5. Pharmacology Division

The development of new treat-ments, especially effective anticancer drugs, is essential for improving the survival of cancer patients. The research activities of the Pharmacology Division can be divided into four categories. (1) Identification of the molecular targets of cancer chemotherapy to obtain clues as to the development of new anticancer drugs; (2) Basic studies for the clinical application of gene therapy; (3) Pharmacokinetic and pharmacodynamic analyses of new anticancer drugs to develop the most appropriate schedules of administration; (4) Phase I, II and III clinical trials of new anticancer agents and combined modalities.

Molecular and Biochemical Pharmacology

Ganglioside GM₂ is one of the major cell surface gangliosides expressed in human tumors. A mouse/human IgG₁ chimeric anti-GM₂antibody, KM966, displayed anti-tumor activity in human tumor cells both in vitro and in vivo. Increased GM₂ expression, detected by flow cytometry, and thin-layer chromatography, was observed in the SBC-3/ADM and AdR MCF7 adria-mycin resistant cell lines. Increased N-acetyl galactosaminyltransferase mRNA was detected in adriamycin resistant cell lines by Northern blot analysis. Significantly higher killing via KM966 was observed in adriamycin resistant cell lines by antibody or complement dependent cytotoxicity assay.⁽⁵⁹⁾ The daphnane-type diterpene gnidimacrin, isolated from the Chinese plant Stellera chamaejasme L., was found to strongly inhibit cell growth in human leukemia, stomach cancer, and non-small cell lung cancer in vitro at concentrations of 10^-9 to 10^-10M. This compound showed significant antitumor activity against murine leukemias and solid tumors in vivo. In K562, a sensitive human leukemia cell line, gnidimacrin induced blebbing in the cell surface and arrested the cell cycle transiently to G₂, and finally to G₁, phase at growth-inhibitory concentrations. It inhibited PDBu binding to K562 cells and directly stimulated protein kinase C (PKC) activity.⁽⁶⁰⁾ Topoisomerase I inhibitors and cisplatin showed a synergistic effect against human small cell lung cancer cells, SBC-3. Increased DNA interstrand cross links analyzed using an alkaline elution assay were observed by simultaneous exposure to cisplatin and topoisomerase I inhibitors, while cisplatin augmented the topoisomerase I inhibitory activity of NB506 and CPT-11.⁽⁶¹⁾ Reports related to this work can be found in the attached list of references.^(62-73)

Gene Therapy

The advantages of adenovirus vectors are their non-dependence on host cell proliferation, broad host range and potential capacity for large foreign DNA inserts. An Adex1CA vector, with a regulatory sequence of chicken b-actin serving as the promoter and an enhancer derived from cytomegalovirus, produced a higher transduction ratio and greater exertion levels than adenovirus vectors with other promoter systems. Transduction with Adex1CA vectors containing the human IL-2 gene (Adex1CAhIL-2) resulted in enhanced secretion of IL-2 from the gene- modified cells. Treatment with normal human serum inhibited gene transduction by Adex1CAhIL-2. The secretion of IL-2 from the gene-modified cells irradiated at 100 Gy before transduction continued for 8 days.

Pharmacokinetics and Pharmacodynamics

The circadian changes in pharmacokinetics were evaluated in patients receiving etoposide infused at a constant rate. The percent plasma etoposide concentration at 21:00 was significantly lower than those at any times during infusion (P=0.024).
In phase I studies of 24-hr and 3-hr infusions of paclitaxel, the maximum tolerated doses were 180 and 240 mg/m², and the recommended doses were 180 and 240 mg/m², respectively. Granulocytopenia was more pronounced in patients receiving the 24-hr infusion of paclitaxel.

Clinical Trials

A Phase II study of paclitaxel given as a 3-hr infusion was conducted in patients with previously untreated, unresectable stage III or IV non-small cell lung cancer. Twenty-three (38%) of 60 assessable patients achieved a partial response, with a median duration of 3.2 (range 2.3-11.1) months. The median survival for all patients was 11.2 months, and the one-year survival rate was 48%. Thirty (50%) patients developed grade 4 neutropenia. Nonhematological toxicities were mild, except for pulmonary toxicity in one (1.7%) patient.⁽⁷⁴⁾ To assess the feasibility of treatments for patients with small cell lung cancer (SCLC) showing a poor performance status (PS), the outcome was reviewed in 13 SCLC patients showing poor PS of ECOG 3 or 4. The PS of most patients improved with treatment, but no improvement was seen in 5 patients. Chemoradio-therapy was tolerable in PS3 SCLC patients. PS4 patients with severe conditions or combined disease are not candidates for chemoradiotherapy.⁽⁷⁵⁾ Reports related to this work can be found in the attached list of references.^(76,77)

List of papers from this division

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