Lynn G. Feun

Clinical pharmacology of 4-demethoxydaunorubicin (DMDR)

SummaryDMDR, a daunorubicin derivative with a higher therapeutic index and lower cardiotoxicity than either the parent drug or doxorubicin, is active when given PO in experimental animals. We studied its pharmacokinetics in ten patients receiving DMDR IV or PO or IV and PO sequentially at 10–12.5 mg/m2. DMDR and its metabolites were quantified by high-performance liquid chromatography and fluorometry. In nine patients who received DMDR IV the unchanged drug disappeared from the plasma biphasically with a mean terminal half-life of 27.0±5.5 h, an apparent volume of distribution of 63.9±12.61 kg-1, and a total clearance of 1.9±0.41 kg-1 h-1. In 24 h only 5.1%±1.1% of the dose was excreted in the urine. In comparison, in 19 studies the plasma half-life of DMDR given PO was 34.8±6.7 h, 2.3%±1.3% was excreted in the urine in 24 h, and the maximum plasma drug concentration was reached in about 1 h. The bioavailability of DMDR given PO was about 39% according to comparison of the areas under the plasma DMDR concentration versus time curves for the two routes, but 45% according to comparison of the 24-h cumulative urinary excretion rates. In one patient with severe liver dysfunction following oral administration, the plasma DMDR half-life was 56.8 h, more than twice the average length. By either route, the drug was quickly metabolized to one major metabolite, DMDR-ol. The plasma half-life of DMDR-ol was 72.5±24.7 h, or 35.7±7.4 when DMDR was administered IV or PO. In the plasma, DMDR-ol always exceeded DMDR in concentration. Moreover, the 24 h cumulative urinary excretion of DMDR-ol as a percentage of the dose of DMDR administered was 7.8 following IV and 7.4 following PO administration.

Phase I clinical trial of intralesional or intraventricular leukocyte interferon for intracranial malignancies

SummaryEight patients were treated with leukocyte interferon for a variety of neurological malignancies that had failed or recurred after conventional therapy. Three patients with malignant astrocytoma received intratumoral interferon in dosages up to 9 million units 3×/ week, with total dosages of up to 160 million units. Interferon was administered intraventricularly in 4 patients with leptomeningeal metastases and one patient with multiple brain metastases. Dosages increased from 1 to 10 million units 3×/ week, and total dosages of up to 113 million units were given intraventricularly. Acute side effects of fever, nausea, vomiting, and headache occurred almost exclusively with intraventricular injections, and these subsided after the initial injection. Fatigue, loss of appetite, weight loss, and hematologic toxicity developed a few weeks after onset of treatment, independent of the dose given. A modest tumor regression was seen on CT scans of one patient with a malignant astrocytoma, who was treated with interferon for 8 months. In a114 patients with leptomeningeal metastases, the CS F became free of malignant cells for 6 to 10 weeks, while clinical improvement was less dramatic.

A Phase I study of chemoembolization with cisplatin and lipiodol for primary and metastatic liver cancer

Twenty patients with either unresectable primary hepatocellular carcinoma or hepatic metastases were entered into a Chemoembolization program with cisplatin and lipiodol; 19 patients were evaluable for response. Doses of cisplatin ranged from 40 to 100 mg/m2. Toxicity was tolerable and reversible and included abdominal pain, transient elevation in serum creatinine, serum bilirubin, and serum transaminases. Less common side effects include fever, ascites or pleural effusion, and hiccups. Two of four patients with ocular melanoma had partial responses. Duration of response was 10 and 11 months. Among 8 patients with unresectable hepatoma, 2 patients had partial response for 10+ and 13 months, 2 had minor response for 2 months and 4+ months, 1 patient had stable disease for 5+ months, and 3 patients failed to respond. Of the six colon cancer patients treated, one had a partial response in the liver, but developed progressive nodal disease, and another patient had a partial response for 3 months. Chemoembolization of the liver with cisplatin and lipiodol is feasible and doses of cisplatin at least 100 mg/m2 are tolerable. Antitumor activity in metastatic ocular melanoma is encouraging but requires further study.

Technetium-99m labeled monoclonal antibodies in the detection of metastatic melanoma

Twenty-six stage ll/lll malignant melanoma patients with 321 measurable metastatic lesions were imaged using Fab fragments of an IgG murine monoclonal antibody labeled specifically with 10-30 mCi Tc-99m with a bifunctional chelating method (NeoRx, Seattle, WA). There were no side effects or adverse reactions. Immunoscintigraphy demonstrated 66.6% of lesions larger than 1 cm and 92.5% of lesions larger than 3 cm. Most frequently detected metastases were in lymph nodes, subcutaneous areas, and bone. Of lesions less than 1 cm, 23.6% were detected if superficial cutaneous lesions were excluded. The smallest detectable lesion was 4 mm. Twenty-one additional clinically unsuspected sites were visualized in 12 of the 26 patients studied. Of these, 56% were confirmed as metastasis by other tests. There were apparent nonspecific localizations owing to other causes, including fracture, varicosities, skin abscess and pneumonitis. Increased experience in image analysis facilitates correct interpretation of these localizations. This study demonstrates that imaging with Tc-99m labeled antibody fragments detects melanoma lesions in organs routinely surveyed and in other areas not routinely assessed by other imaging techniques. The procedure is readily performed and safe. The principal advantage of the test is its ability to survey the entire body and all organs with a single test. Its principal limitation, in common with other diagnostic imaging procedures, is its poor sensitivity for detecting lesions less than 1 cm.

Comparison of CNS Penetration, Tissue Distribution, and Pharmacology of VP 16–213 by Intracarotid and Intravenous Administration in Dogs

Eight beagle dogs received [3H]VP 16-213 at 2 mg/kg administered intravenously (IV) or intra-arterially (IC) through a catheter inserted into the internal carotid artery. Blood, urine, bile, and cerebrospinal fluid (CSF) samples were collected at intervals. At 1, 6, 24 hr, and 2 weeks after drug administration the dogs were sacrificed and the major organs analyzed for drug concentration. VP 16-213 concentration was determined by radiochemical assay and high pressure liquid chromatography. The plasma t1/2 in the IC group of dogs was 1.0 hr, the volume of distribution was 1.7 L/kg and the clearance was 1.5 ml/hr/kg. In the IV group the values were 1.7, 3.9, and 1.6, respectively. The CSF concentration peaked at 1 hr by both routes, but was higher at all time points in the IC group. At 24 hr and 2 weeks after IC VP 16-213, drug concentration in brain tissue was at least four times higher in the IC group compared with the IV group. In extracranial organs the reverse was true, with the bone marrow cell concentration 1.6 times higher by IV compared to IC (267.2 ng/g and 164.5 ng/g, respectively). Two major and one minor metabolites were found in plasma, urine, bile, and tissue by both routes, however, not all metabolites were found in all organs and body fluids. No acute neurologic toxicity was noted in the IC group and no histopathologic changes by light microscopy were found in the brain or other organs. IC VP 16-213 produced higher drug concentration in the brain of dogs compared with IV administration and was well tolerated at the dosage used.

Clinical pharmacology of intracarotid etoposide

SummaryPharmacokinetics studies were performed in ten patients who received VP-16 by intracarotid infusion at 100–300 mg/m2. VP-16 was analyzed by high-pressure liquid chromatography. ESTRIP and NONLIN were used to characterize VP-16 pharmacokinetics. VP-16 disappeared biphasically, with a t1/2 β of 6.1±1.4 h; the total clearance was 26.8±2.8 ml/min/m2, and the Vss was 8.8±1.6 l/m2. The pharmacokinetics was not significantly different after administration by the IV route. However, at a lower dosage, <140 mg/m2, the half-life appears to be shorter. This may or may not be significant, since VP-16 pharmacokinetics is quite variable and the number of patients studied is relatively small. Overall, the brain and brain tumor do not appear to have any first-pass effect on VP-16 pharmacokinetics.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Autophagic Protein Cleavage in Melanoma Cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring protein molecule in humans. Previous studies established that TRAIL is capable of inducing apoptosis of cells which express its cognate surface receptors. It is also known that TRAIL toxicity is specific for cancerous cells but not for normal ones. This has led to the development of TRAIL-derived drugs such as soluble recombinant TRAIL for the purpose of cancer treatment. However, resistance to TRAIL has also been reported in various cancer types including melanoma, a malignant tumor notorious for its resistance to therapies. In our research on the arginine-deprivation treatment for melanoma, we found that TRAIL can be synergistic with arginine depletion in causing cell death through apoptosis, and further investigations revealed that the cleavage of autophagic proteins such as Beclin-1 and Atg5 played an important part in switching autophagy toward apoptosis in melanoma cells. In this chapter, a more comprehensive review on TRAIL-induced cleavage of autophagic proteins in melanoma and relevant results from other types of cancers are discussed. The purpose of this review is to shed more light on the significance of this transition from autophagy to apoptosis through autophagic protein cleavage. These findings could be applied to the treatment of melanoma and other suitable cancers which use autophagy for survival after anticancer therapies.