Gerald D. Weinstein

Autoradiographic analysis of cell proliferation kinetics in human genital tissues

Abstract The human cervical and vaginal cell generation cycle (T c ) and its component parts (T g 1 , T s , T g 2 , T m ) have been defined in normal tissues using in vivo autoradiographic techniques. The most active proliferative compartment is composed of the first and second parabasal layers and accounts for about 90 per cent of reproductive capacity. The single basal layer probably exists primarily as a reserve cell compartment for the parabasal compartment and can be activated by an appropriate stimulus, such as exogenous estrogen stimulation. For example, T c is about 3 days for the parabasal cell and 30 days for the basal cell in normal ovulatory and postmenopausal women; estrogen stimulation can accelerate T c to 1.7 and 11 days, respectively, which is apparently due to shortening of T g 1 . Initial studies indicate marked acceleration of T c in squamous cell carcinoma of the cervix. Clinically, knowledge of normal and abnormal cell proliferation kinetics should provide insight into selective chemotherapeutic programs and dose-time relationships.

Systemic Chemotherapy For Psoriasis: A National Survey

A questionnaire that was mailed to 510 randomly selected dermatologists in the United States surveyed their use of three systemic chemotherapeutic agents for the treatment of psoriasis during the two-year period of 1973 to 1974. Methotrexate was used by 52% of the surveyed dermatologists, while hydroxyurea and azaribine were used by 10% and 2%, respectively. Seventy-five percent of the dermatologists who used methotrexate treated ten or fewer psoriatic patients with this drug. Multiple dose therapy with methotrexate divided over a period of 36 hours each week was the preferred schedule of 66% of the dermatologists. Liver biopsy specimens and creatinine clearance tests were obtained for only 17% and 35% of patients, respectively, prior to initiating methotrexate therapy. The estimated number of dermatologist-treated psoriatics nationwide receiving methotrexate is 25,000.

Cell kinetics and programmed chemotherapy for gynecologic cancer

The results of current investigation into cellular kinetics of both normal and abnormal human genital tissue have stimulated interest in programming chemotherapeutic drug regimens for the treatment of genital cancer. This report outlines the results of cell kinetic studies of normal and abnormal squamous epithelium of the female genital tract and presents preliminary results of a regimen utilizing methotrexate, hydroxyurea, and vincristine in patients with far-advanced squamous-cell cancer of the vulva, vagina, and cervix. A total of 92 patients have received 444 courses of programmed chemotherapy by either pelvic intra-arterial infusion or systemic administration of the drugs. Our results are presented and the theoretical basis of the research is discussed.

Cell proliferation patterns in human malignant melanoma, in vivo

Cell kinetics were studied, in vivo, in 19 patients with metastatic melanoma by autoradiographic technics. Multiple tumor labeling indices (L.I.) were determined with intralesional H3‐TdR in 19 patients and were correlated with the presence of melanin. Serial biopsies were obtained to derive percent labeled mitoses (PLM) curves for 9 individual patients. Duration of the S and G2 phases were calculated using 50 and 37% intercepts from the PLM curves, as well as by two computerized cell‐cycle analysis programs, and the results were compared. Tumor L.I.s were found to be reproducible for distant metastases of similar size in the same patient. Tumor L.I.s had a bimodal distribution for the 19 patients examined. The two significantly distinct subgroups had L.I.s of 18.2 ± 3.4% and 6.7 ± 2.1%. The presence of melanin correlated with the higher L.I. subgroup. The difference in L.I. may reflect a higher growth fraction or a shorter germinative cycle in melanotic tumors. However, the presence of melanin did not correlate with a change in the duration of S or G2 phases. The sum of Ts and Tg2 was approximately 24 hours, regardless of the analytic method. These kinetic parameters are being monitored during chemotherapy for prognostic indicators.

Cutaneous photosensitization by topical hematoporphyrin derivative formulations; potential clinical applications

Photoradiation therapy provides a valuable approach for the selective therapy of diseases localized to the skin and mucous membranes. The topical delivery of photo-reactive drugs provides a means of further enhancing this selectivity by decreasing the undesired prolonged cutaneous phototoxicity associated with the systemic use of such agents. In this study vehicles were selected for effective topical delivery of hematoporphyrin derivative (HPD). Irradiation with either red light (600 nm) or long wave ultraviolet light (UVA) (360 nm) produced localized cutaneous phototoxicity and selective inhibition of epidermal cell proliferation in guinea pigs. Topical delivery produced a higher HPD concentration in dysplastic mouse epidermis versus surrounding normal epidermis. Preliminary clinical studies have demonstrated a partial clinical response in vaginal intraepithelial neoplasia. Studies are in progress to evaluate topical HPD in the treatment of intraepithelial neoplasia of the female genital tract, and hyperproliferative skin diseases, such as psoriasis.Photoradiation therapy provides a valuable approach for the selective therapy of diseases localized to the skin and mucous membranes. The topical delivery of photo-reactive drugs provides a means of further enhancing this selectivity by decreasing the undesired prolonged cutaneous phototoxicity associated with the systemic use of such agents. In this study vehicles were selected for effective topical delivery of hematoporphyrin derivative (HPD). Irradiation with either red light (600 nm) or long wave ultraviolet light (UVA) (360 nm) produced localized cutaneous phototoxicity and selective inhibition of epidermal cell proliferation in guinea pigs. Topical delivery produced a higher HPD concentration in dysplastic mouse epidermis versus surrounding normal epidermis. Preliminary clinical studies have demonstrated a partial clinical response in vaginal intraepithelial neoplasia. Studies are in progress to evaluate topical HPD in the treatment of intraepithelial neoplasia of the female genital tract, and hyper...

Topical hematoporphyrin derivative (HPD) photodynamic therapy for psoriasis

Topical 1% HPD in a vehicle containing 1-dodecylazacycloheptan-2-one (Azone) was tested in a double-blind clinical study in 16 patients with plaque psoriasis. HPD or the Azone vehicle was applied twice daily for 8 weeks. Treatment sites were irradiated twice weekly with long-wave ultraviolet light (UVA), with dose escalations of 1-2 Joules/cm2, to a maximum dosage of 20 Joules/cm2. Lesions were scored weekly for erythema, scale, and elevation. There was a 25% overall improvement in lesions treated with HPD and UVA compared to HPD-treated lesions without UVA irradiation. A similar degree of improvement was obtained in lesions treated with vehicle alone and UVA irradiated. The use of occlusion in an attempt to enhance HPD penetration did not effectively increase therapeutic response. Lack of response is attributed to ineffective penetration of HPD in the thick psoriatic plaque.Topical 1% HPD in a vehicle containing 1-dodecylazacycloheptan-2-one (Azone) was tested in a double-blind clinical study in 16 patients with plaque psoriasis. HPD or the Azone vehicle was applied twice daily for 8 weeks. Treatment sites were irradiated twice weekly with long-wave ultraviolet light (UVA), with dose escalations of 1-2 Joules/cm2, to a maximum dosage of 20 Joules/cm2. Lesions were scored weekly for erythema, scale, and elevation. There was a 25% overall improvement in lesions treated with HPD and UVA compared to HPD-treated lesions without UVA irradiation. A similar degree of improvement was obtained in lesions treated with vehicle alone and UVA irradiated. The use of occlusion in an attempt to enhance HPD penetration did not effectively increase therapeutic response. Lack of response is attributed to ineffective penetration of HPD in the thick psoriatic plaque.