Pharmacodynamics of taxol in human head and neck tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 1996-05, Vol.56 (9), p.2086-2093
• Main Authors: YUEBO GAN, WIENTJES, M. G, SCHULLER, D. E, AU, J. L.-S
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Chemotherapy; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics
• ISSN: 0008-5472; 1538-7445

The pharmacodynamics of taxol in human head and neck squamous cell carcinoma were studied using histocultures of surgical specimens from patients (n = 22). Tumors were treated with taxol for 24 h. The inhibition of DNA synthesis was determined by 48 h cumulative bromodexyuridine (BrdUrd) incorporation. The induction of apoptosis was measured by morphological changes, in situ DNA end labeling, post-exonuclease III BrdUrd labeling, and DNA fragmentation. Inhibition of the BrdUrd labeling index (LI) by taxol was incomplete, with 11 tumors showing maximal inhibition (Emax) of 30-50% and the remaining 11 tumors showing and Emax of 50-80%. For both groups, the inhibition approached maximum values at 1 microM taxol concentration; an additional 10-fold increase in drug concentrations did not significantly enhance the inhibition. The taxol concentrations required for a 30% inhibition (IC30) were 4.2 and 0.3 microM for the first and second groups, respectively. The IC30 correlated with the Emax (r2 = 0.39; P < 0.001). Taxol induced apoptosis in all tumors, 11 tumors showed a maximal fraction of apoptotic tumor cells between 3 and 10% and 11 tumors between 13 and 28%, whereas untreated controls showed a maximal apoptotic index of < 1%. For individual tumors, the maximal apoptotic index occurred between 0.1 and 3 microM, and correlated with the BrdUrd LI for the untreated control (r2 = 0.37; P < 0.01). It is interesting that > 95% of apoptotic cells were BrdUrd labeled, whereas not all BrdUrd-labeled cells were apoptotic. To investigate the basis of the variable tumor response to taxol, we determined the expression of multidrug resistance P-glycoprotein (Pgp), p53, and bcl-2 proteins, using immunohistochemical staining and Western blot analysis. Eleven (50%), 10 (45%), and 7 (32%) tumors expressed Pgp, p53, and bcl-2, respectively. Patients with Pgp-positive tumors showed a higher number of affected lymph nodes than those with Pgp-negative tumors (P < 0.05). Compared with moderately and well differentiated tumors, the poorly differentiated tumors expressed p53 and Pgp more frequently and showed a lower maximum inhibition of DNA synthesis and a higher apoptotic fraction after taxol treatment (P < 0.05 in both cases). Pgp expression correlated differently with taxol-induced inhibition of DNA synthesis than with apoptosis; Pgp-positive tumors showed a significantly higher Emax (63%) and IC30 (4.2 microM) but also a higher apoptotic index (17%) than Pgp-negative tumors (E