Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

Lum, Bert L.; Kaubisch, Sonia; Yahanda, Anne M.; Adler, Kent M.; Jew, Lyle; Ehsan, Mohamed N.; Brophy, N A; Halsey, Joanne; Gosland, Michael P.; Šikić, Branimir I.

doi:10.1200/jco.1992.10.10.1635

Cited by 276 publications

(88 citation statements)

References 29 publications

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“…Recently, oral dexverapamil has been found to increase the AUC of paclitaxel twofold (Berg et al, 1995), while it had no effect on the steady-state concentration of etoposide (Wilson et al, 1995a). With cyclosporin A and its analogue PSC 833, an increase in AUC and toxicity has been a consistent finding with any of the cytotoxic drugs tested so far (Lum et al, 1992;Bartlett et al, 1994;Boote et al, 1996). In contrast, the effects of other Reversal of epirubicin resistance in breast cancer 1161 chemosensitizers on the pharmacokinetics and -dynamics of cytotoxic drugs appear to depend on the particular agents used in combination.…”

Section: Discussionmentioning

confidence: 80%

“…In two randomized trials in metastatic breast cancer, quinidine and verapamil were not able to enhance epirubicin activity (Mross et al, 1993a;Wishart et al, 1994). Various studies have evaluated the effects of chemosensitizers on the pharmacokinetics and toxicity of cytotoxic agents (Kerr et al, 1986;Bisset et al, 1991;Lum et al, 1992;Philip et al, 1992;Mross et al, 1993b;Scheithauer et al, 1993;Bartlett et al, 1994;Berg et al, 1995;Motzer et al, 1995;Wilson et al, 1995a;Boote et al, 1996). The data from these studies have suggested that an increase in the area under the plasma concentration-time curve (AUC) and toxicity of cytotoxic drugs by chemosensitizers may be indicative of having achieved chemosensitizer concentrations that are high enough to effectively inhibit P-gp function (Fisher et al, 1996).…”

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confidence: 99%

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Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

Lehnert

Mross²,

Schueller³

et al. 1998

Br J Cancer

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Summary Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase 11 trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m-2 i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 gg ml-1 h-1, P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 gM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, Cl 5-39%, s.e.,p 0.079). The remissions lasted 3, 8, 11 and 11 + months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

Lehnert

Mross²,

Schueller³

et al. 1998

Br J Cancer

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“…Phase I studies showed that both CsA and PSC 833 increased the area under the curves of etoposide, daunorubicin and doxorubicin. [50][51][52][53][54] However, a disadvantage of this increase in plasma levels is that drug doses should be reduced to limit the toxic sideeffects. Side-effects have been reported at the clinically achievable concentrations of PSC 833, CsA and Vp used in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…14 Samples with more than 70% of leukemic cells in the control wells after 4 days of culture (without drug) and a control OD value higher than 0.050 arbitrary units (adjusted for blank values) were used to calculate the LC 50 value, ie the concentration of drug that is lethal to 50% of the cells (in g/ml). 13,16 The LC 50 of DNR in the presence of the modulator was corrected for the cell kill mediated by the modulator itself. The modulating effect on DNR cytotoxicity was expressed as the ratio between the LC 50 value of DNR with and without modulator: a ratio Ͼ1 indicates a sensitizing effect of the modulator, ie the LC 50 of single DNR was higher than the LC 50 of DNR in the presence of the modulator; a ratio Ͻ−1 indicates an adverse effect of the modulator, ie the LC 50 of DNR in the presence of the modulator is higher than the LC 50 of single DNR.…”

Section: In Vitro Drug Resistance Assaymentioning

confidence: 99%

“…13,16 The LC 50 of DNR in the presence of the modulator was corrected for the cell kill mediated by the modulator itself. The modulating effect on DNR cytotoxicity was expressed as the ratio between the LC 50 value of DNR with and without modulator: a ratio Ͼ1 indicates a sensitizing effect of the modulator, ie the LC 50 of single DNR was higher than the LC 50 of DNR in the presence of the modulator; a ratio Ͻ−1 indicates an adverse effect of the modulator, ie the LC 50 of DNR in the presence of the modulator is higher than the LC 50 of single DNR.…”

Section: In Vitro Drug Resistance Assaymentioning

confidence: 99%

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The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 M PSC 833 (P = 0.025), 1.5-fold using 4 M CsA (P = 0.003) and 1.6-fold using 6 M Vp (P = 0.012) whereas the adverse effect of 25 M genistein was median 1.8-fold (P Ͻ 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of Pgp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

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Penetration of Chemotherapy Into Vitreous Is Increased by Cryotherapy and Cyclosporine in Rabbits

Wilson

Chan²,

Moselhy³

et al. 1996

Arch Ophthalmol

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Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

Cited by 276 publications

References 29 publications

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

Penetration of Chemotherapy Into Vitreous Is Increased by Cryotherapy and Cyclosporine in Rabbits

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