Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies

Hall, AG; Tilby, M.J.

doi:10.1016/0268-960x(92)90028-o

Cited by 180 publications

(89 citation statements)

References 40 publications

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“…The basis for alkylating-agent resistance in MM or other neoplastic cells may be multifactorial, including diminished drug uptake, decreased DNA binding, increased glutathione (GSH) levels, or enhanced repair mechanisms, among others. 49 The unimpaired ability of UCN-01/PD184352 to induce apoptosis in 8226/LR5 cells suggests that none of these mechanisms is involved in conferring resistance to this drug combination. Finally, the phenomenon of cell adhesion-mediated drug resistance (CAM-DR) has recently been described in MM cells, suggesting that integrins can raise the threshold for drug-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6–independent mechanism

Dai

Landowski

Rosen

et al. 2002

Blood

113

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Section: Discussionmentioning

confidence: 99%

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6–independent mechanism

Dai

Landowski

Rosen

et al. 2002

Blood

113

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“…Alkylating agents have in common the ability to damage DNA and/or impair DNA replication, but among the class, there is a spectrum of antitumor activity and toxicity (7). These differences have been attributed to various individual biological properties, including the type of DNA damage, the specificity for attacking DNA versus other cellular components, the mechanisms by which the cell repairs the particular type of DNA damage, entry into and disposition of the drug within the tumor and normal cells, and relative susceptibility to tumor resistance mechanisms (7)(8)(9)(10). In view of the diversity of mechanisms that influence their efficacy and/or safety, new alkylating agents with a distinct biological profile and potential advantages over currently available drugs merit consideration for clinical evaluation in patients with hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

Giles

Thomas

Garcia‐Manero

et al. 2004

Clinical Cancer Research

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Purpose: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS).Experimental Design: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m 2 was escalated by ϳ33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8.Results: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m 2 for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m 2 was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m 2 and 1 with acute myeloid leukemia treated with 600 mg/m 2 , achieved complete remission.Conclusions: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

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“…In view of the presumed distal site of action for the UCN-01/PD184352 combination (i.e., downstream of IL-6/MEK/MAP kinase signaling), it seems likely that this regimen simply bypasses the block to steroid action. The basis for alkylating agent resistance in MM or other neoplastic cells may be multifactorial, including diminished drug uptake, decreased DNA binding, increased GSH levels, or enhanced repair mechanisms, among others 49 . The unimpaired ability of UCN-01/PD184352 to induce apoptosis in 8226/LR5 cells suggests that none of these mechanisms is involved in conferring resistance to this drug combination.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization of Human Mammary Carcinoma Cells by Specific Inhibition of Signal Transduction Cascades

Dent¹

2002

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302 and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank)2. REPORT DATE August 2002 TITLE AND SUBTITLE Radiosensitization of Human Mammary Carcinoma Cells by Specific Inhibition of Signal Transduction Cascades REPORT TYPE AND DATES COVEREDAnnual Summary (1 Aug 01 - AUTHOR(S)Paul Dent, Ph.D. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Virginia Commonwealth University Richmond, Virginia 23298-0568 E-Mail: pdent@hsc.vcu.edu We investigated the impact of combined exposure to the check-point abrogator (UCN-01) in conjunction with MEK1/2 inhibitors upon survival of mammary carcinoma cells. Treatment of cells with UCN-01 resulted in prolonged activation of the MAPK pathway. Inhibition of MEK1/2 caused modest reductions in basal MAPK activity and suppressed UCN-01-stimulated MAPK activity below that of MEK1/2 inhibitor alone. Significantly, combined, but not individual, exposure of cells to UCN-01 and MEK1/2 inhibitors enhanced BAX association with mitochondria and triggered release of cytochrome c into the cytosol, accompanied by activation of effector pro-caspases, resulting in a synergistic potentiation of apoptosis within 18-24h. Radiation exposure of drug treated cells did not further enhance apoptosis. Treatment of cells with both caspase 9 and caspase 8 inhibitors was required to completely inhibit apoptosis in carcinoma cells. Over-expression of Bcl-x L blocked cytochrome c release and cell killing induced by the drug combination. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)UColony forming assays demonstrated that cells exposed to both agents exhibited a substantial reduction in clonogenic survival compared to either drug alone; moreover, radiation further reduced clonogenic survival despite failing to promote additional apoptosis. [9]. It is thought that UCN-01 at physiologic concentrations promotes cell death via Cdk dephosphorylation rather than by inhibition of PKC enzymes [10]. SUBJECT TERMSThe ability of the "classical" mitogen activated protein kinase (MAPK) pathway to regulate proliferation versus differentiation and survival appears to depend upon the amplitude and duration of MAPK activation. A short activation of the MAPK cascade by growth factors has been correlated with enhanced progression through the Gl-S transition [11]. In contrast, prolonged elevation of MAPK activity has been demonstrated to inhibit DNA synthesis through s...

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Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies

Cited by 180 publications

References 40 publications

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6–independent mechanism

Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6–independent mechanism

A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

Radiosensitization of Human Mammary Carcinoma Cells by Specific Inhibition of Signal Transduction Cascades

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