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Fluoropyrimidines induce cytotoxicity, in part, by inhibiting the proliferation-coordinated enzyme thymidylate synthase (TS), which is essential for DNA synthesis. Tumor TS levels are clinically predictive of post-surgical tumor recurrence and of response to fluoropyrimidine chemotherapy. Fluoropyrimidine drug toxicity and efficacy each vary reproducibly in humans and animals, depending upon their circadian timing. In vivo, normal tissues and some tumor tissues exhibit circadian coordination of cellular proliferation. We therefore asked whether TS activity is coordinated rhythmically throughout the day in the normal proliferative tissues most damaged by fluoropyrimidine drugs. To assess tissue and time of day TS activity differences, we harvested normal tissues from female mice living on a 12:12 hr light:dark schedule at each of 6 different equispaced times throughout a 24 hr cycle and measured TS catalytic activity. We observed up to 10-fold differences in vivo in TS activity among different normal tissue types, roughly paralleling their proliferative state and relative fluoropyrimidine sensitivity. In normal tissues most damaged by fluoropyrimidines (bone marrow, small intestinal mucosa and oral mucosa/tongue), TS activity varies up to 2-fold throughout each day. In bone marrow, the circadian pattern of TS activity parallels the circadian rhythm in proliferation in this tissue. This circadian organization of TS, one of the primary fluoropyrimidine targets in normal tissues, probably contributes in vivo to the time of day differences in the toxic-therapeutic ratio of circadian-timed fluoropyrimidine drug therapy.

To understand whether mammalian circadian time structure measurably affects the host-cancer balance, we studied tumor-take frequency after s.c. tumor cell inoculation and the number of pulmonary tumor nodules after i.v. tumor cell injections at each of 6 equispaced times of day. We employed 2 genetically distinct mouse strains and 2 different tumor model systems, a methylcholanthrene A-induced fibrosarcoma of C(3)HeJ mice and 2 B(16) melanoma cell lines of vastly different metastatic efficiency in C57 Black/6 mice. Fibrosarcoma cells were injected s.c. in 1 of 8 different doses, at 1 of 8 permutated anatomic sites and at 1 of 6 equispaced circadian times, in 96 female C(3)HeJ mice maintained under a synchronizing schedule of 12 hr light alternating with 12 hr dark. Regardless of tumor cell dose and inoculum location, tumor-take frequency depended strongly upon the circadian stage of tumor cell inoculation. Injections of between 2,000 and 50,000 live tumor cells inoculated near the daily sleep/wake interface resulted in the lowest incidence of tumor take compared with inoculation at other times of day. In the experimental i.v. B(16) melanoma metastatic model (N = 110), the capacity of both high and low metastatic potential clones to successfully metastasize to lung depended, to a large extent, upon when in the day each of these clones was injected. Similar to the fibrosarcoma data, the daily sleep/wake boundary was the time of day associated with the greatest resistance to metastatic spread.

The toxicity and/or efficacy of more than twenty anticancer agents have been shown in various experimental systems to be dependent upon the circadian timing of their bolus administration or the circadian shaping of their continuous infusion. In cancer patients, the toxicity of several single agents, given either as bolus or infusion, and a growing number of drug combinations have been shown to similarly depend upon their timing. While clinical trials currently underway demonstrate that the circadian stage of drug toxicity and dose intensity each depend upon their circadian timing, definitive investigations of whether or not cancer control and patient survival are similarly dependent upon circadian treatment timing are currently under way. Both clinical trials of treatment timing and chronotherapy depend totally upon the development and use of programmable wearable and implantable, single-channel and multi-channel, open and eventually closed loop delivery systems. First generation intelligent delivery systems are currently available, work well, are economical and are destined, for economic reasons, to be more widely used. When used, each system requires temporal input, making it impossible to avoid specification of drug sequence, interval between drugs or treatment cycles and circadian treatment timing. The advent of biological therapy with cytokines and growth factors makes it likely that the precise timing of cancer therapies will be of growing importance.

Although metastatic bladder cancer is difficult to treat effectively, chemotherapy combinations and schedules have emerged recently that can result in long-lasting complete responses in some patients. Response rates, response durations, and survival patterns of the entire patient population are, however, unsatisfactory. Whereas survival times of these patients following therapy with cisplatin alone or in combination with other drugs are not significantly different, complete response rates are higher and disease-free survival is longer when combinations are used. Higher dosages are associated with better response rates but also with substantial toxicity. Extensive local pretreatment or prior systemic chemotherapy reduces the likelihood of clinically meaningful disease response. Several adjuvant studies have demonstrated an advantage in length of disease-free survival for chemotherapy-treated patients when compared to those who are observed following operation. Metastatic transitional cell bladder cancer is a chemotherapeutically treatable malignancy. Locally advanced disease may be most effectively treated by aggressive surgery followed by cisplatin-based combination chemotherapy. The highest response rates and longest disease-free survivals are uniformly associated with aggressive and prolonged multidrug therapy.

The introduction to medical practice of chemical agents for fighting human cancer some 30 years ago brought hope to a field of medicine previously shrouded in despair and impeded by superstition. Gradually more and better agents have become available to the physician and to the patient suffering from cancer. The physician-scientist has, in turn, learned a great deal about normal and abnormal cellular biology by using these drugs as probes. The observations that certain tissues and certain tumors share patterns of drug toxicity have led to a broadening of biologic understanding and to the use of combinations of drugs with shared antitumor activity and unshared toxicities. This empiric art of cancer chemotherapy has resulted in great progress in the treatment of a large number of advanced cancers. As important, however, is that this experience has resulted in knowledge which is leading to the development of rationally designed therapeutic regimens; to drug analogues seeking greater therapeutic-toxic ratios; to the development of methods for chemically interfering with toxic drug effects while allowing or enhancing antitumor effect; and to work defining effects of drug timing. Drug timing research considers drug dosage in respect to the timing of a drug relative to the timing of other drugs (drug-time-drug interactions) or to other doses of that same drug (drug-drug interval); the order of drugs (drug-drug sequence); and the timing of drugs relative to an internal organismic time structure (time-drug interactions). Data in this brief review clearly show that drug timing needs to be considered when designing rational chemotherapy for a living organism suffering from a cancer. The beautiful spatiotemporal complexity of life is not to be ignored or avoided, but should be considered as a golden opportunity to use what few imprecise chemical weapons we have a little more effectively.

A preclinical murine renal model system is available for evaluation of the effectiveness of therapeutic agents. Clinical review reveals that objective response rates to hormonal agents reported since 1971 have been substantially lower than those reported prior to 1971. Many chemotherapeutic agents have not been adequately evaluated clinically or with the experimental model. Vinblastine to date may be the most active single agent with a 25% objective response rate. At the present time, it is uncertain whether combination chemotherapy or hormonal chemotherapy add to response rates obtained with single agents. There is some evidence that immunotherapy may be of some adjuvant benefit and, thus may provide an additional avenue of investigation.

The toxicity and efficacy of at least a dozen of the most commonly used anticancer drugs vary predictably depending on when in the day they are given. In a series of murine experiments involving CD2F1 mice, we have demonstrated that the safest time for FUDR administration is the mid- to late activity span. In a clinical pilot study, an implantable programmable drug-administration device (Medtronic, Inc), allowing automatic dose modifications of continuous long-term infusion, was employed to investigate whether this is also true in cancer patients. Toxicity of FUDR given as continuous flat infusion was significantly greater than that of time-modified infusion regardless of the route of drug administration. Responses have occurred with at least equal frequency, and patients are currently being followed to see if the pattern of drug delivery has an effect on patient survival.

We treated 25 patients with progressive metastatic renal cell carcinoma with continuous infusion of 5-fluoro-2-deoxyuridine (FUDR) by implanted pump. FUDR was infused for 14 days at monthly intervals. Starting dose was 0.15 mg/kg/day intravenous or 0.25 mg/kg/day intra-arterial; intravenous doses were increased or decreased in increments of 0.025 mg/kg/day as permitted by toxicity. Circadian time modification of the infusion shape (sinusoidal with the peak centered around 6 p.m.) significantly lowered serious intravenous infusion-associated toxicity, allowing higher dose intensity. In 24 evaluable patients, two complete responses (8%), six partial responses (25%), and one minor response were seen. One secondary partial response was observed after infusional velban (total objective response rate 37.5%). Previously progressive disease was controlled in greater than 80% of our patients. During a median follow-up period of 8 months (range of 2-26 months), the overall survival for all 25 patients is 75%. Our results indicate that metastatic renal cell cancer responds to infusional chemotherapy and that the circadian shape of infusion markedly affects our ability to deliver effective doses.