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R F Kallman

Publications and source records attributed to R F Kallman.

At least 37 records · Page 2Linked to original sources
PubMed1986

Tumor oxygenation and reoxygenation during radiation therapy: their importance in predicting tumor response.

The degree of oxygenation of a tumor is a major determinant of the effectiveness of radiotherapy. From animal experiments, it is known that hypoxia is common in tumors, that there can be marked heterogeneity in cellular oxygenation within a given tumor, and that the hypoxic fraction is influenced by tumor size and site. The three methods used in obtaining such information are discussed. They are not applicable to tumors in man, but other kinds of evidence suggest qualitatively that the patterns of oxygenation in human tumors are not dissimilar to those in animals. Reoxygenation of animal tumors appears to proceed rapidly after single conditioning radiation doses, but its rate and extent depend upon the size and scheduling of the conditioning dose(s). The importance of reoxygenation in determining the outcome of fractionated radiotherapy may be inferred from the results of recent tumor growth delay experiments wherein we have found that reoxygenation in the RIF-1 sarcoma is nearly complete by 24 hr. after the completion of 5 daily 5 Gy fractional doses.

Animals↗
PubMed1986

Reoxygenation of the RIF-1 tumor after fractionated radiotherapy.

The regrowth delay assay was used to assess hypoxic fraction in the RIF-1 tumor. Results approximating those of earlier paired survival curve data were obtained for previously untreated tumors and tumors treated with a single dose of 15 Gy. Further studies showed that after 5 daily fractions of 5 Gy, the hypoxic fraction returned to approximate pretreatment values within 24 hr.

Animals↗
PubMed1986

Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diamminedichloroplatinum (II) and irradiation.

The interaction of cis-diamminedichloroplatinum(II) (c-DDP) and irradiation was investigated in the RIF-1 tumor, skin and duodenum in C3H/Km mice. The c-DDP enhanced the effects of fractionated irradiation in the tumor, as measured by both growth delay and cell survival determined by excision and colony formation in vitro. This enhancement was at least additive and possibly supra-additive. The combined treatment was effective in clinically relevant treatment regimens. The same doses of c-DDP failed to enhance acute radiation skin reactions and caused only a moderate enhancement of the radiation-induced cell killing in duodenal crypt cells. The latter was found when c-DDP was administered immediately before each irradiation dose in a fractionated treatment schedule, but not when it was given in a single larger dose 24 h before the start of fractionated radiotherapy. Comparing the effects on tumor with those on normal tissues, the optimum treatment appeared to be c-DDP given once a week 24 h before daily fractionated irradiation.

Animals↗
PubMed1985

The effect of treatment in fractionated schedules with the combination of X-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin.

RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatment in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SRI and SRII, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo. Maximum supra-additivity for cis-Pt was afforded by divided doses of the drug (5 X 2.4 mg/kg/day) given immediately before X ray (5 X 1000 rad/day) on 5 consecutive days, although 3 other schedules also produced significant supra-additivity. Maximum supra-additivity for cyclo was seen for a single dose of 100 mg/kg followed 1 day later by a course of 5 daily X ray doses (5 X 1000 rad/day), and at least one other schedule produced almost as great an effect.

Animals↗
PubMed1984

Reoxygenation in the RIF-1 tumor.

The proportion of hypoxic cells in the RIF-1 tumor was examined for 13 days following a 15 Gy conditioning dose. The paired survival curve technique indicated that 100% of the surviving cells were hypoxic immediately following this treatment. However, within 1 hour, only about 50% remained hypoxic; this proportion continued to drop to about 10% but did not reach the pretreatment level of 1.1% for the duration of the study.

Animals↗
PubMed1983

Recruitment of noncycling tumor cells into proliferation by isoproterenol.

The resistance of tumors to conventional anticancer therapy is partially determined by the fraction of noncycling cells they contain. In several normal tissues, isoproterenol can stimulate cell proliferation. The effect of isoproterenol on the EMT6/St tumor grown both intradermally in BALB/c mice and in vitro as multicell spheroids was investigated. The incorporation of [3H]thymidine (5 microCi/g, 6.7 Ci/mmol) into DNA was determined as a function of time after i.p. injection of isoproterenol (0.15 mg/g). Tissue section autoradiographs of the EMT6 tumors were prepared, and labeling indices were determined. EMT6 spheroids were exposed to isoproterenol and labeled with [3H]thymidine in a manner designed to simulate drug exposure in vivo. In EMT6 tumors, the labeling index rose from a control level of 30% to a peak of 53% at 25 hr; it then declined gradually for the next 30 hr. This may be interpreted as evidence that cells were recruited into proliferation. In contrast, isoproterenol had minimal effects on EMT6 spheroids, implying that recruitment caused by this drug was not a direct effect on individual cells.

Animals↗
PubMed1983

SACCAS. A semiautomated counting machine with an accommodating threshold selector.

SACCAS, the Stanford Automated Cell/Colony Autoradiograph Scanner, is a system designed to expedite the analysis of autoradiographs made from tumor cells. Cells are viewed for grain counting under reflected darkfield illumination. The image is transmitted to the computer's digitizing hardware via a TV camera. The ability of this machine to count tritium grains accurately and reproducibly depends upon proper thresholding of grains from the underlying nucleus. Thresholding is performed automatically using a gray-value-histogram evaluation algorithm. For 489 nuclei, the grain counts using SACCAS compared favorably to the manual counts of two experienced operators. The coefficients of variation were 12.8% between two manual counts and 13.0% between two machine counts. A plot of mean manual against mean SACCAS counts showed a correlation coefficient of 0.98.

Autoanalysis↗
PubMed1981

The effect of x-irradiation on cell loss in five solid murine tumours, as determined by the 125IUdR method.

The rate of cell loss in irradiated RIF-1, EMT6, KHJJ, B16 and KHT tumours was studied using the 125IUdR loss technique. Administration of 125IUdR preceded localized tumour irradiation by 2 days. Loss of tumour radioactivity was measured for 6-8 days after irradiation. The blood flow to some tumours was occluded during, and for 30 min following, injection of the label to measure the amount of radioactivity entering the tumour as a result of reutilization of label from the gut epithelia and influx of labelled host cells. Irradiation did not significantly alter the amount of radioactivity entering these clamped tumours during the 8-10 days after injection of 125IUdR. This permitted comparison of irradiated and control groups based on the loss of radioactivity from the non-occluded tumours. Irradiation of RIF-1, EMT6, KHJJ or B16 tumours with doses of 600, 1400, 2400 or 4400 rads produced no significant increase in the rate of loss of tumour radioactivity. This suggested that, in the population of labelled cells, cell lysis following irradiation proceeded slowly. In contrast, KHT tumours showed a significant increase in loss rate following each radiation dose, although the increase was dose-independent. In all tumour systems, the constant rate of cell loss after radiation appeared to coincide with published reports of tumour growth responses after irradiation. The present data suggest that the manner of expression of radiation-induced cell killing results from the cellular proliferative status, i.e. whether a cell is cycling or non-cycling.

Animals↗
PubMed1980

Determining the labeling index in autoradiography.

A method is proposed for estimating the labeling index in autoradiographs. It is based on a model for the frequency distribution of grain counts for those cells which have few grains. The method does not require extensive grain counting and provides reasonable estimates even when the background level is high. It is particularly suited for experiments where tumnor cells, labeled in vivo, are autoradiographed after being cultured in vitro.

Autoradiography↗
PubMed1980

Cell loss and influx of labeled host cells in three transplantable mouse tumors using [125I]UdR release.

The [125I]UdR loss technique was used to estimate cell loss from RIF-1, EMT6 and KHJJ tumors in order to determine the length of the delay between labeling and the beginning of the loss of labeled cells, and also to calculate a value for phi, the cell loss factor. To determine the importance of reutilization of label released from the gut and/or the influx of labeled host cells, the blood flow to some tumors was occluded during and for 30 min after injection of the label. Relatively small amounts of radioactivity entered occluded RIF-1 tumors during 9 days after injection of [125I]UdR, indicating that reutilization of systemic label and influx of labeled host cells are not significant in this system. In contrast, substantial amounts of radioactivity entered occluded EMT6 and KHJJ tumors, reaching 40% of the total activity in non-occluded tumors during 6 days following injection. After corrections were made for this influx of label, the [125I]UdR loss curves from RIF-1 and EMT6 tumors were essentially exponential from the first day following injection of label. This was interpreted as indicating the loss of proliferating as well as non-proliferating cells from both tumors. The cell loss factor derived from the [125I]UdR loss curves corrected for influx appeared to agree well with published values derived from analysis of percent labeled mitoses curves. In contrast, the corrected [125I]Udr loss curves from KHJJ tumors showed that loss of activity began three days after injection of label, indicating that primarily nonproliferating cells are lost from this tumor.

Animals↗
PubMed1980

A new mouse tumor model system (RIF-1) for comparison of end-point studies.

A new tumor model system (RIF-1) was developed that is very suitable for studies in which clonogenic survival is compared with growth delay and control probability following various forms of treatment. The tumor was a radiation-induced sarcoma in the inbred female C3H/Km mouse. It had a low median tumor dose, had a satisfactory plating efficiency direct from in vivo to in vitro, was nonimmunogenic or minimally immunogenic, and metastasized only at a relatively advanced stage of growth. The cell line grew either as a monolayer on plastic dishes, as tumor spheroids in spinner culture, as lung nodules following injection of a single-cell suspension into the tail veins of syngeneic mice, or as a solid tumor. Both diploid and tetraploid clonogenic cells were found in monolayer cultures of the RIF-1 line.

Animals↗
PubMed1980

125IUdR loss as a measure of tumour cell loss: influence of reutilization and influx of labelled host cells.

Two potential artifacts, the reutilization of label released from the gut and the influx into solid tumours of labelled host cells, have been measured by occluding the blood flow to tumours during, and for 30 min after, injection of 125IUdR. Previous work has shown that occluded EMT6 and KHJJ tumours exhibit a substantial increase in label, to 30-40% of the total activity in non-occluded tumours within 4 days post-125IUdR injection. In B16 and RIF-1 tumours the influx of label is minimal. Almost all of this entry of 125IUdR results from the influx of labelled host cells. Significant influx was also demonstrated in Lewis lung and KHT tumours. Minimal changes in the extent of influx of labelled host cells were found following irradiation of EMT6 and RIF-1 tumours with 600 or 1400 rad. These doses also resulted in little or no additional loss of 125IUdR despite the fact that 60 to 95% of the tumour cells were killed. Thus, the lysis of the killed cells must proceed very slowly. The conditions necessary for the use of 125IUdR loss to assess cell killing, as opposed to cell lysis, are reviewed.

Animals↗