Response of a "Resistant" Plasmacytoma to Alkylating Agents and X-Ray in Combination with the "Excision Repair Inhibitors Caffeine and Chloroquine

Gaudin, D.; Kl, Yielding

doi:10.3181/00379727-131-34119

Cited by 58 publications

(16 citation statements)

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“…Multiple studies have been published indicating that genetic or pharmacological interference with autophagy can enhance the response to radiation (for example, Gaudin and Yielding, 1969;Pazmino and Yuhas, 1974;Zhao et al, 2005;Apel et al, 2008;Livesey et al, 2009;Solomon and Lee, 2009;Jiang et al, 2010;Chaachouay et al, 2011;Bristol et al, 2012;Lim et al, 2012;Wilson et al, 2011). In contrast, our studies indicate that 4T1 cells could not be sensitized to radiation in vitro by pharmacological inhibition of autophagy with chloroquine treatment, by silencing of the autophagyrelated gene Atg12, or by chloroquine in vivo.…”

Section: Discussioncontrasting

confidence: 53%

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Bristol

Emery

Maycotte

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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Recognition of the cytoprotective functions of autophagy that occur in tumor cells exposed to various forms of chemotherapy or radiation has generated intense interest in the possibility that pharmacological interference with autophagy could provide a clinical strategy for overcoming therapeutic resistance. Multiple clinical trials are currently in progress to evaluate the antimalarial agent chloroquine (generally in its clinical formulation as hydroxychloroquine) and its impact on various forms of cancer therapy. In this commentary/review, we focus on the relatively limited number of studies in the literature where chloroquine has been tested in combination with chemotherapy or radiation in experimental tumor-bearing animal models. We also present recent data from our own laboratories, in cell culture experiments as well as in vivo studies, which demonstrate that neither chloroquine nor silencing of an autophagy regulatory gene was effective in conferring radiation sensitivity in an experimental model of breast cancer. The capacity for sensitization by chloroquine appears to be quite wide-ranging, with dramatic effects for some drugs/tumor models and modest or minimal effects in others. One possible caveat is that, with only a few exceptions, experiments have generally been performed in xenograft models, thereby eliminating the involvement of the immune system, which might ultimately be proven to play a central role in determining the effectiveness of autophagy inhibition in chemosensitization or radiosensitization. Nevertheless, a careful review of the current literature suggests that caution is likely to be warranted in translating preclinical findings relating to autophagy inhibition as an adjunctive therapeutic strategy.

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Section: Discussioncontrasting

confidence: 53%

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Bristol

Emery

Maycotte

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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“…SCEs have been frequently used as highly sensitive indicators of DNA damage and/or subsequent repair. The ability to excise and repair various types of damage to DNA is probably a general property of living cells [17]. Unrepaired damage, expressed as SCEs, in normal cells caused by certain chemicals may indicate inability for repair of damage induced by the same chemicals in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic and Cytogenetic Effects of Platinum(II) and Palladium(II) Complexes with Pyridine-2-Carboxyaldehyde-Thiosemicarbazone

et al. 1998

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The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)₂] and [Pt(PyTsc)₂]. Next in order of magnitude in inducing antineoplastic and cytogenetic effects is the compound [Pt(HPyTsc)₂]Cl₂ while the rest, i.e. [Pd(PyTsc)Cl], HPyTsc, [Pd(HPyTsc)₂]Cl₂, and [Pt(PyTsc)Cl], show marginal cytogenetic and antineoplastic effects.

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“…It must be emphasized that rodent assays may be confusing in testing these premises because of their reduced ability to excise the relevant damage. Nevertheless, in vivo rodent assays using caffeine have already shown some "beneficial" sensitization (Gaudin & Yielding, 1969;Cohen, 1972;Cohen & Carbone, 1972), though this is to be expected from the enhanced sensitivity of excision-deficient rodent DNA repair pathways. Even human tumours in athymic mice probably cannot be used to determine therapeutic usefulness, since the dose-limiting normal rodent tissues would be expected to be more sensitive than the repair-competent human tumour target cells.…”

Section: Discussionmentioning

confidence: 99%

Mice, men, mustards and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents

Byfield¹,

Murnane²,

Ward³

et al. 1981

Br J Cancer

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Summary.-The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylatingagent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents canbe increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by appropriate concentrations of MX. Trimethylxanthine (caffeine) and the 2 clinically useful dimethylxanthines (theophylline and theobromine) appeared equally effective in sensitizing cells. The sensitization was dependent upon a slightly cytotoxic concentration of the MX and a suitably prolonged period of post-damage MX exposure. Of these 3 classic MXs, only theobromine might be clinically useful. The levels required for alkylating-agent sensitization exceed the clinically tolerable level of theophylline, and probably approach the tolerance of man to caffeine. The most likely mechanism by which MX sensitization is achieved is reversal of the inhibition of DNA replicon initiation which follows the infliction of significant DNA damage. Through the selection of suitable clinically useful alkylating agents (those dependent on active cellular transport for cell penetration) and appropriate MX scheduling, an enhanced therapeutic ratio might be achieved, potentially increasing the clinical usefulness of these alkylating agents. MX would thus form a useful class of agents adjuvant to conventional anticancer drugs.DESPITE THE GROWING VOLUME of agents, or from a more effective use of cancer treatment research in the world already established single agents. today, effective treatment for many human Perhaps the most paradoxical clinical cancers is not yet available. Improve-observation is that tumours that grow ments in cancer chemotherapy currently most rapidly are often the most sensitive appear to offer the most promise. Such to chemotherapy. This might be expected improvements could result from new for chemotherapeutic regimens utilizing drugs, better combinations of existing antimetabolites that affect DNA syn-

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Response of a "Resistant" Plasmacytoma to Alkylating Agents and X-Ray in Combination with the "Excision Repair Inhibitors Caffeine and Chloroquine

Cited by 58 publications

References 0 publications

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Antineoplastic and Cytogenetic Effects of Platinum(II) and Palladium(II) Complexes with Pyridine-2-Carboxyaldehyde-Thiosemicarbazone

Mice, men, mustards and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents

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