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References1 . Rutgers JL. Young KH. Scully RE. The testicular 'tumour' of the adrenogenital syndrome. Am. J. Surg. Pathol. 1988: 12: 503-51 3. 2. Lawrence WD, Young RH. Scully RE. Sex cord stromal tumors. In: Talerman A, Roth LM. eds. Pathology of the Testis and its Adnexa. Edinburgh: Churchill Livingstone. 1986: 67-92. 3. Burke EF. Gilbert E. Uehling DT. Adrenal rest tumors of the testes. J. Urol. 1973: 109; 649-652. 4. Cunnah D, Perry L. Dacie JA et a!. Bilateral testicular tumors in congenital adrenal hyperplasia: a continuing diagnostic and therapeutic dilemma. Clin. Endocrinol. 1989: 30; 141-147. 5. Franco-Saenz R. Antonipillai. Tan SY et al. Cortisol production by testicular tumors in a patient with congenital adrenal hyperplasia (21-hydroxylase deficiency).

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Summary We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. While a 24 h exposure to 0.1 M TMQ inhibited cell growth by 50-60% in both cell lines, it did not reduce clonogenic survival. A 24 h exposure to 1 and 10 ILM TMQ produced 42% and 50% lethality in C4 cells, but did not affect H630 cells. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > 85% in both cell lines; in addition, the reduction in apparent free DHFR binding capacity (,<20% of control), depletion of dTTP, ATP and GTP pools and inhibition of [6-3H]deoxyuridine incorporation into DNA were similar in C4 and H630 cells. TMQ produced a more striking alteration of the pH step alkaline elution profile of newly synthesised DNA in C4 cells compared with 630 cells, however, indicating greater interference with DNA chain elongation or more extensive DNA damage. When TMQ was removed after a 24 h exposure to 0.1 tM, recovery of DHFR catalytic activity and apparent free DHFR binding sites was evident over the next 24 -48 h in both cell lines. With 1 and 10 JAM, however, persistent inhibition of DHFR was evident in C4 cells, whereas DHFR recovered in H630 cells. These data suggest that, although DHFR inhibition during TMQ exposure produced growth inhibition, DHFR catalytic activity 48 h after drug removal was a more accurate predictor of lethality in these two cell lines. Several factors appeared to influence the duration of DHFR inhibition after drug removal, including initial TMQ concentration, declining cytosolic TMQ levels after drug removal, the ability to acutely increase total DHFR content and the extent of TMQ-mediated DNA damage. The greater sensitivity of C4 cells to TMQ-associated lethality may be attributed to the greater extent of TMQ-mediated DNA damage and more prolonged duration of DHFR inhibition after drug exposure.

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