Tumor Chemotherapy: Efficacy Dependent on Mode of Growth2

Hagemann, Ronald F.; Schenken, Larry L.; Lesher, S.

doi:10.1093/jnci/50.2.467

Cited by 23 publications

(11 citation statements)

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“…A number of studies have evaluated the response of various experimental tumour systems to this drug. Hagemann, Schenken and Lesher (1973) have studied the response of P815 x 2 mastocytoma cells grown in culture, ascites and solid forms. They found that solid tumours were far less 8 sensitive to the drug than either of the other forms and suggested that this was a consequence of the failure of the drug to reach significant numbers of cells at risk.…”

Section: Discussionmentioning

confidence: 99%

Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour

Stanley¹,

Shipley²,

Steel³

1977

Br J Cancer

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Summary.-Radiation survival curves for Lewis lung tumours in the lungs ranging in size from 0-5 to 20 mm3 have been obtained, and a size-dependent variation in hypoxic fraction was found. Cell-survival studies following treatment of various sizes of s.c. tumours indicated that the effects of 60Co y-rays and the chemotherapeutic agents 1,3-bas(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide are all size-dependent. Large pulmonary nodules which had regressed but had not been cured by cyclophosphamide regrew with a radiosensitivity that was characteristic of previously untreated tumours. The results give additional experimental support to the clinical interest in early adjuvant therapy of micrometastases, and sequential combined modality therapy for larger tumours.THE relationship between tumour size and therapeutic sensitivity has been the subject of a number of studies. Experiments from this laboratory have indicated that cells in 0-5-mm3 pulmonarv metastases of the Lewis lung (LL) tumour are considerably more radiosensitive under normal in situ conditions than those in 500-mm3 subcutaneous tumours (Shipley, Stanley and Steel, 1975). At the level of cell survival studied, the presence of a hypoxic fraction could not be detected in 0-5-MM3 pulmonary tumours, whereas the hypoxic fraction in large s.c. tumours was estimated to be 0-36. Fu, Phillips and Wharam (1976), working with the EMT6 tumour system, have also compared the radiosensitivity of large s.c. tumours with that of pulmonary nodules, and have found the smaller tumours to be considerably more radiosensitive and their hvpoxic fraction to be correspondingly lower. DeWys (1972) and Steel and Adams (1975) have found independently, in cell-survival studies with the LL tumour, that small pulmonary nodules are more sensitive to cyclophosphamide than are large s.c. tumours. Twentyman and Bleehen (1976) saw no size-dependent effect when the EMT6 tumour was treated with cyclophosphamide, although their data for the same tumour indicated that sensitivity to BCNU decreased with increasing tumour size.Any effect of tumour size on therapeutic response has important clinical implications for the use both of prophylactic cytotoxic therapy against subclinical disease and of combined modality treatment of larger tumours. The project described in this report was designed to study in greater detail the response of the LL tumour to radiation and drug treatment over a range of sizes, and to investigate the radiosensitivity of regrowing lung nodules which had been treated initially with cyclophosphamide.

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Section: Discussionmentioning

confidence: 99%

Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour

Stanley¹,

Shipley²,

Steel³

1977

Br J Cancer

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“…The results of Barranco et al (1973a) andHagemann et al (1973) both of whom added BCNU directly to the existing medium in which the cells were growing, could therefore have been influenced by changes in drug binding properties between exponential and plateau phase medium. Nevertheless, Hahn et al (1974) were able to show that plateau phase cells are somewhat more sensitive to BCNU than exponentially growing cells, even when exposed to the drug without serum being present.…”

Section: Hn2mentioning

confidence: 99%

Changes in sensitivity to cytotoxic agents occurring during the life history of monolayer cultures of a mouse tumour cell line

Twentyman¹,

Bleehen²

1975

Br J Cancer

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Our studies of the cytotoxic drug, bleomycin, have shown Bleehen, 1973, 1975) that in early plateau phase the sensitivity is reduced from that shown by exponentially growing cells. In late plateau phase, however, the sensitivity increases again and becomes greater than that of exponential phase cells. In this paper we report results obtained in exponential, early plateau and late plateau phases for 5 other cVtotoxic drugs. MATERIALS AND METHODSFull details of the cell line and of the drug response assay have been described previously (Twentyman and Bleehen, 1975). Briefly, 105 EMT6 mouse tumour cells were inoculated on Day 0 into Falcon tissue culture flasks containing 5 ml of Eagle's medium supplemented with 20% calf serum. Change of medium was carried out daily from Day 2. Drugs were added directly to the growth medium approximately 24 h after the previous medium change. At the end of the drug exposure period, the medium was removed, the monolayer was rinsed with fresh medium and cells were then trypsinized from the surface. After resuspension, counting and diluting, the cells were plated into plastic Petri dishes and incubated for 10 days. At the end of this period the dishes were fixed and stained and then colonies containing more than 50 cells were counted.The drugs used in the current series of experiments are shown in Table I. All drugs were added in a volume of between 0-04 and 0-2 ml. As a control for the alcohol solvent used for BCNU and CCNU, it was established in a preliminary experiment that the addition of 0-2 ml of absolute methanol to cultures for 1 h had no effect on cell survival.

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“…by Hagcmann ct al. [5] in the P815X2 mastocytoma sys tem. For BCNU, these authors showed maximum sensitivity in cell cultures, and least in solid tumors, with ascites tumors in between.…”

Section: Discussionmentioning

confidence: 99%

“…These results with BCNU were confirmed by Begg et al [I], who found that BCNU caused extensive cell killing as determined by the in vivo-in vitro assay method [10], but only a moderate amount of growth delay. Our previous results using BCNU, chlorozotocin (CLZ), or a combination of both, only produced growth delay and a slope change in the tumor growth curve, but no cures were observed [2], The same was true when we added vitamin A to the combination treatment [8], On the assumption that this lack of success was due in part to inadequate drug reaching the tumor cells [5], and that there were too many tumor cells to be killed by such doses even in small 0.5-cm diameter tumors, we have presently studied the effects of 13 nitrosoureas on EMT6 ascites tumors. This model tumor allowed increased activity of the nitrosoureas at the tumor cell level and an assessment of drug efficacy for this tumor.…”

Section: Introductionmentioning

confidence: 99%

Cure Rates and Tumor Resistance in Cured Mice after Nitrosourea Treatment of EMT6 Ascites Tumors

Feola¹,

Maruyama²

1986

Oncology

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Single-dose BCNU or chlorozotocin (CLZ) treatment of EMT6 mammary carcinoma tumors of the BALB/c mouse has only a transient effect on tumor growth, after which tumors follow control growth patterns. To test the hypothesis that drug access to tumor cells might be a factor in cell killing, we adapted the EMT6/KY tumor to ascites form. Injection of 10⁵ EMT6/KY cells i.p. kills BALB/c mice with a mean survival time of 13.0 ± 1.0 days. We have surveyed several nitrosoureas for their effects on the EMT6/KY ascites tumor after intraperitoneal injection of the drugs. Cure rates and percent increase in life span were used as endpoints. Also, we tested for induced host tumor resistance (TR) in cured mice, by challenging survivors with live EMT6 cells. Highest cure rates were obtained for treatment on days 2, 3, or 4 after inocula of 10⁵ cells: CLZ (10 mg/kg), 83.3%; cis-acid (20 mg/kg), 75%, and CCNU (30 mg/kg), 70%. Other nitrosoureas, i.e. BCNU, PCNU, GANU, STZN, FCNU, ACNU, MeCCNU, NSC-88104 produced lower cure rates. Cured mice surviving challenges of 106 EMT6 cells were considered TR. TR mice did not correlate with cure rates for the 3 nitrosoureas giving high cure rates. As percent of survivors, TR mice were (for day 3 treatment): FCNU, 100%, BCNU, 100.0% and CLZ, 50.0%. Thus, cure rates and TR seem to depend on the structure of the nitrosourea, but through different mechanisms.

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Tumor Chemotherapy: Efficacy Dependent on Mode of Growth2

Cited by 23 publications

References 0 publications

Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour

Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour

Changes in sensitivity to cytotoxic agents occurring during the life history of monolayer cultures of a mouse tumour cell line

Cure Rates and Tumor Resistance in Cured Mice after Nitrosourea Treatment of EMT6 Ascites Tumors

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