Purpose
To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy.
Methods
MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis.
Results
ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg.
Conclusions
This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development.
The in vivo biodistribution and pharmacokinetics of 1329, a novel spectinamide antibiotic with anti-tubercular activity, were studied during intravenous administration of an tritium-labeled compound for nine consecutive, 12-hourly doses to rats. Serial blood samples were collected after the first and the eighth dose, and major organs and tissues were collected 1 h after the ninth dose. Urinary and fecal excretion was monitored throughout the dosing period. Radioactivity in the collected samples was assessed by scintillation counting. During the course of treatment, 86.6% of the administered radioactivity was recovered in urine, feces, organs, and muscle tissue. Urinary excretion was the major route of elimination, with 70% of radioactivity recovered from urine and 12.6% from feces. The time profiles of radioactivity in serum after the first and the eighth dose were identical for the first 2 h post-dose, with similar Cmax (3.39 vs. 3.55 mCi/L) and AUC0-τ (5.08 vs. 5.17 mCi • h/L), indicating no substantial accumulation of 1329 during multiple dosing. Radioactivity in major target organs for pulmonary tuberculosis infection, the lungs and spleen, was 2.79- and 3.06-fold higher than in the blood. Similarly, the intracellular uptake of 1329 into macrophages was sixfold higher than for streptomycin. Overall, these observations suggest biodistribution properties favorable for targeting pulmonary tuberculosis infections.
The use of 99m Tc-sulfur colloid lymphoscintigraphy for the determination of lymph flow patterns from a tumor site and localization of the sentinel node has been widely adopted. However, the effects of multiple injections of the radiopharmaceutical can range from mild discomfort to pain. pH-adjusted lidocaine HCl coadministered with 99m Tc-sulfur colloid presents a risk of introducing instability of the radiopharmaceutical, which could lead to aggregation, possibly impeding the kinetics of lymphatic drainage from the tumor site. Methods: In the present study, lidocaine pH-adjusted with 4.2%, 6.3%, or 8.4% sodium bicarbonate was added to the 99m Tc-sulfur colloid radiopharmaceutical to monitor effects on radiochemical purity, zeta-potential, particle size, and pH. These parameters were then used to evaluate the shortterm stability of the preparation. Results: The study revealed that the formulation of lidocaine pH-adjusted with 8.4% sodium bicarbonate added to 99m Tc-sulfur colloid demonstrated a similar change in zeta-potential (24.09 6 2.90 mV) and particle size (10-330 nm) to that of control filtered 99m Tc-sulfur colloid (25.09 6 1.68 mV and 11-343 nm, respectively). However, the 4.2% preparation showed a zeta-potential of 23.01 6 2.24 mV and a particle size range of 10-351 nm. The pH of the 8.4% buffered preparation, at 7.1, was closer to physiologic pH than was the control, at 6.0. The 6.3% pH-adjusted lidocaine-99m Tc-sulfur colloid preparation failed radiochemical purity; thus, it was not included in the analysis. Conclusion: Compared with other 99m Tc-sulfur colloid test formulations of 4.2% and 6.3% pHadjusted lidocaine, the 8.4% sodium bicarbonate pH-adjusted lidocaine-99m Tc-sulfur colloid preparation, taken as a whole, yielded superior quality-control parameters. This formulation would be an acceptable alternative to the control.
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