Although it is now apparent that the intracellular pH may rise considerably above neutrality under physiological conditions, information on the effect of alkaline pH on microtubule assembly and disassembly is still quite fragmentary. We have studied the assembly/ disassembly of bovine brain microtubule protein at alkaline pH in vitro. When microtubules are assembled to a steady state at pH <7 and pH is then made more alkaline, they undergo a rapid disassembly to a new steady state. This disassembly is reversed by acidification. The degree of disassembly is determined largely by the pH-dependence of the critical concentration, which increases five to eight times, from pH 7 to 8. A fraction of assembly-incompetent tubuhn is identified that increases with pH, but its incompetency is largely reversed with acidification. Measurements of microtubule lengths are used to indicate that disassembly occurs by uniform shortening of microtubules . A comparison of shortening by alkalinization with dilution suggests that the intrinsic rate of disassembly is accelerated by increasing pH .The capacity for initiating assembly is progressively lost with incubation at alkaline pH (although some protection is afforded by sulfhydryl-reducing agents) . However, direct assembly from depolymerized mixtures is possible at least up to pH 8.3, and the steady state achieved at these alkaline pH values is stable . Such preparations are readily disassembled by cold and podophyllotoxin (PLN) . Disassembly induced by PLN is also markedly enhanced at alkaline pH, suggesting a corresponding enhancement of "treadmilling."The implications of physiological events leading to alkaline shifts of pH for microtubule assembly/disassembly are discussed, particularly in the light of recent hypotheses regarding treadmilling and its role in controlling the distribution of microtubules in vivo .

Thomsen TK, Pfeiffer P, Bertelsen K. Teniposide or carboplatin in patients with recurrent or advanced cervical carcinoma: A randomized phase II trial. Int J Gynecol Cancer 1998; 8: 310–314. The aim of the present study was to investigate response rates, time to progression, and survival with teniposide or carboplatin in patients with advanced or recurrent cervical cancer and to estimate the toxicity of each drug regimen. Twenty‐eight patients with recurrent or advanced cervical cancer entered the study. Two patients were ineligible (severe renal impairment, n = 1; performance status 3, n= 1) and were excluded from the analysis. The remaining 26 patients were randomized to either carboplatin (400 mg/m2 on day 1, intravenously every four weeks) or teniposide (125 mg/m2 on days 1, 2 and 3, intravenously every four weeks). Twelve patients were randomized to the carboplatin arm and 14 patients to the teniposide arm. They were all comparable with respect to age, performance status, histology, primary FIGO stage, and prior therapy. Response was seen in four patients in each group (33% and 29%, respectively), all but one being partial. (One patient in the teniposide group had complete response). Time to progression and median survival were similar in the two groups (median time to progression 20/17 weeks and median survival 40/41 weeks, respectively.) In general, toxicity was moderate. Leukopenia (WHO grade 3 or 4) was seen in one patient treated with teniposide, and thrombocytopenia (WHO grade 3 or 4) in one patient treated with carboplatin. Eleven patients (79%) in the teniposide group had alopecia requiring a wig. The study implies that both drugs have some activity in cervical cancer. Carboplatin has the advantage that it can be administered on an out‐patient basis.

Background : The increased risk of colonic malignancies in individuals with ulcerative colitis has prompted a search for early biomarkers of disease progression. Aim : To characterize Phase II detoxication enzyme expression during acute and chronic colitis. The mouse model of dextran sulphate sodium (DSS)‐induced colitis represents a relevant system with which to sequentially evaluate the spectrum of biochemical changes associated with colorectal cancer risk. Methods : Acute and chronic colitis were induced in Swiss Webster mice by administering DSS in the drinking water (5%) for 1–4 cycles. Each cycle consisted of 7 days DSS and 14 days of water. The glutathione S‐transferase (GST) activity, γ‐glutamylcysteine synthetase (γ‐GCS) activity and glutathione content of the colonic tissues were determined at various time points throughout the experiment. Alterations in GST isozyme expression were confirmed by Western and Northern blot. Results : GST activity was reduced significantly in the colon by the end of Cycle 1 (84% of control values). Specific activities continued to decrease with subsequent cycles of DSS exposure. By the end of Cycle 4, glutathione levels and γ‐GCS activity had reached 29% and 56% of control, respectively. Conclusions : These data suggest that detoxication enzyme depletion is associated with both acute and chronic colitis and may be an important event in the progression of ulcerative colitis to colon cancer.

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