Dynamics of tumor cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide

Milas, Luka; Nakayama, Takashin; Hunter, Nancy; Jones, Sandra; Lin, T. M.; Yamada, Satoshi; Thames, Howard D.; Peters, Lester J.

doi:10.1016/0167-8140(94)90465-0

Cited by 40 publications

(15 citation statements)

References 19 publications

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“…Our results show that repopulation of surviving cells occurs in vitro after the second treatment with melphalan (days [14][15][16][17][18][19][20][21] at all levels of pHe tested (Figs. 2 -4).…”

Section: Discussionmentioning

confidence: 91%

Reduction of Intracellular pH as a Strategy to Enhance the pH-Dependent Cytotoxic Effects of Melphalan for Human Breast Cancer Cells

Wong

Lee

Tannock

2005

Clinical Cancer Research

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The microenvironment within solid tumors is slightly acidic, and manipulation of this extracellular acidity to cause intracellular acidification might be used to increase selective antitumor effects of some anticancer drugs. Potential mechanisms include inhibition of repair of DNA damage and inhibition of repopulation of tumor cells between successive courses of chemotherapy. Here, we evaluate the influence of extracellular pH (pHe) and of two agents that lead to intracellular acidification (cariporide and S3705) on toxicity of melphalan for two human breast cancer cell lines (MDA-MB231and MCF7). Both the total number and number of colony-forming cells were evaluated during and after three sequential weekly drug treatments. Our results indicate the following: (a) Slow or absent repopulation after the first course of treatment that is influenced minimally by pHe. (b) Rapid repopulation after the second course of treatment that may be inhibited at low pHe. (c) Effects of low pHe following treatment with melphalan to increase cell kill. (d) Small effects of incubation in cariporide and S3705 at low pHe to increase the net cell kill after treatment with melphalan. Although these results add to evidence that manipulation of intracellular pH within the acidic environment of solid tumors can influence the effects of chemotherapy, they are too small and inconsistent to warrant clinical evaluation.

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Section: Discussionmentioning

confidence: 91%

Reduction of Intracellular pH as a Strategy to Enhance the pH-Dependent Cytotoxic Effects of Melphalan for Human Breast Cancer Cells

Wong

Lee

Tannock

2005

Clinical Cancer Research

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“…There are many publications on experimental tumours that have shown rates of repopulation after radiotherapy that are equal to or often faster than the rates of cell repopulation in tumours without radiotherapy (Hermens and Barendsen, 1967;Suit and Urano, 1969;Abe et al, 1991;Begg et al, 1991;Milas et al, 1994). Intervals between chemotherapy doses are needed to allow repopulation of normal tissues.…”

Section: Repopulation and Tumour Doubling Timementioning

confidence: 99%

“…Intervals between chemotherapy doses are needed to allow repopulation of normal tissues. During these intervals, however, the surviving tumour cells can proliferate and repopulate (Stephens and Peacock, 1977;Rosenblum et al, 1976;1983;Milas et al, 1994).…”

Section: Repopulation and Tumour Doubling Timementioning

confidence: 99%

Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy

2003

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Induction chemotherapy of non-small-cell lung cancer (NSCLC) stage III with gemcitabine and cisplatin for downstaging of the tumour with the aim for further treatment with ionising radiation is one of the treatments for lung cancer patients. The purpose of this study was to investigate the influence of the waiting time for radiotherapy, that is, the interval between induction chemotherapy and radiotherapy, on the rate of tumour growth for patients with NSCLC. Interval times between the end of induction chemotherapy and date of diagnostic CT, planning CT and first day of radiotherapy were determined for 23 patients with NSCLC. Increase in gross tumour volume was measured for 18 patients by measuring the dimensions of the primary tumour and lymph node metastases on the diagnostic CT after induction chemotherapy and on the CT used for radiotherapy planning. For each patient, the volume doubling time was calculated from the time interval between the two CTs and ratio of the gross volumes on planning CT and diagnostic CT. The mean time interval between end of chemotherapy and day of diagnostic CT was 16 days, and till first day of radiotherapy 80.3 (range 29 -141) days. In all, 41% of potentially curable patients became incurable in the waiting period. The ratio of gross tumour volumes of the two CTs ranged from 1.1 to 81.8 and the tumour doubling times ranged from 8.3 to 171 days, with a mean value of 46 days and median value of 29 days. This is far less than the mean doubling time of NSCLC in untreated patients found in the literature. This study shows that in the time interval between the end of induction chemotherapy and the start of radiotherapy rapid tumour progression occurs as a result of accelerated tumour cell proliferation: mean tumour doubling times are much shorter than those in not treated tumours. As a consequence, the gain obtained with induction chemotherapy with regard to volume reduction was lost in the waiting time for radiotherapy. We recommend diminishing the time interval between chemo-and radiotherapy to as short as possible.

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“…Repopulation of tumor cells following radiotherapy is well documented but repopulation following chemotherapy has not been studied extensively. Limited studies have found that the rate of proliferation of surviving tumor cells may increase following chemotherapy (19)(20)(21)(22). The objectives of the present study Reoxygenation and repopulation at 24 hours in PC-3 tumors treated with pimonidazole and: saline (control; black), docetaxel (8 mg/kg; blue), TH-302 (150 mg/kg; purple) or combination (orange).…”

Section: Discussionmentioning

confidence: 98%

Chemotherapy Rescues Hypoxic Tumor Cells and Induces Their Reoxygenation and Repopulation—An Effect That Is Inhibited by the Hypoxia-Activated Prodrug TH-302

Saggar

Tannock

2015

Clinical Cancer Research

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Purpose: Chemotherapy targets rapidly proliferating tumor cells, but spares slowly proliferating hypoxic cells. We hypothesized that nutrition of hypoxic cells would improve in intervals between chemotherapy, and that hypoxic cells destined to die without treatment would survive and proliferate.Experimental Design: We therefore evaluated repopulation and reoxygenation following chemotherapy, and the effects of the hypoxia-activated prodrug TH-302 on these processes. Tumor-bearing mice were treated with doxorubicin or docetaxel AE TH-302. Pimonidazole (given concurrent with chemotherapy) and EF5 (given 24 to 120 hours later) identified hypoxic cells. Proliferation (Ki67) and oxygen status (EF5 uptake) of formerly hypoxic (pimo positive) cells were quantified by immunohistochemistry.Results: Chronically hypoxic cells had limited proliferation in control tumors. After chemotherapy, we observed reoxygenation and increased proliferation of previously hypoxic cells; these processes were inhibited by TH-302.Conclusions: Chemotherapy leads to paradoxical sparing of hypoxic cells destined to die in solid tumors in absence of treatment, and their reoxygenation and proliferation: TH-302 inhibits these processes.

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Dynamics of tumor cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide

Cited by 40 publications

References 19 publications

Reduction of Intracellular pH as a Strategy to Enhance the pH-Dependent Cytotoxic Effects of Melphalan for Human Breast Cancer Cells

Reduction of Intracellular pH as a Strategy to Enhance the pH-Dependent Cytotoxic Effects of Melphalan for Human Breast Cancer Cells

Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy

Chemotherapy Rescues Hypoxic Tumor Cells and Induces Their Reoxygenation and Repopulation—An Effect That Is Inhibited by the Hypoxia-Activated Prodrug TH-302

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