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Geraniol, an acyclic end product of a plant isoprene pathway and a pyrophosphorylated intermediate in plant and animal pathways, caused a concentration-dependent increase in the population doubling time of murine P388 leukemia cells in suspension culture and of B16 melanoma cells in monolayer culture. The suppression of the growth of P388 cells by geraniol (0-0.9 mM) and by mevinolin (0-0.25 microM), a competitive inhibitor of mevalonate biosynthesis, was reversed by the addition of 0.5 mM mevalonolactone to the growth medium. Flow cytometry of asynchronous B16 cells grown with geraniol (0-0.15 mM) revealed a population characterized by larger cells with altered nuclear characteristics. Over the course of four studies, dietary geraniol increased the 50% survival time of mice by 10, 29, 33, and 50% following the i.p. transfer of P388 cells. The results of the latter study showed that, following the i.p. transfer of 1 x 10(5) P388 cells, the control group of female C57BL x DBA/2 F1 mice had a 50% survival time of 24 days and a maximum survival of 27 days. Mice fed a diet containing 0.1% geraniol for 14 days prior to and following the P388 cell transfer had a 50% survival time of 36 days, and 20% of the mice remained free of tumors during the 50-day trial. These studies support the possibility that monoterpenes and other isoprenoid products of plant metabolism are in part responsible for the anticarcinogenic actions of diverse fruits, vegetables, and cereal products.

In an attempt to optimize the chemotherapeutic treatment of mouse tumor Sarcoma 180, liposomes containing cis-dichlorodiammineplatinum(II) (PDD), having transition temperatures of few degrees higher than the rectal temperature of mice, were used in combination with local hyperthermia. The uptake of radioactive PDD by tumors heated for 1 hr at 42 degrees was almost four-fold greater when the drug was associated in liposomes than if administered as free drug. Uptake of liposome-administered radioactive platinum by liver was twice that obtained with free PDD, whereas its incorporation by the kidney was the same by either method of drug administration. The effect of various combinations of hyperthermia, drug-containing liposomes, and free PDD on tumor growth was also studied. Treatment with liposome-associated PDD plus local heating resulted in a dose-modifying factor of 7 when compared with free drug and no hyperthermia. The dose-modifying factor was 2.5 when PDD liposomes and heat were compared within free drug and heat. Thus, PDD could be specifically released from liposomes by heat and resulted in both a greater drug uptake and a delayed tumor growth following treatment. Potential normal tissue toxicity problems, however, still need to be resolved before clinical application of this combined modality will be possible.

Previously, we reported that local lidocaine infusion of a CA 755 mammary adenocarcinoma growing in C57BL X DBA/2 F1 mice, when combined with local heating for 1 hr in a 43.5 degrees water bath, significantly increased survival and inhibited tumor growth more than heating alone. Because of its clinical implications, systemic lidocaine was tested in the above model system and in a murine fibrosarcoma tumor model. An equivalent supraadditive, tumor-inhibitory effect of heat and lidocaine was obtained with both systemically and intratumor-administered lidocaine. The serum levels of lidocaine necessary to achieve tumor regression were within the therapeutic range for the control of arrhythmia in humans. Several treatment schedules, varying the mode of drug delivery, were evaluated. The effects of treatment on tumor growth characteristics were analyzed using an extension of the Cox survival model.

Hyperthermia alone and hyperthermia with lidocaine cause changes in the fine structure of the CA755 tumor cell as well as the breakdown of the tumor vasculature. The first structural change, observed immediately after termination of hyperthermia of 43.5 degrees for 1 hr, is the vesiculation of the Golgi apparatus. Other structural changes occur later but with variable times of onset. The changes appear to be unrelated to the presence of lidocaine. Vascular breakdown results in hemorrhaging within the tumor, and its onset and intensity appear to vary directly with the size of the tumor. Breakdown of the tumor cell plasmalemma and degenerative changes of the cytoplasm and nucleoplasm are seen more frequently in large tumors and in the interior of small tumors at any given time after the end of hyperthermia. The vesiculation of the Golgi persists in treated cells for as long as 30 hr. This modification may represent an intensification in the function of the Golgi apparatus; however, it closely corresponds to that found in a variety of other cells treated with a class of compounds, including lidocaine, that specifically inhibits the function of the Golgi apparatus. The effect of these compounds is rapidly reversible, unlike hyperthermia. Since the Golgi apparatus probably is crucial in repairing any deleterious effects of hyperthermia, any impairment of its normal function would place most treated tumor cells in a difficult position. The rate of tumor destruction may ultimately depend on the breakdown of the tumor vasculature following hyperthermia and lidocaine.