No abstract

A B S T R A C T Radiation therapy to either mediastinum or pelvis causes a rapid decrease in circulating lymphocytes of both B and T types and in addition an impairment in the function of the remaining lymphocytes, as measured by their ability to proliferate in response to mitogens. The acute depression is short-lived. Substantial recovery is apparent within 3 wk after cessation of therapy; however, most patients show a modest, chronic depression in both numbers and functional capacities of circulating lymphocytes. T cells are somewhat more sensitive than B cells, but both are affected.Irradiation of the thymus per se seems to have little influence on the acute changes which occur, as patients receiving pelvic and mediastinal (including thymic) radiotherapy show a similar degree of lymphopenia and depression of lymphocyte responsiveness.

Caffeine has been previously reported to enhance the lethal potential of many DNA-damaging agents in rodent cells1-5. This effect has most commonly been ascribed to the binding of caffeine to single-stranded DNA6, and the resulting inhibition of post-replication repair7-10, which is associated with the synthesis of abnormally small nascent DNA fragments7, 11-13. However, certain aspects of this theory remain unclear:(1) why does the addition of caffeine to damaged cells elevate the level of DNA synthesis when it supposedly blocks post-replication repair10,14, and (2) as pointed out by Cleaver15, why does caffeine continue to exert its synergistic lethal effects until completion of the S phase16, 17, even though the size of newly synthesized DNA seems normal much earlier18-20? The present studies with nitrogen mustard (HN2) fail to demonstrate any effect of non-lethal concentrations of methylated xanthines (MXs) on removal of DNA damage or post-replication repair in conditions producing synergistic lethal effects. We demonstrate an influence by MXs on initiation of DNA synthesis in damaged replicons, and propose that this effect is primarily responsible for the synergistic lethal properties of these drugs.

5-Fluorouracil (FUra) has emerged as the most promising clinical radiosensitizer now available. FUra's capacity to render human cells more sensitive to x-rays was established soon after its synthesis. However, the recognition that the drug's unusual pharmacology dictated explicit scheduling requirements in man was not realized until recently when work in the author's laboratory identified the extra-cellular drug concentration X time factors necessary to create the intra-cellular radiosensitive state. Subsequent clinico-pharmacologic investigations led to the realization that only prolonged continuous infusions combined with appropriately fractionated, cyclical radiation therapy would maximize the clinical utility of this approach. Infused FUra radiation-sensitization therapy reaches its maximum efficacy against the squamous-transitional cancers. This group of human malignancies comprises about 15% of all human cancers. Preliminary data also suggests substantial promise in the local/regional control of rectal and breast cancers. Infused FUra used as a radiosensitizer has the potential to eliminate the need for about 90% of all radical cancer surgery.

The effects on cell survival in tissue culture of Adriamycin, of various Adriamycin derivatives and of the parent compound, daunomycin, have been studied. Adriamycin and three of its C-14 derivatives show similar toxicities towards cells chronically exposed in culture. Acute (30 min) exposures are significantly less toxic than exposures to the drug throughout the period of colony formation. Daunomycin, the parent compound, is significantly more toxic than any Adriamycin compound. Both high-dose, pulsed exposures and low-dose, chronic exposures result in shoulders on the cell survival curves. Split-dose experiments show little evidence for a significant acute repair of Ad damage. Ad toxicity is additive to X-rays at high levels of cell survival and synergistic at low levels of cell survival. Both excision repair-competent and excision-deficient cells show sensitization to X-irradiation when significantly cytotoxic levels of Ad are used. No evidence for an induction of Ad resistance by previous irradiation was found. Ad does not appear to inhibit the repair of sub-lethal X-ray damage. Since Ad produces molecular lesions similar to those induced by X-rays it is hypothesized that both radiation "enhancement" and the recall of latent X-ray injuries result from the induction of Ad of DNA damage similar to that occurring following X-ray exposure. The implications of these findings with respect to clinical drug and X-ray scheduling is discussed.