Proliferative characteristics of primary and metastatic human solid tumors by DNA flow cytometry

Frankfurt, Oskar S.; Greco, William R.; Slocum, Harry K.; Arbuck, Susan G.; Gamarra, Marie; Pavelic, Zlatko P.; Rustum, Youcef M.

doi:10.1002/cyto.990050612

Cited by 62 publications

(19 citation statements)

References 11 publications

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“…These investigators noted that the Feulgen-measured DNA aneuploidy detected for low to high abnormalities was independent of the microscopic malignancy grading. Generally, however, such a clear relationship between morphology and DNA content or DNA Index has not been firmly established for other major human epidermoid carcinoma types such as head and neck, lung, or the uterine cervix (e.g., see 8,15,16,25,34). In the present retrospective study of epidermoid head and neck cancers, a high-degree DNA abnormality, as detected by flow analysis, was not necessarily reflected in the histomorphology scoring as high malignancy grade (e.g., see Figs.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometric analysis of head and neck carcinoma DNA index and S‐fraction from paraffin‐embedded sections: Comparison with malignancy grading

et al. 1985

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Archival, paraffin-embedded, pathology specimens representing pretreatment tissue biopsies from 73 patients with epidermoid carcinoma of the head and neck were analyzed for DNA Index and %S-phase cells by flow cytometry and were scored for quantitative histomorphology. The DNA fluorescencefiight scatter size patterns derived from paraffinembedded specimens were shown to be essentially the same as those from mechanically disaggregated, ethanol-fixed cells obtained from the same tissue specimen. Patterns ranged from lymphocyte-like to highly abnormal DNA Index cytokinetic patterns. The DNA Index values ranged from 0.70 to 3.50 (median 1.42), with an aneuploidy frequency of 63/73 (86%). DNA distribution %S ranged from 4% to 45% (mean 19), with the microscopic malignancy grading showing broad heterogeneity (mean 2.1, range 1.0-3.0, where 1.0-1.7 = well differentiated, 1.8-2.3 = moderately differentiated, 2.4-3.0 = poorly differentiated). Cross-comparison of these data showed that (1) the tumor %S was dependent on DNA Index (higher %S at higher ploidy), (2) low to high malignancy tumors were randomly distributed between diploidhear diploid tumors and high-degree DNA abnormality tumors, and (3) proliferative activity values broadly overlapped between low to high malignancy scored tumors. However, those carcinomas characterized by high DNA Index ( 2 1.50) and high %S-phase fractions ( 2 20) had a five fold higher incidence of high -degree malignancy, invasive tumors than diploidhear diploid (%S < 19) tumors.Key terms: Human head and neck carcinomas, DNA Index, cytokinetics, malignancy, grading, paraffin-embedded specimens Historically, microscopic-based morphology detection and classification of malignant disease has undergone a progressive development toward the use of more detailed tissue and cellular features in order to achieve improved diagnosis and subclassification of human neoplasms. Presently, however, uncertainty still exists as to the reliability of histomorphology as a predictor of in situ tumor biological behavior, such as the growth properties, propensity for metastasis, or therapy response of human solid tumors, and is not predictable based on pathology. This is considered due in large part to the subjective and qualitative nature of microscopic malignancy grading, in addition to the inherent uncertainties of tumor heterogeneity and sampling error.Static (1-3,10,46) and flow cytometry (5,8,12,16,34, 38,40,43) techniques provide more quantitative and objective measurements of tumor cytogenetic, cytokinetic, and phenotypic features, and this information has proved useful for supplementing clinical and pathology classification of malignant disease (6-9,29,31-34,40,45). Accumulating evidence supports the contention that (1) cytometric detection of abnormal GI DNA content in cells in most cases is a reliable marker of malignancy (2,3,5-9,31,34,45) and (2) that the degree of DNA abnormality andor proliferative activity expressed in in vivo, spontaneous tumor stemlines may reflect the degree of malignancy and b...

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Section: Discussionmentioning

confidence: 99%

Flow cytometric analysis of head and neck carcinoma DNA index and S‐fraction from paraffin‐embedded sections: Comparison with malignancy grading

et al. 1985

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“…It is worth highlighting that studies of a variety of human solid tumors suggest that approximately 10% to 20% of malignant cells within a tumor are actively dividing-a relatively small proportion of the total tumor cell population (43). Moreover, the average tumor volume doubling time of many human solid tumors in patients is on the order of months or years (44).…”

Section: Payloadsmentioning

confidence: 99%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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“…cytometric technique of DNA distribution analysis is applied in tumors (11,12,16,21). It is not possible to discriminate between cycling and noncycling cells.…”

Section: Nusse Et Almentioning

confidence: 99%

“…Blocks at certain stages of the cycle, recruitment of resting cells into the proliferating component, and variations in the length of the G1-, S-and G2-phases are important effects induced in the tumor by irradiation. The knowledge of such data is critical to the identification of the dynamic processes that determine how the tumor as a whole responds to irradiation.Flow cytometric techniques as well as labeling techniques with radioactive DNA precursors are widely used to study cell cycle kinetics in cells in tumors (11,12,15,16,(18)(19)(20)(21). Besides technical problems, the main …”

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Cell cycle kinetic measurements in an irradiated rat rhabdomyosarcoma using a monoclonal antibody to bromodeoxyuridine

Nüsse¹,

Afzal²,

Carr³

et al. 1985

Cytometry

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Cell cycle kinetics after X-irradiation were studied in a solid rat rhabdomyosarcoma using a monoclonal antibody to bromodeoxyuridine (BrdUrd) in cells in which the DNA was labeled by BrdUrd. It could be shown that this tumor was composed of about 80% diploid host cells, and only 20% of the cells in the dissociated tumor were actually tetraploid tumor cells. When rats were injected intraperitoneally with BrdUrd to label S-phase cells in the tumor, only a fraction of both tqpes of cells became labeled with BrdUrd during Sphase, even 24 h after injection. The diploid BrdUrd-labeled cells progressed rapidly into cycle; 4 h after injection of BrdUrd, labeled diploid G1-phase cells could be observed. Only 25% of the tetraploid S-phase cells could be labeled by a single injection of BrdUrd (160 mgkg body weight). These labeled tetraploid cells progressed through the cell cycle with similar velocities as did labeled diploid cells. Using a "Mini Osmotic Pump" containing bromodeoxycytidine (BrdCyd) at high concentration (0.3 mol/L) that released BrdCyd continuously into the organism where it was converted to BrdUrd, it could be shown that after 2 days about 60% of cells in S-phase and 70% of cells in G2-phase were labeled. The fraction of labeled G2-phase cells in irradiated tumors (D = 10 and 20 Gy) was enhanced between 10 and 50 h after irradiation due to a radiation-induced G2 block in cycling tetraploid tumor cells. No effect of irradiation on incorporation of BrdUrd in S-phase could be observed in the continuous labeling experiments in contrast to the pulse labeling with RrdUrd, where a small retardation of DNA synthesis was observed in the irradiated tumors during the first 15 h after irradiation. When dissociated cells of the tumor were plated in medium containing 20 pmol/L BrdUrd, only the tetraploid tumor cells were able to incorporate BrdUrd and to enter cycle.Key terms: Tumor cell cycle kinetics, flow cytometry, monoclonal antibody to BrdUrd, X-ray irradiation, continuous labeling with bromodeoxycytidineThe response of a rat rhabdomyosarcoma system to irradiation with heavy charged particles and X-rays has been extensively investigated previously with experiments conducted both in vivo and in vitro (5)(6)(7)(22)(23)(24). The radiobiological end-points studied included tumor volume response (22,231, cell survival after tumor irradiation in situ (24), and survival of oxic and hypoxic cells irradiated and assayed in vitro (7). It is known that the redistribution of cells within the cell cycle after irradiation is a n important factor affecting the speed of tumor regrowth. Therefore, measurement of the movement of both the total and the clonogenic population of tumor cells in vivo through the cell cycle as a function of time after irradiation is of special interest in this context. Blocks at certain stages of the cycle, recruitment of resting cells into the proliferating component, and variations in the length of the G1-, S-and G2-phases are important effects induced in the tumor by irradiation. The knowledge of s...

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Proliferative characteristics of primary and metastatic human solid tumors by DNA flow cytometry

Cited by 62 publications

References 11 publications

Flow cytometric analysis of head and neck carcinoma DNA index and S‐fraction from paraffin‐embedded sections: Comparison with malignancy grading

Flow cytometric analysis of head and neck carcinoma DNA index and S‐fraction from paraffin‐embedded sections: Comparison with malignancy grading

Antibody Drug Conjugates: Preclinical Considerations

Cell cycle kinetic measurements in an irradiated rat rhabdomyosarcoma using a monoclonal antibody to bromodeoxyuridine

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