Hematological Response of Topotecan in Tumor-Bearing Rats: Modeling of the Time Course of Different Cellular Populations

Segura, Cristina; Bandrés, Eva; Trocóniz, Iñaki F.; Garcı́a-Foncillas, Jesús; Sayar, Onintza; Dios-Viéitez, María del Carmen; Renedo, M. J.; Garrido, María J.

doi:10.1023/b:pham.0000022402.00699.5c

Cited by 14 publications

(9 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The semi-physiological model of myelosuppression [1] has earlier been applied on both rat neutrophils [46] and patient neutrophils [6,10] following administration of topotecan. In line with the larger sensitivity of topotecan in patients compared with rats [30], the Slope estimate was lower in rats (39 L/mg) than in patients (133-143 L/mg) in these previous reports.…”

Section: Discussionmentioning

confidence: 99%

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

View full text Add to dashboard Cite

show abstract

“…It has also been shown to satisfactorily describe thrombocyte and lymphocyte measurements following chemotherapy [17][18][19]. Some minor modifications of the original model have been introduced in a few publications to improve the model's predictability following various types of anti-cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model

2010

View full text Add to dashboard Cite

A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.

show abstract

“…[26][27][28][29][30][31] The MTD of most chemotherapeutic drugs given to mice is higher than the corresponding allometrically scaled 'equivalent' human dose. 32 Therefore, it is possible that MTD-based dosing in xenograft models could lead to a high rate of false positives. When the clinically equivalent dose was used, the pattern of response in mice was similar to the activity of the drug in the respective human cancer setting.…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29][30][31] It is well-known that hematoxicity represents one of the major limitations of chemotherapy treatment. 32 Therefore, we investigated the doses of evofosfamide and ifosfamide that induced equivalent hematoxicity by conducting a series of studies in both immunocompromised and immunocompetent mice. Neutropenia is defined as <500 neutrophils/ml blood as reported by Walsh et al 33,34 In the present study, and 2 weeks' treatment of ifosfamide at 120 mg/kg induced neutropenia.…”

Section: Discussionmentioning

confidence: 99%

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models

Sun

Liu

Ahluwalia

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater or comparable efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.Abbreviations: BW, body weight; Br-IPM, a brominated analog of isophosphoramide mustard; CAA, chloroacetalde-

show abstract

Hematological Response of Topotecan in Tumor-Bearing Rats: Modeling of the Time Course of Different Cellular Populations

Abstract: The time course of the hematotoxicity induced after two cycles of chemotherapy with TPT in tumor-bearing rats could be described by a semiphysiological model.

Cited by 14 publications

References 23 publications

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models

Contact Info

Product

Resources

About