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The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment. [ABSTRACT FROM AUTHOR]

Carboplatin has been developed for clinical trials as a less nephrotoxic, less emetogenic analog of cisplatin. In preclinical tumor models it was less potent than the parent compound on a molar basis, but reduced toxicity allowed comparable antitumor doses to be given. In phase I studies its dose-limiting toxicities were reversible myelosuppression, especially thrombocytopenia. Leucopenia and anemia occurred to a lesser degree. Other reported toxicities included nausea, vomiting, malaise, myalgia, arthralgia, ototoxicity, hypomagnesemia, and proteinuria. Nausea and vomiting occurred frequently, but was much less severe than that observed with cisplatin. The incidence of serum creatinine elevations was low. The increase was usually reversible and occurred only in association with administration of aminoglycosides, or abnormal pretreatment renal function. Recommended phase II doses by schedule are: bolus every 4 weeks, 400-500 mg/m2 (560 mg/m2 in children); 24 hour continuous infusion every 4 weeks, 320-400 mg/m2; weekly bolus for 4 consecutive weeks with 2 weeks rest, 100-125 mg/m2 (175 mg/m2 in children); bolus for 5 consecutive days every 4 weeks, 77-95 mg/m2. Objective responses were observed during these phase I studies in adult patients (head and neck, breast, renal carcinomas) and children (osteosarcoma, brain stem lesions). In addition to phase II evaluations in all major tumor types, plans for phase III studies in selected tumors are underway.

Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic action have related its antitumor activity with its ability to bifunctionally intercalate with double stranded DNA. Toxicologic studies were carried out in CDF1 mice and beagle dogs using intravenous injections. For the mice studies the dose ranges were 288-692 mcg/kg (864-2076 mcg/m2) by single bolus, and 112-254 mcg/kg/day (336-762 mcg/m2/day) for five consecutive days. In the dog, dose ranges studied were 8.9-89.4 mcg/kg (178-1788 mcg/m2) by single bolus, and 3.4-33.5 mcg/kg/day (68-670 mcg/m2/day) for five consecutive days. The major toxic effects were found in the gastrointestinal, hepatic, and lymphoreticular systems. These were reversible at all but the highest dose, in dogs that had been treated for five consecutive days. Phase I clinical trials using various intravenous schedules were sponsored by the National Cancer Institute. Nausea, vomiting, reversible liver enzyme abnormalities, and allergic reactions were the most common toxicities encountered. Based on results from these studies, the National Cancer Institute has recently begun phase II trials in a broad range of diseases. These trials will further characterize echinomycin's toxic effects and its antitumor activity.

Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.

Hexamethylmelamine (HMM) was selected for development as an antineoplastic agent because it demonstrated activity in a variety of preclinical tumor models. Its mechanism of action is unknown. It has been used in clinical trials since 1964. The clinical toxic effects have consisted of signs and symptoms involving the following systems: gastrointestinal (nausea, vomiting, anorexia), hematologic (leukopenia, mild anemia), and neurologic (critical depression, hallucinations, peripheral motor and sensory deficits). Antitumor activity against advanced ovarian cancer was demonstrated in phase I trials and the drug was quickly incorporated into trials which utilized drug combinations. The majority of these have consisted of phase II trials without an identified control population. As might be predicted, all of the HMM-containing combinations are active. However, the contribution of HMM to the antitumor activity of the combination remains conjectural. Thus, in spite of greater than 15 years of clinical trials with a drug that has single-agent activity, the questions regarding the role of HMM in the treatment of ovarian cancer remain unanswered.

The s-triazine derivatives have shown preclinical antitumor activity against several histologic types. The most widely used compound of this class in the clinic, hexamethylmelamine, has been largely restricted to oral use because of its low solubility and lack of stability in solutions suitable for parenteral administration. New analogs were sought which were soluble and stable and retained antitumor activity. Pentamethylmelamine (PMM), the monodemethylated derivative, showed these promising characteristics. Preclinical toxicology studies of PMM in mice, dogs, and monkeys showed toxic manifestations that involved the hematopoietic, lymphatic, renal, male reproductive, gastrointestinal, and nervous systems; these changes were both infusion-rate- and dose-dependent. Clinical phase I trials of PMM were performed using a variety of infusion durations and frequency schedules. The dose-limiting toxic effect common to all of these trials was protracted nausea and vomiting. In addition, some studies reported dose-limiting central nervous system manifestations in the form of agitation, drowsiness, somnolence, and even coma. Mild to moderate hematologic changes were noted. Because of the severity and frequency of the gastrointestinal and central nervous system toxic effects observed in the completed trials, no new clinical trials of PMM sponsored by the National Cancer Institute are planned. However, the interest in finding a clinically useful parenteral triazine continues.