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Home , Aminopterin, Dihydrofolate reductase, Irinotecan, Topotecan

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Abnormal banding regions (ABRs), 98 9-Aminocamptothecin (9-AC), 29, 37 9-AC (9-aminocamptothecin), 29, 37 , 3 Acantholytic carcinoma, 141 , 125 Ac1arubicin, 214 Amiodarone, 52 Acquired immunodeficiency syndrome Anabolism, fluoropyrimidine, 73-74, (AIDS/HIV), 137, 139, 145 84-86 Actinic exposure Androgen, 164, 167, 174 basal cell carcinoma and, 145 Angiogenesis, kinase C Merkel cell carcinoma and, 152 regulation of, 8-9 squamous cell carcinoma and, Anthracyc1ines 137-138 protein kinase C inhibitors and, 11 Actinic keratosis, 138, 141 taxoid compounds and, 185, 186, 193, Actinomycin D resistance, 97 198-199,203 Acute , 125 Antiandrogens, 170 Acute lymphoblastic leukemia, 17 therapy, 115-127 Acute lymphocytic leukemia (ALL), 56 Antilymphocyte globulin, 217 Acute myelogenous leukemia (AML), Aphidicolin, 98 57,61 APUD (amine-percursor, uptake, and Acute myeloid leukemia, 59 decarbolytion) system, 152, 156 Acute nonlymphoblastic leukemia Ara-C, 17, 18 (ANLL), 49-50 Arsenic, 138, 145 Adenoic basal cell carcinoma (BCC), Aspirin, 3 147 Autologous bone marrow deaminase (ADA), 100-101 transplantation, 185,209,210,213, Adenovirus 2,166 217,219 Adriamycin, see AIDS, see Acquired immunodeficiency syndrome Balandol, 15 AJCC (American Joint Commission on Basal cell carcinoma (BCC) , 137, 138, Cancer) staging system, 142, 149 143,144, 145-151 ~-Alanine, 76, 80-81 adenoic, 147 D-Alanine, 125 keratotic, 147 Albinism, 138, 145 pathology of, 145-147 Alkylating agents, 139,209 presentation of, 145 American Joint Commission on Cancer primary control of, 147-151 (AJCC) staging system, 142, 149 risk factors for, 145 Amine-percursor, uptake, and solid,147 decarbolytion (APUD) system, Bazex syndrome, 145 152,156 BCC, see Basal cell carcinoma

227 B-celllymphoma, 8 B cells, 12 peripheral blood progenitor Benign prostatic hypertrophy, 164 autografting and, 209, 211-212, 5-Benzyloxybenzyluracil, 87 218,219 Bilirubin, 60 resistance to, 45 Bisindolmaleimides, 15 resistance, 45 Bladdercancer,37 Casein kinase II, 9 Catabolism, ftuoropyrimidine, 74-78, basal cell carcinoma and, 148, 150, 85-86 151 CD33 cells, 212 resistance to, 45 CD34 cells, 59, 212-213, 216, 217 squamous cell carcinoma and, CDDP, see Cis- 143-144 diamminedichloroplatinum(lI) Bone marrow transplantation, cDNA autologous, 185,209,210,213, dihydropyrimidine dehydrogenase, 217,219 77-78 Bowen's disease, 141, 142 protein kinase C, 10-11 CED-3 , 127 dihydropyrimidine dehydrogenase in, Cell adhesion molecules, protein kinase 83-84 C regulation of, 8-9 and, 163, Cervical carcinoma, 18, 33 178-179 CGP 41251,8,15 ftuoropyrimidines and, 71 CHzFH4 , see 5-10 gene amplification and, 102, 103 Methylenetetrahydrofolate leucovorin and 5-ftuorouracil for, 115 Chloramphenicol resistance, 96 5-10 methylenetetrahydrofolate and, Chlorpromazine, 19 121 Cholyl-CoA-bile acid N- multi drug resistance and, 50-51, acetyltransferase, 76 58-59,61 Chronic granulocytic leukemia, 125 peripheral blood progenitor Chronic leukemia, 105 autografting and, 209, 211, 216, Chronic lymphocytic leukemia (CLL) , 219 17 phorbol esters and, 9 multidrug resistance in, 61 protein kinase C inhibitors and, 9, 16 squamous cell carcinoma and, 139 serine hydroxymethyltransferase and, Chronic myelogenous leukemia (CML) , 124-125 17,216 tamoxifen and, 16 Chronotherapy, 84-86 taxoid compounds and, 185-203 Cis-diamminedichloroplatinum(lI) 5,6,7,8- and, 121 (CDDP) and, 37 basal cell carcinoma and, 151 Broders tumor classification, 139, 141 protein kinase C inhibitors and, 11- Bromovinyldeoxyuridine, 87 12 Bryostatin 1, 5, 8,16-19 , 20 breast cancer and, 9 basal cell carcinoma and, 148, 149, phase I study of, 18-19 150-151 bryostatin 1 and, 18 estramustine phosphate and, 176- CAD gene, 99-100,103 178,180 Calcium, 3, 5, 7,13 hydroxyurea and, 105 Calcium channel blockers, 55-56 and, 33 Calmodulin, 16 Merkel cell carcinoma and, 156, 157 Calphostin C, 19 peripheral blood progenitor , 31,107 autografting and, 211, 212, 214 Camptothecin analogues, 29-37 resistance to, 45, 105

228 safingoland,16 (dUMP), 99,115,121-122,123, squamous cell carcinoma and, 138, 124 143-144 Dermatofibrosacroma protuerans, 137 taxoid compounds and, 202 DES (diethylstilbestrol), 170, 173, 179 topotecan and, 36 N-Desmethyl-tamoxifen, 58 13 Cis-retinoic acid, 144 Dexniguldipine, 56 c-jun gene, 12 DHFR, see Dihydrofolate Clear cell squamous cell carcinoma DHPase (), 75, 76 (SCC),141 Diacylglycerol (DAG), 3-5, 7,10, c-myc gene, 103, 104, 106, 107 12-13,19 Colchicine, 97, 180 Diethylstilbestrol (DES), 170, 173, 179 Collagenase, 8 Differentiated squamous cell carcinoma Colon cancer (SCC),141 9-aminocamptothecin and, 37 , 3 estramustine phosphate and, 178 Dihydrofiuorouracil (FUH2), 75 5-fiuorouracil and, 84, 125, 126 (DHFR), 116, irinotecan and, 32 119,127 thymidylate synthetase and, 99, 115 Dihydrofolate reductase (DHFR) gene, I and, 30 100,103 topotecan and, 36, 37 hydroxyurea and, 103, 104 Copper resistance, 96 resistance and, 98-99 CPT-II, see Irinotecan protein kinase C inhibitors and, 11 Cutaneous lymphoma, 137 Dihydropyrimidinase (DHPase), 75, 76 Cutaneous neuroendocrine carcinoma, Dihydropyrimidine dehydrogenase 152-154 (DPD), 72-73, 75, 78-87 biochemical and molecular studies of, basal cell carcinoma and, 150 76-78 estramustine phosphate and, 176 deficiency of, 79-84 Merkel cell carcinoma and, 156-157 development of assay for, 78-79 peripheral blood progenitor genetic polymorphism of, 82-84 autografting and, 211-212, 213- Dmins, see Double minutes 214,215,218,219 DNA resistance to, 45 extrachromosomal, see and, 16 Extrachromosomal DNA Cyclosporin A hydroxyurea and, 105, 107 multidrug resistance reversed with, protein kinase C and, 12, 13 56-58,60,62 thymidine kinase and, 86 peripheral blood progenitor topoisomerase II and, 9 autografting and, 217 DNA-topoisomerase I complex, 29, 30, Cyproterone acetate, 173 31 Cytosar, 216 ,185-203 , 71 background on, 186-188 Cytosine arabinoside (), 45, as first-line , 190-193 214 phase I and II clinical trials of, 188-190 as second-line chemotherapy, 193- DAG, see Diacylglycerol 198 resistance, 61 Double minutes (dmins), 97,102 cyclosporin A and, 56-58 defined,101 gene amplification and, 97 hydroxyurea and, 103-104, 106 Death , 127 methotrexate resistance and, 98, 99 1-Deazauracil,87 Doxorubicin, 150-151, see also Dectinomycin, 157 Doxorubicin resistance 2' -Deoxyuridine-5' -monophosphate basal cell carcinoma and, 149 229 breast cancer and, 186, 187,201,202 estramustine phosphate and, 178, 180 camptothecin analogues compared topoisomerase II and, 9 with,30 resistance, 50, see also estramustine and, 165 Epirubicin Merkel cell carcinoma and, 156-157 calcium channel blockers and, 56 peripheral blood progenitor cyclosporin A and, 57 autografting and, 214 quinidine and, 58-59 as protein kinase C inhibitor, 15, 16, Episomes, 101 19 EPOCH (/prednisone/ safingol and, 16 /cyclophosphamide/ squamous cell carcinoma and, 143 doxorubicin),56 taxoid compounds and, 201, 202 Erythroplasia of Queyrat, 141 topoisomerase II and, 9 Estradiol, 165, 168, 178 Doxorubicin resistance, 20, 61, see also 17-~-Estradiol, 163, 166, 167, 169, 179 Doxorubicin Estradiol benzoate, 170 breast cancer and, 187 Estramustine, 163-180 calcium channel blockers and, 55 clinical pharmacology of, 167-169 cyclosporin A and, 57,60 clinical studies of, 170-179 gene amplification and, 97 experimental studies of, 169-170 liposomal carriers and, 47 mechanism of action, 163-166 multiple myeloma and, 50 of, 166-167 progesterone and, 58 Estramustine binding protein kinase C and, 10 (EMBPs), 164-165, 168, 170 taxoid compounds and, 187 Estramustine phosphate, 163-164, 165, DPD, see Dihydropyrimidine 170, 179-180 dehydrogenase clinical pharmacology of, 167 -169 Drug resistance, 95 -108, see also for malignancies other than prostate Multidrug resistance cancer, 178-179 to estramustine, 165-166 metabolism of, 166-167 extrachromosomal DNA and, see with other agents for prostate cancer, Extrachromosomal DNA 176-178 gene amplification and, see Gene as single, primary therapy in prostate amplification cancer, 170-174 hydroxyurea and, see Hydroxyurea as single agent in hormone-refractory protein kinase C inhibitors and, prostate cancer, 174-176, 179 10-12 Estrogen, 163, 166, 169, 170 to taxoid compounds, 187-188 Estrogen receptors dUMP, see 2' -Deoxyuridine-5'• estramustine and, 163, 164, 165, monophosphate 178-179 protein kinase C inhibitors and, 9 Estromustine, 167, 168, 169-170, 178 Estrone, 168, 179 Edatrexate, 120 5-Ethynyluracil (5-EU), 87 EGF (epidermal growth factor), 4, 5 Etoposide EGR1 gene, 12 cyclosporin A and, 57 EMBPs (estramustine binding estramustine and, 178, 180 proteins), 164-165, 168, 170 extrachromosomal DNA elimination Endothelin, 5 and,107 Epidermal growth factor (EGF) , 4, 5 irinotecan and, 33 Epidermal keratinocytes, 138 Merkel cell carcinoma and, 156, 157 Epidermodyslasia verruciformis, 139 peripheral blood progenitor Epidoxorubicin, 186 autografting and, 209, 211, 212, Epirubicin, see also Epirubicin 214 resistance resistance to, 57, 61 230 topoisomerase II and, 9 irinotecan and, 33 topotecan and, 36 leucovorin and, 115 5-EU (5-ethynyluracil), 87 metabolism of, 72-73 Ewing's sarcoma, 152 MTHF and, 120 Extrachromosomal DNA, 96, 99 peripheral blood progenitor hydroxyurea elimination of, 103-108 autografting and, 217 muitidrug resistance and, 97-98 resistance to, 45 in tumor cell lines and primary serine hydroxymethyltransferase and, tumors, 101-103 124-126 squamous cell carcinoma and, 143-144 2- Fluoro-~-ureidopropionate (FUPA), FBAL (2-fluoro-~-alanine), 75 75-76 5-Fluorouridine (FUrd), 73 FdUMP, see 5-Fluorodeoxyuridylate Flutamide, 173, 174, 179 FdUrd, see Fluorodeoxyuridine FMR-1 gene, 127 FH4, see 5,6,7,8-Tetrahydrofolic acid Follicular lymphoma, 216 Fibroblast growth factor (FGF) , 4, 9 Folypolyglutamyl synthetase (FPGS), Filgrastim, 214, 215, 216 118 2-Fluoro-~-alanine (FBAL), 75-76 fos gene, 12 5-Fluoro-2'-deoxymonophosphate 5-FU, see 5- (FdUMP), see 5- FUH2 (dihydrofluorouracil), 75 Fluorodeoxyuridylate FUPA (2-fluoro-~-ureidopropionate), Fluorodeoxyuridine (FdUrd), 71, 85- 75 86,99,115,123 FUrd (5-fluorouridine), 73 anabolism of, 73-74 Fusic acid, 96 chronotherapy with, 84 dihydropyrimidine dehydrogenase inhibitors and, 86-87 Gastric cancer, 71 metabolism of, 72 9-aminocamptothecin and, 37 5-Fluorodeoxyuridylate (FdUMP), 99, estramustine phosphate and, 178 115-116,119,127,seealso irinotecan and, 33 Thymidylate synthetase-5- protein kinase C inhibitors and, 6 fluoroodeoxyuridylate ligand• topotecan and, 36 binding assay G-CSF, see Granulocyte colony Fluoropyrimidines, 71-87, see also stimulating factor specific types Gelatinase~, 8 anabolism of, 73-74, 85-86 Gene amplification, 95-96, 97-103, catabolism of, 74-78, 85-86 108 chronotherapy with, 84-86 hydroxyurea and, 103-105, 106-107 irinotecan and, 32 methotrexate resistance and, 97, metabolism of, 71-78, 85-86 98-99 one-carbon cycling and, multi drug resistance and, 97-98 115-127 P ALA resistance and, 99-100, 104 resistance to, 99 thymidylate synthetase and, 99 5-Fluorouracil (5-FU), 71, 99,126-127 Germ cell tumors, 209 anabolism of, 73-74 GF 109203X, 15 basal cell carcinoma and, 148, 150 Gliomas catabolism of, 74-76, 77 estramustine and, 165, 178 chronotherapy with, 84-85 hydroxyurea and, 104 in dihydropyrimidine dehydrogenase topotecan and, 36 assay, 78-79 Glycine, 123, 125, 126 dihydropyrimidine dehydrogenase GM-CSF, see Granulocyte-macrophage deficiency and, 79-84 colony stimulating factor

231 Granulocyte colony stimulating factor Interferon a-2a, 144 (G-CSF) Interferon a-2b, 149 bryostatin 1 and, 18 Interferon a-2c, 149 irinotecan and, 33 Interferon y, 149 peripheral blood progenitor Interleukin-1 (IL-1), 127,215,217 autografting and, 210-211,213, Interleukin-1 ~converting 214,215,217,218 (ICE),127 taxoid compounds and, 188, 192, 193 Interleukin-2 (IL-2), 13, 19 topotecan and, 35, 36, 37 Interleukin-2 (IL-2) receptor, 13, 17 Granulocyte-macrophage colony Interleukin-3 (IL-3) stimulating factor (GM-CSF) estramustine and, 166 bryostatin 1 and, 18 peripheral blood progenitor peripheral blood progenitor autografting and, 215, 217 autografting and, 210-212, 214, protein kinase C inhibitors and, 18 215,217 Interleukin-6 (IL-6), 18, 19 Growth factors, 210-212, 213-215, see Intracellular signalling, protein kinase also specific types Cin,3-5 Invasion, protein kinase C regulation of,8-9 H7,14 lonomycin, 18 H8,14 Iontophoresis, 148 HBx, 7 IP3 (-1,4,5-triphosphate), 3-4, Head and neck cancer, 35 12-13 Hepatocellular carcinoma, 61 Irinotecan,29,30,31-33,34 HER-2/neu gene, 103 Isoquinolinesulphonamides, 14 High-dose chemotherapy, 209-220 HIV, see Acquired immunodeficiency syndrome K-252a, 15 Hodgkin's disease, 217 Kaposi's sarcoma, 137, 139, 148 Homogeneously staining regions Keratotic basal cell carcinoma (BCC) , (HSRs), 98,101,102,104 147 Hormones, multidrug resistance reversed with, 58 HTLV-3 (human T lymphocyte virus- Leucovorin (LV), 115-116, 126-127 3), 145 antifolate effects related to, 118-120 Hydrocarbons, 138 serine hydroxymethyItransferase and, Hydroxyurea 124 extrachromosomal DNA elimnation structure of, 116-117 by, 103-108 Leukemia as in vivo tumor model, 107-108 acute, 125 methotrexate resistance and, 98, 104 acute lymphoblastic, 17 acute lymphocytic, 56 acute myelogenous, 57, 61 ICE (interleukin-1~ converting acute myeloid, 59 enzyme), 127 acute nonlymphoblastic, 49-50 , 216 chronic, 105 , 157,212,214 chronic granulocytic, 125 IGF-1 (insulin-like growth factor-I), 4 chronic lymphocytic, see Chronic IL, see Interleukin lymphocytic leukemia Immunosuppression, 139 chronic myelogenous, 17, 216 , 14-15 estramustine and, 165 Inositol-1,4,5-triphosphate (IP3), 3-4, gene amplification and, 104 12-13 hydroxyurea and, 105 Insulin-like growth factor-1 (IGF1), 4 lymphoblastic, 122

232 lymphocytic, 16 assessment of expression, 59 methotrexate resistance and, 98, 99 consequences of normal tissue multidrug resistance and, 49-50, 56, inhibition of, 60 57,59,61 estramustine and, 166 peripheral blood progenitor expression in human tumors, 48-51 autografting and, 216 expression in normal tissue, 51 promyelocytic, 104 need for measurement of expression protein kinase C inhibitors and, 16, in tumors, 62 17 prognostic significance of, 59-60 serine hydroxymethyltransferase and, protein kinase C inhibitors and, 10 125,126 Medroxyprogesterone acetate, 173 topotecan and, 35 Melanoma, 137, 138, 139, 155 LHRH agonists, 170, 173, 179 estramustine phosphate and, 178 Lipid ether analogues, 19 Merkel cell carcinoma differentiated Liposomal carriers, 47 from, 152 , dihydropyrimidine protein kinase C inhibitors and, 17 dehydrogenasein,84 , 50, 59, 97,157 Lometrexate, 120 Mercuric ions, 96 Lometrexol,119-120 Merkel cell carcinoma (MCC) , 137, , see also Non-small cell 151-157 lung cancer; Small cell lung cancer Metabolism 9-aminocamptothecin and, 37 of estramustine, 166-167 gene amplification and, 103 of fiuoropyrimidines, 71-78, 85-86 protein kinase C and, 12 Methionine, 127 topotecan and, 37 Methotrexate, see also Methotrexate LV, see Leucovorin resistance Lymphoblastic leukemia, 122 basal cell carcinoma and, 150 Lymphocytic leukemia, 16 interleukin-1 and, 127 Lymphocytic lymphoma, 139 leucovorin and, 118, 119-120 Lymphoma serine hydroxymethyltransferase and, B-cell,8 125 cutaneous, 137 squamous cell carcinoma and, follicular, 216 143-144 Hodgkin's, 217 Methotrexate resistance, 45, see also irinotecan and, 33 Methotrexate lymphocytic, 139 gene amplification and, 97, 98-99 Merkel cell carcinoma differentiated hydroxyurea and, 98,104 from, 152 8-Methoxypsoralin, 138 multi drug resistance and, 50, 55, 56, 5-10 Methylenetetrahydrofolate 61 (CH2FH4), 115-116, 127 non-Hodgkin's, 50 as folypolyglutamyl synthetase peripheral blood progenitor substrate, 118 autografting and, 209, 216 ligand-binding assay of, 121-124 protein kinase C inhibitors and, 8, 17 serine hydroxymethyltransferase and, serine hydroxymethyltransferase and, 122-125 125 structure of, 116-117 Lysophingolipidis, 15-16 Methylprednisolone, 198 Mezerein, 8 Micronuclei, 106 mAMSA,9 proteins (MAPs), 165, 166 MAPs (microtubule proteins), 165, 166 , 186 MCC, see Merkel cell carcinoma , 174-176, 185 mdm-2 gene, 103 , 9,186 mdrl gene, see also P-glycoprotein Moh's technique, 147, 148

233 MTHF, 115, 120, 123, 127 Ovarian carcinoma Mucoepidermoid carcinoma, 141 estramustine and, 165 Multidrug resistance (MDR), 45-63, fiuoropyrimidines and, 71 see also Drug resistance; mdrl gene amplification and, 102, 103 gene; P-glycoprotein irinotecan and, 33 considerations in modulation trial methotrexate resistance and, 98, 99 design, 61-62 multidrug resistance and, 61 current controversies in clinical peripheral blood progenitor research, 59-61 autografting and, 218 to estramustine, 165-166 thymidylate synthetase and, 99 gene amplification and, 97-98 topotecan and, 35 protein kinase e inhibitors and, 6, 10-11,14,20 strategies to overcome, 45-48 ,185-203 to taxoid compounds, 187-188 background on, 186-188 Multiple myeloma, 50 calcium channel blockers and, 56 myc gene, 127 camptothecin analogues compared Mycosis fungoids, 137 with, 30 Myeloma cyclosporin A and, 57 multi drug resistance and, 55, 57, 59, estramustine and, 165 61 as first-line chemotherapy, 190-193 multiple, 50 Merkel cell carcinoma and, 157 peripheral blood progenitor microtubule proteins and, 165 autografting and, 216 peripheral blood progenitor autografting and, 214, 219 phase I and II clinical trials of, NADP,118 188-190 NADPH, 75, 77, 78, 79,118 protein kinase e inhibitors and, 20 Navelbine, 186 resistance to, 56, 57, 61 as second-line chemotherapy, 193- gene amplification and, 103 198 hydroxyurea and, 104 small cell lung cancer and, 157 multidrug resistance and, 49, 61 topotecan and, 36-37 peripheral blood progenitor P ALA resistance, 99-100, 104 auto grafting and, 216 , 61, 170, 178 protein kinase e inhibitors and, 5 PBP autografting, see Peripheral blood Nevoid basal cell carcinoma (BeC) progenitor autografting syndrome, 145 PDGF (platelet-derived growth factor), , 157, see also Nor- 4,5 nitrogen mustard Penicillinase resistance, 96 N-myc gene, 103, 104 Peripheral blood mononuclear cells Non-Hodgkins lymphoma, 50 (PBMs), dihydropyrimidine Non-small cell lung cancer dehydrogenase in, 80, 83-84,85 estramustine and, 164 Peripheral blood progenitor (PBP) irinotecan and, 33 autografting, 185,209-220 topotecan and, 36, 37 factors predicting collections of, Nor-nitrogen mustard, 163, 165, 166, 212-213 167,169,178,179 growth factors and, 210-212, 213- NSe 628503, see Docetaxel 215 NSe 125923, see Paclitaxel stem-cell characteristics of, 216-217 tumor contamination of, 215-216 p53 gene, 138 One-carbon folate cycling, 115 -127 P-glycoprotein, 45-63, see also P• Orchiectomy, 170, 173-174, 179 glycoprotein inhibitors

234 camptothecin analogues and, 30 Protein kinase C inhibitors consequences of normal tissue in intracellular signalling, 3-5 inhibition of, 60 regulatory functions of isoforms, 5-6 estramustine and, 165 substrate of, 7 expression in human tumors, 48-51 Protein kinase Ca (PKCa), 5, 6, 7, 9, expression in normal tissue, 51 10,11 gene amplification and, 97 Protein kinase q (PKq), 9 outcome based on effective inhibition Protein kinase C~ (PKC~I), 5,11,15 of, 61 Protein kinase C~II (PKC~II), 5, 7, 15 protein kinase C inhibitors and, Protein kinase C8 (PKC8), 7 10-11,14,16 Protein kinase 0; (PKO;), 5,12 selective inhibition without effect on Protein kinase CTj (PKCTj), 5, 7 normal tissue, 60 Protein kinase Cy (PKCy), 5, 7, 9,11 taxoid compounds and, 188 Protein kinase Ct (PKCt), 5 P-glycoprotein inhibitors, see also P• Protein kinase CA (PKCA), 5 glycoprotein Protein kinase Ct (PKCt), 5 clinical trials of, 51-59 Protein kinase Cz (PKCz), 5 concurrent administration with Protein kinase C (PKC) inhibitors, 3- chemotherapy, 48 20, see also Protein kinase C Phorbol esters in catalytic domain, 14-15 breast cancer and, 9 in regulatory domain, 15 -18 methotrexate resistance and, 98 PSC 833,57-58,60,62 protein kinase C inhibitors and, 8-9, Psoriasis, 138 13,16-17 Puromycin resistance, 97 Phosopholipid phosphatidylinositol-4,5- biphosphate (PIP2), 4, 5 Phosphatidyl inositoI4,5-biphosphate, Quinidine, 58-59 12 Phosphatidyl inositol-3-kinase, 5 Phosphatidyl inositol-3,4,5- Radiation triphosphate, 5 protein kinase C and, 12 Phospholipase C~, 4 ultraviolet, 98, 138 Phospholipase Cy, 4, 12-13 Radiation therapy Phospholipase D, 5 basal cell carcinoma and, 147, 148, PIP2 (phosopholipid 149 phosphatidylinositol-4,5- Merkel cell carcinoma and, 155 biphosphate), 4, 5 squamous cell carcinoma and, 139, PKC, see Protein kinase C 141 , 96 raf gene, 12 Platelet-derived growth factor (PDGF), ras gene, 5, 12 4,5 5-a-reductase, 166 Polymyxin B, 19 Renal cell carcinoma, 10,36,59,61 Prednisone resistance, 50, 59 Rhodamine 123, 49, 60 Progesterone, 58,166 , 105 Prolonged infusion chemotherapy, 47 RO 31-7549,15 Pro myelocytic leukemia, 104 RO 31-8220,15 Prostate cancer Rombo syndrome, 145 estramustine/estramustine phosphate RP 56976, see Docetaxel and, 163, 164, 165, 166,167, 169-178,179,180 topotecan and, 36 Safingol, 16 Proteases, protein kinase C regulation Sapintoxin A, 5 of, 8-9 SCC, see Squamous cell carcinoma Protein kinase C (PKC), 3-13, see also SCF (stem-cell factor), 215, 217

235 Scrotal cancer, 138 Stromelysin 1, 8 L-Serine, 123, 124-125 resistance, 96 Serine hydroxymethyltransferase Sun exposure (SHMT), 116-117, 118, 127 basal cell carcinoma and, 145 in vitro one-carbon flux through, squamous cell carcinoma and, 138 124-126 , 15 in vivo one-carbon flux through, Sweat gland carcinomas, 137 122-124 Sheep dip workers, 138 SHMT, see Serine Tamoxifen, 16, 58, 62 hydroxymethyltransferase Taxoid compounds, 185-203, see also Signet ring squamous cell carcinoma specific types (SCC),141 background on, 186-188 Skin carcinoma, 71, 137-157, see also as first-line chemotherapy, 190-193 specific types phase I and II clinical trials of, Small cell lung cancer 188-190 irinotecan and, 32-33 as second-line chemotherapy, 193- Merkel cell carcinoma and, 152, 156, 198 157 Taxol, see Paclitaxel peripheral blood progenitor Taxotere, see Docetaxel auto grafting and, 216 Tcells, 12, 13, 17-18 topotecan and, 35 Testosterone, 169, 170, 174, 179 SN-38, 30, 31-32, 33 Tetracycline resistance, 96 Soft tissue sarcomas, 49, 61 12-0-Tetradecanoylphorbol-13-acetate Solid basal cell carcinoma (BCC), 147 (TPA), 5, 7-8,10,11 Solid tumors, see also Tumors 5,6,7 ,8-Tetrahydrofolic acid (FH4)' multi drug resistance and, 56, 61 116,127 protein kinase C inhibitors and, 16 as folypolyglutamyl synthetase Soot warts, 138 substrate, 118 SPC-100221,16 ligand-binding assay of, 121-124 SPC-100270, see Safingol serine hydroxymethyltransferase and, Sphingomyelinase, 5 122-125 Sphingosine, 19 TGF-~1 (transforming growth Spindle cell squamous cell carcinoma factor~I), 8, 9 (SCC),141 , 218, 219 Squamous cell carcinoma (SCC), Thymidine kinase (TK), 85-86 137-145 Thymidylate synthetase (TS) acantholytic,141 drug resistance and, 99 clear cell, 141 5-fluorodeoxyuridylate inhibition of, differentiated, 141 115-116, 119, 127 mucoepidermoid,141 leucovorin and, 118, 119, 126-127 pathology of, 141 Thymidylate synthetase-5- presentation of, 137 fluorodeoxyuridylate (TS-FdUMP) risk factors for, 137-138 ligand-binding assay, 121-124 signet ring, 141 , 71, 77 spindle cell, 141 TNF-a (tumor necrosis factor-a), 12, staging of, 142 13,17,19 treatment of, 143-145 TNM staging system, 142 verrucous, 141 Topoisomerase I, 29-30 src gene, 12 Topoisomerase II, 9-10, 187 Staurosporine, 11, 14-15 Topoisomerase II inhibitors, 20, 61 Stem-cell factor (SCF), 215, 217 Topotecan, 29, 30, 34-37 Stem-cells, 216-217 TPA, se 12-0-Tetradecanoylphorbol- Streptomycin resistance, 96 13-acetate

236 Transforming growth factorp1 basal cell carcinoma and, 148, 151 (TGFP1), 8, 9 breast cancer and, 185 Triftuorperazine, 19 estramustine and, 165, 166, 178, 179 Triphenylethylenes, 16 protein kinase C inhibitors and, 20 TS, see Thymidylate synthetase safingol and, 16 Tubulin, 165, 187 resistance, see also Tumor necrosis factor-a (TNF-a), 12, Vinblastine 13,17,19 cyciosporin A and, 57 Tumors, see also Solid tumors gene amplification and, 97 extrachromosomal DNA in, 101-103 hydroxyurea and, 105 hydroxyurea as in vivo model of, Vinca alkaloids, 11 107-108 Vincristine, see also Vincristine mdr1 in, 48-51 resistance mdr1 gene expression measurement basal cell carcinoma and, 150 needed,62 camptothecin analogues compared peripheral blood progenitor with,30 autografting contamination and, Merkel cell carcinoma and, 156 215-216 Vincristine resistance, 61, see also kinases, 4, 5 Vincristine cyciosporin A and, 57 gene amplification and, 97 UCN-01,15 multiple myeloma and, 50 Ultraviolet radiation, 98, 138 , 33, 186 , 71, 77 VM26,9 VP-16, see Etoposide

V AD (vincristine/doxorubin/ decadron),55,57 Verapamil,l1 Waldenstrom's macroglobulinaemia, 17 estramustine and, 166 multidrug resistance reversed by, 51, 55-56,62 Xeroderma pigmentosum, 138, 145 safingol and, 16 X-rays, 145 Verrucous carcinoma, 141 Vinblastine, 179, see also Vinblastine resistance Zoladex, 173

237