Haematopoietic stem-cell transplantation in multiple myeloma

Handelsman, H

doi:10.1016/s0305-7372(96)90031-6

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Therefore, we sought to examine the effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on voltage-activated K currents in human myeloma cells . Patients whose myeloma clones produce only light chains, particularly of the ltype, have poorer responses to treatment with early relapse and short survival (Handelsman 1996;Wu et al 1998). Therefore, we discuss the cytotoxicity of these compounds as well as the ionic interaction with the myeloma cell.…”

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Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Shen¹,

Chiu³

1999

Journal of Pharmacy and Pharmacology

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Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high potency against human cancer cells. In the search for potential anticancer drug candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by reaction with various secondary amines and formaldehyde. They were prepared as hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline compounds in the National Cancer Institute in-vitro cancer cell line panel was determined. It was found that they exhibited substantial cytotoxic activity against leukaemia. The log concentration of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, -5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline was selected for further in-vivo testing. The electrophysiological effect of 7-pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI 8226). The outward current was voltage dependent, activating at -40 mV and believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8-hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14 microM. The results suggest that at least part of the cytotoxicity effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to blockade of voltage-activated K+ channels.

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Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Shen¹,

Chiu³

1999

Journal of Pharmacy and Pharmacology

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“…Unfortunately, the treatment of this disease has not progressed since the introduction of melphalan and corticosteroids. Intensive chemotherapy with multiple cytotoxic agents does not significantly improve the outcome of patients with this disease [Foerster, 1993;Handelsman, 1996]. Since K + channels are involved in a variety of physiological and pathophysiological processes [Cook, 1988;Robertson and Steinberg, 1990], the discovery of novel K + channel blockers is of particular interest.…”

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confidence: 99%

Cytotoxicity studies of 2‐hydroxymethyl‐1‐naphthol diacetate on K⁺currents in neoplastic plasma cells

Shen

1999

Drug Development Research

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The present study investigated the effects of 2‐hydroxymethyl‐1‐naphthol diacetate (TAC) on cell proliferation and K+ currents in RPMI‐8226 human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+]i) = 10 nM, depolarizing square pulses from a holding potential of –80 mV elicited instantaneous outward current with slow inactivation, corresponding to voltage‐activated K+ current. TAC (1–100 μM) inhibited IK(V) in a concentration‐dependent manner. A23187 (1 μM), a Ca2+ ionophore, can potentiate Ca2+‐activated K+ current (IK(Ca)). Tetraethylammonium chloride (10 mM) caused a small decrease in the amplitude of IK(Ca) elicited by A23187, whereas TAC (30 μM) and quinidine (10 μM) decreased IK(Ca) more effectively. The present results show that TAC directly blocks voltage‐ and Ca2+‐activated K+ currents in human myeloma cells. TAC inhibited both cell proliferation and voltage‐activated K+ current with an effective dose inducing half‐maximum effects at 3.8 ± 0.8 μM and 10 ± 1.5 μM, respectively. The present study suggests that the cytotoxic effect of TAC in cancer cells may be partially explained by blockade of K+ channels. The delocalization energy of TAC and other analogs was employed to compare their ability to block the voltage‐activated K+ channel in myeloma cells. It was found that naphthol derivatives‐mediated blockade of voltage‐activated K+ channel might relate to the level of delocalization energy and molecular volume. Drug Dev. Res. 47:1–8, 1999. © 1999 Wiley‐Liss, Inc.

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“…Multiple myeloma (MM) accounts for around 10–15% of haematological malignancies and around 1% of all cancers (Handelsman, 1996). The annual age‐standardized incidence in England and Wales was 5·1 for men and 3·5 for women per 100 000 population in 1990 (Coleman et al , 1999), The disease is predominant among the elderly population with a median age at diagnosis of 70 years, although the incidence in those aged under 55 years is rising (Varterasian, 1995).…”

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Cost‐effectiveness of high‐dose chemotherapy in first‐line treatment of advanced multiple myeloma

et al. 2001

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Summary. The cost-effectiveness of high-dose chemotherapy in multiple myeloma was considered as part of a UK National Health Service Executive regional evidence-based appraisal process. The use of high-dose chemotherapy supported by autologous stem cell transplantation in patients under 65 years of age was shown to provide a marginal benefit of 0´7 life-years over conventional chemotherapy. This corresponded to an incremental cost`per life-year gained' figure of approximately £15 000, based upon initial treatment costs and trial-period data only. The use of high-dose chemotherapy in the first-line treatment of advanced multiple myeloma improves event-free and overall survival and appears to be a cost-effective treatment option.

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Haematopoietic stem-cell transplantation in multiple myeloma

Cited by 4 publications

References 33 publications

Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Cytotoxicity studies of 2‐hydroxymethyl‐1‐naphthol diacetate on K⁺currents in neoplastic plasma cells

Cost‐effectiveness of high‐dose chemotherapy in first‐line treatment of advanced multiple myeloma

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Haematopoietic stem-cell transplantation in multiple myeloma

Cited by 4 publications

References 33 publications

Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Synthesis and Cytotoxicity Evaluation of Some 8-Hydroxyquinoline Derivatives

Cytotoxicity studies of 2‐hydroxymethyl‐1‐naphthol diacetate on K+currents in neoplastic plasma cells

Cost‐effectiveness of high‐dose chemotherapy in first‐line treatment of advanced multiple myeloma

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Cytotoxicity studies of 2‐hydroxymethyl‐1‐naphthol diacetate on K⁺currents in neoplastic plasma cells