Linda Simpson-Herren

Cell population kinetics of transplanted and metastatic lewis lung carcinoma.

The growth rate of Lewis lung carcinoma, either as primary subcutaneous tumors or as spontaneous lung metastases, decreases with increasing age or mass. The length of the median cell cycle of the primary tumors increased from 17.6 hr at Day 5 to 25.9 hr at Day 21 with a concomitant increase in experimental doubling time from 2.5 to 9.6 days. The length of the median cell cycle of the metastatic lung nodules was 15.2 hr in the mice bearing 21‐day primary tumors. Two mathematical models were used to analyse the per cent labeled mitoses data and the results are given for comparison.

Diversity of penetration of anti‐cancer agents into solid tumours

Abstract. Failure of anti‐cancer agents to reach all clonogenic cells at cytotoxic concentrations is recognized as an important form of resistance in solid tumours. Subcutaneously implanted mammary adenocarcinoma 16/C was used to evaluate the intratumour distribution of five alkylating, bioreductive alkylating and intercalating agents and two radiation sensitizers. The agents were classified according to their in vivo distribution in well‐ and poorly‐perfused tumour regions, as delineated by lissamine green. The classifications were: (1) distribution in direct proportion to the vascular supply; (2) uniform distribution to well‐ and poorly‐perfused tumour regions; and (3) preferential retention in the poorly‐perfused tumour regions. Our current state of knowledge did not allow reliable prediction of the classification based on chemical structure or mechanism of action.

THE CELL POPULATION KINETICS AND RESPONSE TO AN S‐PHASE SPECIFIC AGENT OF THREE TRANSPLANTABLE COLON TUMOR LINES

The relative cell population kinetics of three transplantable murine colon tumor lines (Colon 26, 36 and 38) with different histological and metastatic characteristics were studied in relation to the response of each line to an S‐phase specific agent. The mean doubling times for the three lines between 0·1 and 1·0 g are similar (4·2 days) but marked differences are apparent in times to tumor appearance (0·1 g) and in median days to death. The length of the cell cycle is about one day and the length of the S‐phase 10–11 hr for Colon 36 and 38. The length of the cell cycle in Colon 26 is difficult to estimate by conventional methods but probably exceeds 24 hr and the S‐phase is 10–11 hr; [3H]TdR pulse labeling indices for Colon 36 and 38 decrease with time and tumor size from about 0·45 in 0·1 to 0·2 g tumors to about 0·33 at 3 g. The decrease in the [3H]TdR labeling index for Colon 26 is more pronounced (from about 0·38 at 0·1 g to 0·21 at 1·0 g). The shapes of the PLM curves and the [3H]TdR labeling index data are consistent with the observed sensitivity to an S‐phase specific agent (Palmo‐AraC, NSC 135962) in Colon 36 and the minimal response observed in Colon 26. Colon 38 is intermediate between Colon 36 and Colon 26 in kinetic properties and in response to the S‐phase agent.

Distribution of Adriamycin in mice bearing mammary adenocarcinoma 16/C

Abstract. The response of solid mammary adenocarcinoma 16/C to treatment with Adriamycin is highly variable and ranges from growth under treatment to complete regression. Tumour and host factors were evaluated to determine the influence of each on the response. We determined that the concentration of Adriamycin in plasma and tumour was a function of tumour size and treatment history in mice bearing mammary adenocarcinoma 16/C. The plasma concentrations following a single dose of Adriamycin (10 mg/kg) increased in proportion to tumour mass without a concurrent increase in tumour concentration. When mice bearing large tumours (>1·0 g) were treated with a multidose protocol, the plasma concentrations were higher and the tumour concentrations lower following the initial dose than following subsequent doses; in tumour‐free mice, prior treatment with Adriamycin did not affect the plasma level achieved after a second dose. The magnitude of the decrease in plasma and increase in tumour concentrations was a function of the initial tumour size and the treatment schedule. The increase in tumour levels represented the sum of residual Adriamycin and drug bound as a result of the dose immediately prior to analysis. At the time of the initial treatment, the Adriamycin was distributed within each tumour in proportion to vascular perfusion. The percent of the tumour mass that was well‐perfused appeared to increase with repeated treatments. The results indicate that the plasma concentration of Adriamycin did not pecessarily reflect the tumour exposure in the mammary adenocarcinoma 16/C model. In hosts bearing mammary adenocarcinoma 16/C—or, possibly, other tumours that produce similar effects on the host—a low initial dose of Adriamycin might modify the distribution, possibly reduce the toxicity and allow escalation of subsequent doses with increased exposure of the tumour.