Niramol Savaraj

Pharmacology of mitoxantrone in cancer patients

SummaryRadioactive mitoxantrone was administered at doses of 1–12 mg/m2 by rapid IV infusion to 11 patients. Of the 11 patients, six had normal liver and kidney function tests while the remaining five had abnormal third space and/or hepatic dysfunction. In the former group, the initial t1/2 was 13.7 min and terminal t1/2 was 37.4 h. The apparent volume of distribution was 13.8 l/kg. The total clearance rate was 230.7 ml/kg/h. The recovery of unchanged mitoxantrone from urine was 6.8% at 24 h and 7.3% at 72 h, while the corresponding recovery of total radioactivity was 9.4% at 24 h and 11.3% at 72 h. In the five patients with abnormal liver function or third space the initial t1/2 was variable and ranged from 11.5–63.6 min, and the terminal t1/2 ranged from 53.3–173.2 h, whereas the total clearance rate varied from 52.7–170.2 ml/kg/h. However, the cumulative urinary excretion of unchanged mitoxantrone was similar to that of patients with normal hepatic function: 3.9 at 24 h and 5 at 72 h. Biliary excretion was studied in one of these patients, who had jaundice and hepatic impairment; only 2.3% of 14C was excreted in 24 h and 2.7% in 96 h, of which 39% and 41%, respectively, were unchanged mitoxantrone. Our results suggest that mitoxantrone is taken up rapidly by tissue from which it is released slowly. Reduction of mitoxantrone dose is therefore advisable in patients with liver dysfunction or abnormal third space.

Pharmacological disposition of 1,4-dihydroxy-5-8-bis[[2[(2-hydroxyethal)amino] ethyl]amino]-9,10-anthracenedione dihydrochloride in the dog

SummaryDHAQ, a new antitumor agent, has been selected for clinical trial on the basis of its activity against a number of transplantable rodent tumors. In anticipation of the clinical trial of this agent, the pharmacology of DHAQ was studied in beagles by high-pressure liquid chromatographic and radiochemical techniques that are specific for the unchanged drug. 14C-DHAQ was administred IV to beagles at a dose of 5 mg/kg, 100–125 μCi total. With a maximal plasma concentration of 75 = 2.7 ng/ml, DHAQ was eliminated from the plasma with a half-life of 28.1 h during the terminal phase. The total clearance of DHAQ was 10.1±0.4 mg/kg/min, while the apparent volume of distribution was 26.6±4.9 l/kg. In 48 h 2.4%±0.6% of the dose was excreted in the urine and 3.0%±0.1% in the bile as the unchanged drug. At autopsy performed 5 h after dosing, the highest percentage of the administered DHAQ was in the liver (49.7%±2.7%), followed by the small intestine (7.1%±0.7%), kidneys (2.7%±0.1%), lung (1.9%±0.3%), spleen (1.6%±0.3%), and stomach (1.3%±0.1%). The heart, large intestine, pancreas, gallbladder, urinary bladder, and brain each retained less than 1% of the dose. However, 24 h after dosing 10.6% of the drug was detected in the liver and 2.9% in the small intestine. In terms of the percentage of the dose, the distribution of DHAQ in the other organs either remained unchanged or increased slightly. In concentrations varying from 10 ng/ml to 10 μg/ml the drug was 70%–80% bound to plasma protein. DHAQ was metabolized to two unidentified metabolites. Thus, this drug appeared to be cleared from the plasma of beagle dogs chiefly by tissue binding, leading to possible persistence of the drug in certain body compartments.

Central nervous system (CNS) penetration of homoharringtonine (HHT)

Generally tritiated homoharringtonine ([3H]HHT, 150 μCi, 430 μg) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

High-Performance Liquid Chromatography (HPLC) of the New Antineoplastic 9,10-Anthracenedicarboxaldehyde Bis[(4,5-Dihydro-1 H-Imidazole-2-yl)hydrazone] dihydrochloride (CL 216,942; Bisantrene)

Abstract 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazole-2-yl) hydrazone] dihydrochloride, (Bisantrene, CL 216,942, or NSC-337766) (Fig. 1) is a new anthracenedione derivative which has significant antitumor activity in a number of animal tumor systems including L1210 leukemia, P388 leukemia, Liberman plasma cell tumor, B16 melanoma, Ridgeway osteogenic sarcoma and colon tumor 26 in mice (1). Although structurally, it bears some resemblance to doxorubicin, bisantrene differs in producing less myocardial toxicity at equitoxic doses. Therefore, Bisantrene may be a useful antitumor agent in doxorubicin sensitive tumors (2). In order to study the pharmacokinetics of the agent in conjunction with the phase I and II clinical trial in our institute, we developed an analytical method for Bisantrene. The sampling and analytical methods are rapid, reproducible, highly sensitive and applicable to the determination of the agent in plasma, urine and cerebrospinal fluid.

Phase I clinical evaluation of oral and intravenous 4-demethoxydaunorubicin

Thirteen patients were treated with both the oral and intravenous preparations of 4-demethoxydaunorubicin (DMDR). The drug was well tolerated in both forms. Neutropenia was the dose-limiting side-effect. Approximately 30% of the compound was absorbed when given orally. The maximum tolerated dose was 12.5 mg/m2 intravenously or 50 mg/m2 (10 mg/m2 q d X 5) orally, given every 21-28 days.

Clinical pharmacolinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1H-imidazol-2-yl)hydrazone]dihydrochloride

SummaryWe studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120–250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6±0.3 h and a terminal t1/2 of 24.7±6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1±5.9 l/kg, and the total clearance was 1045.5±51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4%±1.1% of the dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Mechanisms of l-Arginine-Auxotrophic Response and Their Cancer Therapeutic Implications

l-arginine (Arg) is a semi-essential amino acid. Because there is no specific storage system for the cellular l-Arg pool, Arg needs to be de novo synthesized or directly acquired from an extracellular source to meet physiological need. Different organs have different requirements of Arg. For example, sufficient Arg is synthesized in the liver and kidney of an adult but not sufficient to the growing child (Chaveroux et al. Biochimie 92:736–745, 2010). Arg is essential for fetuses and neonates.

l-Arginine in Cancer Therapy

One method of treating certain cancers is by amino acid depletion. The best example of this is asparaginase, which has been used to lower blood levels of asparagine, a nonessential amino acid in humans. Asparaginase has been used for years to treat acute lymphoblastic leukemia, the most common form of leukemia in children and young adults. Since most human body cells do not require asparagine for their growth and survival, whereas the leukemic cells are auxotrophic for this amino acid, this represents a targeted approach to treatment.

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.