treatment was assessed by an in vivo to in vitro excision assay and bone marrow survival was determined in vitro by CFU-GM. Glutathione (GSH) depletion and recovery kinetics were determined at various times after treatment using high performance liquid chromatography (HPLC) techniques. Following a single 2.5 mmol kg-' dose of BSO, tumour GSH reached a nadir of -40% of control 12-16 h after treatment. Bone marrow GSH was depeleted to -45% of control 4-8 h after treatment but recovered to normal by 16 h. When a range of doses of CCNU, mitomycin C, cyclophosphamide or melphalan (MEL) were given 16 h after mice were exposed to a 2.5 mmol kg-' dose of BSO, only the antitumour efficacy of MEL was effectively enhanced (by a factor of -1.4). This BSO-MEL combination appeared to be selective for the tumour as the bone marrow toxicity was not increased beyond that seen for MEL alone. Since increasing the administered dose of BSO neither increased the extent of thiol depletion in the tumour nor enhanced the antitumour efficacy of MEL, three other protocols for delivering the thiol depletor were explored. BSO was given either as multiple 2.5 mmol kg-' doses administered at 6 or 16 h intervals or continuously at a concentration of 30 mM supplied in the animals' drinking water. Both multi-dose BSO pretreatments were found to increase both the antitumour efficacy and normal tissue toxicity of MEL such that no advantage compared to the single dose combination was achieved. In contrast, maintaining the thiol depletor in the drinking water led to an -1.7-fold increase in the antitumour efficacy of MEL without any corresponding increase in bone marrow stem cell toxicity. For the various pretreatment strategies it was possible, in all cases, to account for the presence or absence of a net therapeutic benefit on the basis of the tumour and bone marrow GSH depletion and recovery kinetics.

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“…The mean arrival time (MATΩLag timeπ1/t 1/2 abs) and mean residence time (MRTΩAUMC/AUC) were approximated (Cheng & Jusko 1988;Veng-Pedersen 1989) using the program MOM (Efthymiopoulos et al 1989). The steady-state distribution volume (V d ) was estimated using the first moment AUC (AUMC) and AUC¬, and assuming an oral bioavailability of 90% for chlorambucil (Farmer 1987;Oppitz et al 1989;Jack 1992). Apparent plasma clearance was approximated using Vdist, a and b (Jusko 1986).…”

Section: Methodsmentioning

confidence: 99%

“…In the fasting state, oral bioavailability is between 70% and 90% (Newell et al 1983;Oppitz et al 1989;Jack 1992), but food decreases it significantly . Chlorambucil is almost entirely metabolized, primarily in the liver by a microsomal enzyme system (McLean et al 1976;Farmer 1987;Dollery 1999). Metabolism is unsaturable in clinical dosages, but very little is known about possible enzyme induction by chlorambucil.…”

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confidence: 99%

Pharmacokinetics of Chlorambucil in Patients with Chronic Lymphocytic Leukaemia: Comparison of Different Days, Cycles and Doses

Silvennoinen¹,

Malminiemi²,

Malminiemi³

et al. 2000

Pharmacology & Toxicology

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The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentrationtime-curve (AUC) from tΩ0 to infinite was in average 3.2 hr*mg/ml for the first cycle, and decreased by 17% in four days (PϽ0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dosecorrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend Ͻ0

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Metabolism and reactions of alkylating agents

Cited by 57 publications

References 330 publications

Combined therapy with disintegrin and melphalan as a new strategy in inhibition of endometrial cancer cell line (Ishikawa) growth.

Combined therapy with disintegrin and melphalan as a new strategy in inhibition of endometrial cancer cell line (Ishikawa) growth.

In vivo therapeutic potential of combination thiol depletion and alkylating chemotherapy

Pharmacokinetics of Chlorambucil in Patients with Chronic Lymphocytic Leukaemia: Comparison of Different Days, Cycles and Doses

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