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Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study.
Clin Cancer Res. 1997 Aug; 3(8):1245-52.CC

Abstract

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming "cleavable complex," a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 "free" topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy.

Authors+Show Affiliations

Departments of Medicine and Biostatistics, Kaplan Cancer Center, New York University Medical Center, New York, New York 10016, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9815806

Citation

Hochster, H, et al. "Effect of Prolonged Topotecan Infusion On Topoisomerase 1 Levels: a Phase I and Pharmacodynamic Study." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 3, no. 8, 1997, pp. 1245-52.
Hochster H, Liebes L, Speyer J, et al. Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. Clin Cancer Res. 1997;3(8):1245-52.
Hochster, H., Liebes, L., Speyer, J., Sorich, J., Taubes, B., Oratz, R., Wernz, J., Chachoua, A., Blum, R. H., & Zeleniuch-Jacquotte, A. (1997). Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 3(8), 1245-52.
Hochster H, et al. Effect of Prolonged Topotecan Infusion On Topoisomerase 1 Levels: a Phase I and Pharmacodynamic Study. Clin Cancer Res. 1997;3(8):1245-52. PubMed PMID: 9815806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. AU - Hochster,H, AU - Liebes,L, AU - Speyer,J, AU - Sorich,J, AU - Taubes,B, AU - Oratz,R, AU - Wernz,J, AU - Chachoua,A, AU - Blum,R H, AU - Zeleniuch-Jacquotte,A, PY - 1997/8/1/pubmed PY - 1998/11/17/medline PY - 1997/8/1/entrez SP - 1245 EP - 52 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 3 IS - 8 N2 - Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming "cleavable complex," a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 "free" topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9815806/Effect_of_prolonged_topotecan_infusion_on_topoisomerase_1_levels:_a_phase_I_and_pharmacodynamic_study_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=9815806 DB - PRIME DP - Unbound Medicine ER -