D M Taylor’s research while affiliated with Institute of Cancer Research and other places

Fractional incorporation (FI) of 3H-thymidine (i.e., the proportion of total tissue 3H incorporated into DNA) has been used as a parameter for judging temporal scheduling of cyclophosphamide and cis-dichlorodiammine platinum (DDP). Differences in the recovery times of FI following a dose of 100 mg CY/kg, between tumor (>12 days), gut (2–3 days), and bone marrow (4 days) suggested a basis for a normal tissue-sparing drug regimen when administering double-agent CY-DDP therapy. When 100 mg CY/kg and 8 mg DDP/kg were administered simultaneously or when the doses were separated by 1 day the survival was 0/10 or 1/10, respectively. However, when the doses were separated by 4 days all rats survived. This 4-day interval was considered to allow time for gut and bone marrow recovery prior to a second insult. Such factors appear crucial to the survival of the animal. These three combinations were similar in their antitumor effect, giving a greater than additive response. Cyclophosphamide was more myelotoxic than DDP, but DDP showed greater gut toxicity. The recovery of bone marrow cellularity was delayed by 2 days compared with FI. Peripheral white blood cell counts returned to normal after a further 2-day delay.

In tumour and normal rat tissues prolonged alkylation of DNA and RNA by chlorambucil-3H occurs over periods of 24 h. It is suggested that this may indicate the slow release of an alkylating moiety from an intracellular drug-macromolecule complex.

Summary In tumour and normal rat tissues prolonged alkylation of DNA and RNA by chlorambucil-3H occurs over periods of 24 h. It is suggested that this may indicate the slow release of an alkylating moiety from an intracellular drugmacromolecule complex.

Two dimethyltriazenoimidazoles, DTIC and BRL 51308, and a benzenoid dimethyltriazene, CB 10286, have been examined for their effects in mice bearing Lewis lung carcinoma. A slight reduction of primary tumor growth was found after treatment with DTIC and BRL 51308, whereas CB 10286 caused no significant effect. On the contrary, all the tested compounds sharply reduced the number of lung metastases and also resulted in a high proportion of animals free of metastases at death. No significant cytotoxic effect of the triazenes was observed in small established pulmonary tumors, as determined by evaluating the effects of treatment on the fractional incorporation of 3H-TdR into DNA of the lung colonies. These results are in contrast to those obtained with a purely cytotoxic agent, cyclophosphamide, and indicate that all three triazene derivatives tested have selective antimetastatic properties.

The effect of serial passage in immune-deprived mice on certain biological and biochemical parameters has been studied in a series of 6 human colorectal tumour xenografts. Histological integrity is maintained for up to 10 serial passages, together with production of epithelial mucins and carcinoembryonic antigen. Passaged tumours retain human lactate dehydrogenase and glucose-6-phosphate dehydrogenase isoenzyme patterns and a human chromosome constitution. The induction of a murine tumour has been identified in this system, and the importance of routine checks for the presence of human tissue during serial passage is stressed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4

The growth characteristics of 6 human colorectal tumours have been examined during serial passage in both male and female immune-deprived mice. Exponential growth is a characteristic feature, especially on very early passages. Growth rates in 5 out of the 6 tumour lines increase during the first few transplant generations. This is accompanied by a shorter exponential growth phase and an increased slope of the growth curves. Lag phases and growth rates for individual tumours are variable within a passage. Growth rates for tumours maintained within the same host are similar, and are at least partially influenced by the host. In one tumour line examined in detail, the increased growth rate is attributable to a decreased cell-loss factor, and the difference in growth rate between human colorectal tumours and their corresponding xenografts may therefore largely be due to a difference in the contribution of this factor.

The relationship between the utilization of 3H-thymidine in situ ([3H]-TdR fractional incorporation or TFI) and tumour growth delay after treatment with various cytotoxic agents has been examined. It is shown that (a) it is not possible to predict tumour growth delay, or to select the most effective agent, from changes in TFI 1 day after treatment; (b) there is a good correlation between tumour growth delay and the time for recovery of TFI to the pretreatment level; (c) there is a relationship within a tumour line between the depression of TFI 4 days after treatment and growth dealy induced by the same treatment. This relationship appears to be independent of the mechanism by which the agent exerts its cytotoxic effect.

The Fractional Incorporation (FI) of [3H] thymidine ([3H]TdR) has been examined in small lung tumours after cyclophosphamide (CY) treatment in vivo and compared to the DNA specific activity (SA) at different times after treatment. FI was found to correlate with the incidence of labelled cells after treatment, whereas SA did not, due to the loss of DNA from drug-killed cells 72 h after treatment. The FI is independent of the precursor concentration in the tissue, and therefore may give a better index of DNA synthesis in irregularly perfused tissues than SA. Following either CY or 60Co radiation treatment, the time necessary for FI to reach the pretreatment level is quite similar to the growth delay measured for the FI depression 45 h after treatment and growth delay has been established in the Lewis lung tumour, which would allow the prediction of growth delay induced by another agent to be made within 2 days of treatment. Images Fig. 2