Ti Li Loo

Human tissue distribution of platinum after cis-diamminedichloroplatinum

SummaryUsing X-ray fluorescence spectrometry, platinum concentrations were determined in autopsy tissue samples from 12 patients who had received cis-diamminedichloroplatinum (DDP) 20–120 mg/m2 up to 6 months antemortem. Tissue platinum concentrations were highest in liver (0.5–3.7 μg/g wet weight), prostate (1.6–3.6 μg/g), and kidney (0.4–2.9 μg/g), somewhat lower in bladder, muscle, testicle, pancreas, and spleen, and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum, Platinum concentrations in tumors were generally somewhat lower than the concentration in the organ in which the tumor was located, with the exception of intracerebral tumors. Different metastatic sites in the same patient had substantially different platinum concentrations and hepatic metasutases had the highest concentrations. Intra-arterial administration of drug may augment tissue concentrations of platinum. In a patient undergoing therapeutic abortion 4 days after treatment, the platinum concentration was 0.5 μg/g in the placenta and 0.3 μg/g in the fetus. The data suggest that for in vitro sensitivity testing, DDP concentrations of ≦7 μg/ml should be used.

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.

Concentrations of vinblastine in human intracerebral tumor and other tissues

SummaryUptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

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.

Immune restoration and/or augmentation of local graft versus host reaction by traditional chinese medicinal herbs

The in vitro restorative effect of aqueous extracts from two traditional Chinese medicinal herbs were studied in 19 cancer patients and in 15 normal healthy donors. Using the local graft versus host (GVH) reaction as a test assay for T‐cell function, the extract from astragalus membranaceus (10 μg/ml) induced a restored reaction in nine of ten patients with an increase in local GVH reaction from 18.2 ± 15.8 mm3 to 112.9 ± 94.2 mm3 (P < 0.01). The extract from ligustrum lucidum, likewise effected an immune restoration in nine of 13 cancer patients with an increase in local GVH reaction from 32.3 ± 36.1 mm3 to 118 ± 104.9 mm3 (P < 0.01). This degree of immune restoration appears to be complete as it equals the local GVH reaction observed among untreated mononuclear cells from normal healthy donors (82.8 ± 41.1 mm3, P > 0.1). These results suggest that both extracts of the traditional Chinese medicinal herbs contain potent immune stimulants which may provide the rational basis for their therapeutic use as biological response modifiers. Cancer 52:70‐73, 1983.

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Abstract[14C]AZQ (2–4 mg/m2, 100–200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18–45% of the total radioactivity in tumor tissue and 30–56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/ g vs. 31 ng/ g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

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.

Treatment of cultured human colon carcinoma cells with fluorinated pyrimidines

The shape of the initial part of the dose‐dependent response curve of LoVo cells, an established human colon carcinoma cell line, exposed for 1 hr to graded concentrations of 5‐FU depended on the medium supplement, i.e., fetal calf serum (FCS), in which the cells were treated and subsequently incubated for colony‐formation. At concentrations of 50–100 μg/ml (equivalent to peak plasma levels following an in vivo bolus dose of 15 mg/kg) cell kill was completely prevented by FCS. The serum did not contain thymidine (TdR) but had significant amounts of uridine (UR). When 5‐FU was delivered in dialyzed FCS, concentrations of 50–100 μg/ml achieved only a modest 15% cell kill after 1 hour treatment. Regardless of medium supplement, the killing effect of 5‐FU did not increase beyond concentrations greater than 2,000 μg/ml. Increasing the exposure interval dramatically increased the killing of LoVo cells by 5‐FU, although the effects of medium supplement on the degree of cell survival persisted for about 12 hours. Virtually all of the incorporated 5‐FU was transformed into 5‐FUR, and a very small proportion eventually was incorporated into nucleic acids, suggesting that the killing effect of 5‐FU on LoVo cells is mediated mostly by ribosidation and not by conversion into the deoxyribonucleoside. This conclusion is supported by the failure of 5‐FUdR to kill LoVo cells after a treatment interval of one hour, even at concentrations of 5000 μg/ml; yet after the same exposure interval, 5‐FUR effectively killed cells at concentrations of 50–100 μg/ml. TdR afforded no protection from cell kill by 5‐FU. In contrast, UR was capable of protecting LoVo cells from the lethal effects of both 5‐FU and 5‐FUR even at concentrations as low as 10 μg/ml. Ftorafur exposed to LoVo cells for 1 hour had a slight killing effect (about 20–25%) at concentrations ranging up to 2000 μg/ml. Although the lethal effect of ftorafur was slightly increased after longer periods of incubation, it failed to reach 90% even after intervals of 48 hours. The results on cellular sensitivity that we obtained for LoVo cells treated with various fluorinated pyrimidines differ substantially from those of other investigators who used different methods to assess cell killing on nonhuman and noncolonic cell systems. The predictive relevance of these data as compared to those obtained in other systems is justified by the suboptimal results with these agents in clinical practice.

Clinical kinetics of 1,4-dihydroxy-5,8-bis [[2- [(2-hydroxyethyl)amino]ethyl] amino]-9,10-anthracenedione

The clinical kinetics of 1,4‐dihydroxy‐5,8‐bis[[2‐[(2‐hydroxyethyl)amino]ethyl]amino]‐9,10‐anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half‐life (t½) of 13.7 min and a terminal t½ of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 ±2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

Human central nervous system pharmacology of pentamethylmelamine and its metabolites

Pentamethylmelamine (PMM) 80 mg/ m2 was administered IN. to 8 patients during surgical resection of intracerebral tumors. PMM concentrations in tumors were generally much higher than concurrent plasma concentrations, ranging from undetectable (< .01 μg/g) to as high as 4.47 μg/g and were much higher in malignant melanoma samples than in astrocytoma samples. PMM was barely detectable or undetectable in most samples of edematous brain tissue adjacent to intracerebral tumor and in temporalis muscle. The PMM metabolites tetramethylmelamine (TeMM), trimethylmelamine (TrMM), and dimethylmelamine (University of Texas Cancer Center M.D. Anderson Hospital and Tumor Institute, Houston, Texas, USADMM) were each detectable in tumor samples from one or two patients. Monomethylmelamine (MMM) was present in tumor samples from all except one patient. MMM was noted in samples of edematous brain tissue adjacent to tumor from 4 of 8 patients. It was the only PMM metabolite found in brain. TrMM, DMM, and MMM but not PMM, and TeMM were found in tumor cyst fluid from a patient with an intracerebral malignant melanoma.Two patients receiving therapeutic doses of PMM had biopsies taken of subcutaneous malignant melanoma deposits. PMM was undetectable in samples from one patient but reached high concentrations in the other patient. In both patients, MMM was the major metabolite. There was no indication that PMM penetrated into extracerebral tumors more readily than into intracerebral tumors.Cerebrospinal fluid (CSF) samples were obtained from one patient without neurological toxicity who received low doses of PMM and from 4 patients receiving high doses of PMM who had developed neurological toxicity. In each case, PMM was barely detectable or undetectable in the cerebrospinal fluid while TeMM was found in only one sample. TrMM was detectable in CSF from all 5 patients and DMM was found in CSF from 4 of the 5 patients. MMM was detected in CSF from 3 of the 4 patients with neurological toxicity but was undetectable in CSF from the patient without neurological toxicity.Thus, PMM penetrates readily into human intracerebral tumors but the concentrations attained may vary with the histology. PMM metabolites attained higher concentrations in brain and CSF than did PMM itself and may account for the drugs neurological toxicity.